Basic Neurologic Life Support

BASIC NEUROLOGIC LIFE SUPPORT
James J. Corbett, MD
McCarty Professor and Chair Department of Neurology University of Mississippi Medical Center Jackson, Mississippi
2004 BC Decker Inc Hamilton London
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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benets anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as, and should not be employed as, a substitute for individual diagnosis and treatment.
This book is dedicated to patients whose lives, or livelihood, are threatened by treatable neurologic problems, and to physicians who recognize these illnesses and take action.
CONTENTS
Foreword Preface Contributors 1. Headache as an Emergency James J. Corbett, MD 2. Giant Cell Arteritis James J. Corbett, MD 3. Approach to the Comatose Patient Michael DeGeorgia, MD and John Andrefsky, MD 4. Approach to Status Epilepticus Michael DeGeorgia, MD and John Andrefsky, MD 5. Spinal Cord Emergency Conditions Robert M. Herndon, MD 6. Respiratory Failure Due to Neuromuscular Disease Robert M. Pascuzzi, MD 7. Ischemic Stroke Patrick S. Reynolds, MD and Terrence W. Bruner, MD, MBA
ix xi xiii 1 20 32
62
76
89 133
Conten t s
8. Neuroleptic Malignant Syndrome Robert L. Rodnitzky, MD 9. Encephalitis Karen L. Roos, MD 10. Bacterial Meningitis Karen L. Roos, MD 11. Cerebellar Hemorrhage and Infarction John B. Selhorst, MD 12. Wernickes Encephalopathy John B. Selhorst, MD 13. Tips on the Neurologic Evaluation James D. Fleck, MD and Jos Biller, MD Index
167 182 190 210 220 236 258
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FO R E W O R D
eurology has long been considered a eld rich in phenomenology and bereft of treatment, but dramatic recent advances have changed all of that. Nearly every category of neurologic disease is yielding to the insights of neuroscience translated into new approaches to the diagnosis and management of human illness. Among the most important areas is the eld of neurologic emergency medicine where modern knowledge may spell the difference between horrible disability and remarkable recovery. It is critical for patients well-being that physicians are up to date and facile with the best evidence-based techniques for the rapid, accurate diagnosis and treatment of critical illnesses affecting the nervous system. This new information is important not only for the students who are the physicians of tomorrow, but also for the currently practicing neurologists, internists, family doctors, and emergency physicians. Of all the areas of emergency and critical care medicine, neurology has been the most neglected in the past, making the continuing education of practicing physicians even more vital. Under the auspices of the Association of University Professors of Neurology, which represents the leadership of American neurology, James J. Corbett has assembled the handbook of Basic Neurologic Life Support analogous to that which is already available for cardiac catastrophes. Using the talents of some of the leading lights in neurology, the book systematically covers the most important and frequently encountered neurologic emergencies. The books
vii
Foreword
12 subject chapters include headache emergencies, giant cell arteritis, coma, status epilepticus, myelopathies, neuromuscular emergencies, ischemic stroke, neuroleptic malignant syndrome, encephalitis, bacterial meningitis, cerebellar hemorrhage and infarction, and Wernickes encephalopathy. The book concludes with a chapter on tips on the neurologic examination in the emergency setting. The content of this book should be required knowledge for all medical students and for any physician or surgeon who encounters patients, because one of the most important aspects of an emergency is to recognize that it exists. For those who actually manage patients with neurologic emergencies, such as neurologists, emergency physicians, and neurosurgeons, the authoritative nature of the chapters written by some of the foremost experts in each eld will be a welcome addition to their personal library. Dr. Corbett has done us all an enormous service by spearheading this effort to put neurologic emergencies in the prominent position they deserve. Martin A. Samuels, MD, FAAN, MACP President, Association of University Professors of Neurology, 20042006 Chairman, Department of Neurology Brigham and Womens Hospital Professor of Neurology, Harvard Medical School, Boston, Massachusetts
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P R E FA C E
edical emergencies are conditions that, if recognized, can be treated to restore health, or at the very least, prevent progression to life-threatening or livlielihood-threatening results. Key information about acutely evolving medical emergencies is scattered throughout years of training and is never concentrated in one place. In the past few years, cardiopulmonary arrest has taken the center spotlight as the quintessential emergency that everyone should know about. Cardiac resuscitation is taught everywhere. Basic cardiac life support and advanced cardiac life support courses are available to everyone, and a cottage industry that provides this training has developed. The neurologic emergencies have not been similarly highlighted in medical education, yet they are frequently encountered, misdiagnosed, and commonly treated incorrectly even if the diagnosis is made. This book is an easy-to-use guide to all the major neurological emergencies, providing key information about, and examples of, their typical presentations, where useful their pathogenisis, and, nally, characteristic patient histories with currently recognized and approved treatment of the condition. A brief bibliography accompanies each condition. Neurologic disease has long been considered arcane, difcult to diagnose, and, above all, untreatable. Every one of the conditions we highlight here is neurologic and, if recognized, eminently treatable. We hope that this book, produced with the Association of University Professors of Neurology, will be the beginning of a
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Prefac e
move to familiarize all physicians with basic neurologic life support in the same way that they have become familiar with cardiorespiratory failure. James J. Corbett, MD 2004
CONTRIBUTORS
John Andrefsky, MD Department of Neurology Cleveland Clinic Foundation Cleveland, Ohio Jos Biller, MD Department of Neurology Loyola University Maywood, Illinois Terrence W. Bruner, MD, MBA Department of Plastic Surgery Baylor College of Medicine Houston,Texas James J. Corbett, MD Department of Neurology University of Mississippi Medical Center Jackson, Mississippi Michael DeGeorgia, MD Department of Neurology Cleveland Clinic Foundation Cleveland, Ohio James D. Fleck, MD Department of Neurology Indiana University School of Medicine Indianapolis, Indiana
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Con t r i b u t or s
Robert M. Herndon, MD Department of Neurology University of Mississippi Medical Center Jackson, Mississippi Robert M. Pascuzzi, MD Department of Neurology Indiana University School of Medicine Indianapolis, Indiana Patrick S. Reynolds, MD Department of Neurology Wake Forest University School of Medicine Winston-Salem, North Carolina Robert L. Rodnitzky, MD Department of Neurology University of Iowa Iowa City, Iowa Karen L. Roos, MD Department of Neurology Indiana University School of Medicine Indianapolis, Indiana John B. Selhorst, MD Department of Neurology Saint Louis University St. Louis, Missouri
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CHAPTER 1
HEADACHE AS AN EMER GENCY

eadaches result in an enormous amount of lost productivity, but they are benign by and large.The diagnosis is made almost entirely by the patients individual headache attack history, personal lifelong headache history, and family headache history.To a much lesser degree, headaches can be characterized by physical examination, although physical ndings usually are not very specic and include facial erythema or pallor, intermittent ptosis, and Horners syndrome in cluster headache. The tendency of the patient to rub or squeeze his or her head and photophobia is seen in migraine and other common headaches. Headache histories that should cause concern and constitute potential emergencies fall into six distinct categories: New headaches in an individual who has never been headache prone in the past. Although these may be totally benign in the young adult who is beginning to have migraines, new headaches in older patients deserve special scrutiny. In this circumstance, a computed tomographic (CT) scan with and without contrast may be warranted and, in older patients, sedimentation rate and C-reactive protein.1 New headaches or a change of headache characteristics in a headache-prone individual. I have had headaches, but this is a different kind of headache. Patients who are familiar with headaches know how their usual
1
Basic Neurologic Life Supp or t
headache feels. If headaches that a patient usually has change in character, location, duration, or severity, they deserve special attention. In this instance, CT or magnetic resonance imaging (MRI) may be used. Pay special attention to the sphenoid sinus for evidence of sinusitis and look for enlarged ventricles, a subdural hematoma, or intracerebral mass lesion. Headache occurring with loss of consciousness or in the presence of fever or other systemic symptoms. This may represent central nervous system infection, inammation, or arteritis, or the headache may be the residue of unrecognized complex partial seizures. Electroencephalography may be of help in this setting. Pulsatile tinnitus or roaring in the ears, visual blurring, horizontal diplopia, and transient visual obscurations suggest elevated cerebrospinal uid (CSF) pressure. CT or MRI and possible lumbar puncture (LP) are called for in the evaluation. Headache arising de novo in a patient over the age of 50 years. This suggests possible giant cell arteritis and requires an immediate erythrocyte sedimentation rate and C-reactive protein and very likely will need a temporal artery biopsy.Abrupt onset of monocular visual loss with or without preceding spells of transient monocular visual loss should prompt careful examination of the patients optic fundus and pupils to look for a relative afferent pupil defect (Chapter 2,Giant Cell Arteritis). Abrupt onset of the worst headache of the patients life.This may herald a subarachnoid hemorrhage (Figure 1-1).2 A rst headache is less useful as an indicator of a neurologic emergency, particularly in young adults,
2
Headache as an Emergency
Figure 1-1 Blood in the anterior interhemispheric ssure (arrow), sylvian fissures (arrowheads), and suprasellar cistern in a patient with a ruptured anterior cerebral ar ter y aneur ysm.
because patients who develop migraine and other benign headaches have to start sometime, and an otherwise benign-sounding rst headache is unlikely to be a problem. Such patients need immediate referral to a neurosurgeon in a hospital setting. Do not delay referral beyond obtaining a CT without contrast to look for blood in the cerebrospinal uid (Figure 1-1).3,4 If in doubt, properly perform LP (see below). Long-standing (72 hours or more) headaches. These may signal increased CSF pressure, infection, or mass lesion. Chronic forms of meningitis such as tuberculosis or cryptococcal or coccidioidal meningitides may present only with chronic headache or headache and optic disk swelling5 but no stiff neck.These patients need to be studied with MRI with and without contrast. Neurologic examination of headache patients should emphasize palpation of temporal arteries and ophthalmoscopic examination, if necessary dilated with tropicamide (Mydriacyl) drops, to look for papilledema or a swollen ischemic optic nerve head. (Figures 1-2 to 1-6 at the end of this Chapter. These gures can be viewed in color on the CD-ROM.) Ocular motility examination should focus on ptosis and unilateral pupil constriction or dilation. Stiff neck (Kernigs and Brudzinskis signs), drift of an outstretched arm, asymmetry of reexes, evidence of an extensor plantar response, and Rombergs testing all help to identify key features of headaches that are true treatable emergencies. The examination should be recorded in its entirety, and specic written comments should be made about these ndings. Abbreviations of cranial nerves II
4
through XII (WNL) without specic mention of pupil, ocular motility, and fundus findings leave subsequent examiners wondering whether the examinations were ever really done. Headache occurring with subarachnoid hemorrhage is usually abrupt in onset and severe, and depending on the location of the aneurysm, there are frequently other complaints or physical ndings: Abrupt loss of consciousness or weakness of the legs and/or loss of bladder control suggest anterior cerebral or anterior communicating artery aneurysm. Third nerve palsy, either partial with or without pupil involvement, or complete with pupil involvement, may occur as a result of intra- or extracavernous aneurysms but usually suggests an internal carotid posterior communicator aneurysm. Neck, back, arm, and leg pain (any or all of these), with or without headache, if abrupt in onset, suggests bleeding of an aneurysm in the posterior fossa and down into the spinal canal.
NOTES AND TIPS ON THE SPECIFIC DETAILS OF DOING A LUMBAR PUNCTURE Positioning the Patient
The patient is placed in the lateral decubitus position. Knees and hips are exed into the abdomen. It is not necessary, and it is actually undesirable to ex the neck forward. Flexion of the lumbar spine opens L34 and L45
5
interspaces. Flexion of the neck does not further open the lumbar interspaces, which are already wide open. Cervical exion not only does not increase the width of the lumbar interspace openings, it also potentially compresses the jugular veins, thereby blocking cerebral venous drainage, increasing cerebral venous sinus pressure, and eventually elevating CSF pressure.
Preparing the Site
Mark the interspace into which you want to place the needle. Clean the skin with iodine and wipe the skin clean 4 gauze. Drape the areas above and below the with 4 lumbar puncture (LP) site. Inltrate the skin and subcutaneous tissue with 1% lidocaine at the level at which you wish to place the needle. Using a Quincke (spinal) needle, place the bevel to the left or right side of the body, not crossways. This way, the bers will be separated, not cut, and this presumably lessens the risk of post-LP headache.
Placing the Needle
Advance the 3.5-inch 22-gauge needle directly in and slightly upward using the upper surface of the lower of the two vertebrae that form the interspace as your landmark. With the stylet in place, you prevent the introduction of epidermal or dermal elements into the subarachnoid space. Once the needle is in a centimeter or so, you may either remove the stylet or advance the needle with the stylet in place as you wish.
6
Years ago, when reusable LP needles were used, they became dull.There was a perceptible pop when the needle passed through the dura; however, with the advent of the one-use sharp cutting needles of today, that pop may be imperceptible.
Preparation of the Patient to Measure LP Pressure
Once the needle is through the interspace and in the subarachnoid space and there is a ow of CSF, replace the stylet and have an assistant passively extend the patients legs and place the head in a neutral (neither exed nor extended) position. Encourage the patient to relax and to take one or two deep breaths. Encourage the patient to breathe regularly and be attentive to the patient who may be hyperventilating (or crying), holding his or her breath, or straining. Changes in PCO2 rapidly alter CSF pressure, as does any Valsalva maneuver. Measurement of CSF pressure in the lateral decubitus position is straightforward and can be accomplished with or without the attachment of a short tube to the petcock and manometer that is incorporated in the LP kit. Measurement of CSF pressure in the prone position, as performed by radiologists, provides the same pressure as found in the lateral decubitus position (Dan Jacobson, personal communication, 2003). LP can be done safely in the sitting position, but there is no reliable, accurate way to measure CSF pressure in the sitting position.Thus, if uid is needed for cytology and pressure is not an issue, the spinal puncture may be accomplished in the sitting position more easily than in the recumbent position.
7
Fluid collection should provide quantities sufcient to perform CSF glucose, protein, cell count,Venereal Disease Research Laboratories (VDRL) test, polymerase chain reaction (PCR) (rapid meningitis panel), a large aliquot for cytology (when necessary), or special stain for tuberculosis (TB). Do not take small amounts of CSF. Take as much as you need because CSF regenerates at a rate of 1 cc every 3 minutes or 20 cc/h. Post-LP headache is a fact of life and, even in the best of hands, occurs in one of three patients.5 If hydration and a couple of intravenous or intramuscular doses of 500 mg caffeine sodium benzoate do not stop the headache, a blood patch should be done. No special precautions regarding bed rest, reverse Trendelenburgs position, intravenous or oral uids, and other such mantras have ever been shown to reliably treat or prevent post-LP headaches. Do you need to have a CT scan before an LP? A CT scan is not required if the patient is awake, alert, and cooperative and has no focal neurologic ndings.A CT scan is required if there are focal lateralized signs or if the patient is febrile or unconscious. CT is required if meningitis is being considered, and this has been studied extensively.6 If you suspect bacterial meningitis, start intravenous corticosteroids and appropriate antibiotics; draw blood for complete blood cell count, prothrombin time, partial thromboplastin time, blood cultures, and international normalized ratio (INR); do a CT scan, and then do the LP. Organisms survive 4 to 6 hours after antibiotic therapy has been initiated (Table 1.1).
8
Table 1-1 Risk Factors for Uncal and Cerebellar Herniation at Time of Lumbar Puncture in Meningitis Immunosuppression Dilated or poorly reactive pupils Papilledema Oculomotor palsies Hemiparesis Recent focal seizures Rapid or major depression of consciousness Bradycardia Tonic seizures Irregular respirations Decerebrate or decorticate posturing
Adapted from Mellor DH.7
PATIENT WITH SUSPECTED SUBARACHNOID HEMORRHAGE
A patient who presents to the emergency department with a headache owing to a ruptured berry aneurysm has made the cut and is in the emergency department alive, for the time being. Rapid recognition of the cause of the headache depends on history taking, physical ndings, and
9
rapid performance of CT scan with and without contrast to look for evidence of subarachnoid blood. Blood in the subarachnoid space will appear immediately (Figure 1-1) and, depending on the quantity of blood, will disappear within 4 to 7 days. If no evidence of blood is found on CT scan and subarachnoid hemorrhage is still being considered as the most likely cause of the patients headache, then LP needs to be performed immediately. Table 1-2 lists contraindications to doing an LP. If you are convinced that the result of the LP was a bloody tap (Table 1-3), repeat LP should be done one spinal interspace higher.The bloody CSF should be spun down and the supernatant CSF uid examined for xanthochromia in good light, against a white background.8,9 The task of doing the LP and examining the uid is not trivial. If you are not going to do it yourself, you should be sure that the LP, done by an anesthesiologist or radiologist under radiographic guidance, includes opening pressure and that the CSF uid is collected and sent immediately for protein, glucose, and cell count, as well as a VDRL test. Fresh bleeding of a subarachnoid hemorrhage may, on occasion, cause the CSF glucose to be depressed (hypoglycorrhachia). Be sure also that CSF is sent for bacteriologic and fungal cultures and that a rapid PCR screen of the uid is done. Ruptured mycotic aneurysms may have more white cells than expected when there is bleeding owing to either a ruptured aneurysm or from a bloody tap. There are other causes of subarachnoid hemorrhage, including pituitary apoplexy, which may have abrupt onset of visual loss in one or both eyes and/or ocular motility disturbances owing to the effects on the cavernous sinuses,
10
Table 1-2 Contraindications to Lumbar Puncture Infection of overlying skin Known intracerebral mass lesion, especially brain abscess or mass lesion with shift Known spinal cord compression Relative contraindication to LP: generalized septicemia has been reported rarely as a cause of meningitis following LP. If LP is being done for suspected meningitis, it should not be withheld because of the concerns regarding septicemia. Bleeding disorder or use of anticoagulants: all patients who undergo LP should have CBC with platelet count, PT, and PTT and INR drawn. LP is safe if there are 40,000 or more platelets. After LP, anticoagulation should be delayed for 1 hour. Papilledema by itself with none of the other abovementioned factors is NOT a contraindication for LP.
CBC = complete blood cell count; INR = international normalized ratio; LP = lumbar puncture; PT = prothrombin time; PTT = partial thromboplastin time.
intracerebral and cerebellar hemorrhage, hemorrhage into metastasis, and arteriovenous malformations. All of these will be obvious on CT or MRI. If you have serious reasons to believe that the patient has ruptured a berry aneurysm, immediate consultation
11
Table 1-3 Differential Features of Subarachnoid Hemorrhage and Traumatic Puncture: The ThreeTube Test CSF Finding Pressure Appearance Subarachnoid Hemorrhage Increased or normal Equal blood in all tubes Traumatic Puncture Normal First or last tube is bloodier, others are clearer Clear, no pigment Gradual decrease from rst to last tube Proportional to RBC count
Supernatant uid color RBC count and hematocrit WBC count
Pigment in excess of protein level Variable in different tubes Proportional to RBC count in earliest stages; relatively increased later Absent
Clot formation
Occurs rarely Usually clear
Repeat puncture Findings similar at higher to those at interspace initial tap
CSF = cerebrospinal uid; RBC = red blood cell count; WBC = white blood cell count. Adapted from Fishman RA.8
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with a neurosurgeon is indicated. Remember, upward of half of all patients who have a ruptured berry aneurysm die of the subarachnoid hemorrhage before they ever reach the hospital. Have a low threshold of suspicion when considering the diagnosis. Anyone with an abrupt-onset, severe headache occurring like a thunderclap or during coitus may well have a benign condition, but they should be treated as if they have a subarachnoid hemorrhage until proven otherwise.10,11,12 Long-standing headache may occur, particularly with generalized malaise or systemic disease with lowered immunity. Chronic meningitis, most often fungal (cryptococcus or coccidioidomycosis), but, occasionally, lowgrade pathogens such as diphtheroids and low-virulence streptococcal species may be the culprit. Here again, CT scan and LP are indicated.
SWELLING OF THE OPTIC DISKS
The nding of swollen optic discs is an indication of relatively subacute to chronic increased CSF pressure. Swelling of the optic disks owing to increased spinal uid pressure is called papilledema. Disks may swell for other reasons, such as unilateral optic neuritis or ischemic optic neuropathy. Rarely are these bilateral, and visual loss is their primary symptom. Recognition of papilledema requires familiarity with normal optic disk appearance and how swelling of the nerve bers on the disk alters its conguration. Lars Frisn has devised a staging scheme for the recognition of papilledema (see Table 1-4 and Figures 1-2 to 1-6 at the end of this chapter.)13
13
If orid or even low-grade papilledema is detected in the emergency department on a background of recent (same day or 2 to 4 days later) head trauma, the disk swelling is never related to the recent head injury. Sudden onset of papilledema (within days) occurs in the setting of a massive increase in intracranial pressure and coma and is usually very hemorrhagic, with preretinal hemorrhages and nerve ber layer infarcts. Sustained high pressures seen in closed head injury rarely produce papilledema even after 5 to 7 days of continuously increased pressure.14 If disks are swollen as soon as the patient is seen shortly after the onset of headache or after injury, almost certainly they have been swollen for at least 2 or more weeks. The presence of hemorrhages and nerve ber layer infarcts (soft exudates) does not inuence the grading of papilledema because these ndings are all quite variable and nonessential. Nerve ber layer infarcts probably contribute to visual loss, but they are not used in grading papilledema severity.
14
Figures 1-2 through 1-6 can be viewed in color on the CD-ROM.

OD OS
Figure 1-2 Grade I papilledema: C-shaped swelling of both disks with preser ved cup and sharp temporal margin. OD OS
Figure 1-3 Grade II papilledema: 360 swelling of the disk margins, which are gray and indistinct.
15
OD
OS
Figure 1-4 Grade III papilledema: 360 swelling of the disk margins and par tial obscuration of blood vessels on the disk. Veins, especially OD, are tor tuous. OD OS
Figure 1-5 Grade IV papilledema: 360 swollen margins papilledema with complete obscuration of some vessels are the head.
16
OD
OS
Figure 1-6 Grade V papilledema: dome-shaped 360 swelling with no cup, completely obscured vessels, sphincter hemorrhages and circumpapillar y hard exudates.
Table 1-4 Frisn Scale of papilledema

Grade I Blurring of disk margins all but temporally. C-shaped swelling. Grade III Same as II but vessels partially obscured. Blurring is seen at margin of disk. Cup is partially obscured. Grade II 360 swelling of disk margins but only slight partial obscuration of blood vessels. Cup is preserved. Grade V Smooth domeshaped swelling and obscured vessels. No cup is visible. Gliosis is beginning to occur.
Grade IV Same as III but many vessels are totally obscured as the cup lls in and is no longer visible.
Adapted from Digre KB, Corbett JJ.13

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REFERENCES 1. Edmeads JG. Headache in the elderly. In: Olesen J, TfeltHansen P, Welch KMA, editors.The headaches. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 94752. 2. Duffy GB. The warning leak in spontaneous subarachnoid hemorrhage. Med J Aust 1983;28:5146. 3. Bonita R, Thompson S. Subarachnoid hemorrhage: epidemiology, diagnosis, management and outcome. Stroke 1985;16:5914. 4. Fontanorosa PB. Recognition of subarachnoid hemorrhage. Ann Emerg Med 1989;18:1199205. 5. Mokri B. Headache associated with abnormalities in structure or function: low cerebral spinal uid pressure headache. In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolf s headache and other head pain. 7th ed. USA: Oxford University Press; 2001. 6. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001;345: 172733. 7. Mellor DH.The place of computed tomography and lumbar puncture in suspected bacterial meningitis. Arch Dis Child 1992;67:14179. 8. Fishman RA. Cerebrospinal uid in diseases of the nervous system. 2nd ed. Philadelphia:WB Saunders; 1992. 9. MacDonald A, Mendchow AD. Xanthochromia revisited: a re-evaluation of lumbar puncture and CT scanning in the diagnosis of subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry 1988;51:3424. 10. Newman LB, Lipton RB. Emergency department evaluation of headache. Neurol Clin North Am 1995;16:285303. 11. Silberstein SD. Evaluation and emergency treatment of headache. Headache 1992;32:369404.
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12. van Crevel H, Hijdra A, de Gans J. Lumbar puncture and the risk of herniation: when should we rst perform CT? J Neurol 2002;249:12937. 13. Digre KB, Corbett JJ. Practical viewing of the optic disc. Burlington (MA): Butterworth Heinemann; 2003. 14. Steffen H, Eifert B, Aschoff A, et al. Diagnostic value of optic disc evaluation in actute elevated intracranial pressure. Ophthalmology 1996;103:122932.
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CHAPTER 2
GIANT CELL ARTERITIS

iant cell arteritis (GCA), also known as temporal arteritis, consists of an inammatory arteritis of mediumto large-sized arteries that have an elastic membrane.14 It occurs in patients almost exclusively over the age of 50 years and progressively increases in frequency each decade to the ninth decade, where it occurs in about one patient per thousand. A clinical variation of GCA is polymyalgia rheumatica (PMR), which does not always have the ominous implication for visual loss that is true of GCA.3,4 The symptom complex of PMR and GCA overlaps.Thus, there is an occult form of GCA identied when the dreaded arteritic anterior ischemic optic neuropathy blinds one or both eyes without premonitory symptoms.5,6 There is GCA with symptoms of transient visual loss or diplopia, headache, fever, and night sweats. GCA may occur with PMR where, in addition to the symptoms of GCA, there is pain in the neck, shoulders, and hips, and PMR may occur alone with no visual loss, stroke, or other vascular complication.The syndromes can only roughly be divided, and PMR symptoms even without headache must be considered an important red ag for GCA and a potential cause of anterior ischemic visual loss.3,5,7
SYMPTOMS
The patient with GCA is usually over 60, much less com20
Giant Cell Ar ter i t is
monly in the early fties, and will develop a new type of headache that is different from the patients previous headaches. Usually, it is a generalized headache, and it causes the scalp to be tender. The tenderness is great enough that brushing or combing the hair is painful and placing the head on a pillow is uncomfortable. The headache is constant but may vary in severity over time, and it may be accentuated by palpation tenderness of the temporal arteries or other scalp vessels. Neck pain was found by Hayreh and colleagues to be even more common than headache in patients with GCA.8 In one large series, they found that 90% of patients with biopsy-proven GCA had severe neck pain without tenderness. Pain occurs in the shoulders (yoke) and hips and upper thighs,8 which are also nontender to palpation. Electromyography and muscle biopsy show no abnormalities. The polymyalgia is constant and enervating and is part of the overall feeling of malaise and being unwell but may be so gradual in onset that it is written off by the patient as a symptom of old age. 9 Appetite is poor, and weight loss is common.2,3 Sometimes loss of appetite is made worse by jaw, tongue, and throat (swallowing) claudication. Premonitory symptoms include transient monocular or binocular visual loss that is indistinguishable from embolic amaurosis fugax. Less common symptoms include tongue and throat pain, chest pain, postprandial abdominal pain, and exertional leg pain. Confusion, frank memory loss, and dementia are reported,10 and it is likely that mental confusion is occasionally responsible for delays in diagnosis.
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SIGNS
Occasionally, the scalp over the temporal artery will become erythematous and swollen.3,8 Rarely, there will be true ischemic gangrenous breakdown of the skin. The scalp arteries are frequently locally tender; they may be nonpulsatile and ropey, but even grossly arteritic vessels may be soft, compressible, pulsatile, and nontender. Fever is rarely more than 100F, but night sweats are common.3 Night sweats are also common with serotonin reuptake inhibitors, which are ubiquitous.This may confound the use of night sweats as a sign. Diplopia may occur owing to ischemic damage to either oculomotor nerves or muscles.3 This weakness tends to resolve within 3 to 6 months.The most feared complication of GCA is infarction of the anterior optic nerve owing to occlusion of the short posterior ciliary arteries by the arteritis (Figure 2-1). Peripheral neuropathy, both symmetric distal polyneuropathy and mononeuritis multiplex, occurs more commonly than previously recognized because the neuropathies are frequently asymptomatic.10 Muscles are not tender to palpation, but strength testing may be impaired slightly by pain.
CLINICAL DIAGNOSIS
GCA should be suspected in patients over the age of 50 who have any or all of the following: onset of a new type of headache, scalp tenderness, aching pain in the shoulders and hips, transient monocular or binocular transient visual loss, anterior ischemic optic neuropathy, fever, malaise,
22
night sweats, anorexia and/or weight loss. Patients may deny any symptoms because the condition has slowly crept up on them. They may recognize that they had symptoms only when the symptoms disappear on corticosteroid treatment. Furthermore, an insidious ischemic confusional state may prevent the patient from giving a coherent history, and it may be the family that has noticed that the patient is having trouble with memory, sleep, appetite, and weight loss or has complained of headache.12 One should have a high level of suspicion for GCA in all elderly patients.
LABORATORY DIAGNOSIS
GCA has characteristically been associated with an elevated erythrocyte sedimentation rate (ESR) (Westergren method), with only about 5 to 10% having a normal ESR. Whereas the ESR is characteristically elevated in GCA, an elevated ESR is also commonplace as a nonspecic acutephase reactant. GCA is in the lower ranks in frequency on the list of causes of elevated ESR. Furthermore, the ESR may be depressed by the common use of nonsteroidal anti-inammatory drugs being used to treat the arthritic symptoms of PMR. Although it is the most widely available study, the ESR is not the most accurate test, largely owing to variability produced by time, temperature, and vibration in the laboratory. C-reactive protein (CRP) is another one of many acute-phase reactants that are elevated in GCA. CRP is a more accurate test because it is not subject to the above-mentioned effects, and inexpensive kits are available, in contrast to other, much more
23
24
Headache, amaurosis fugax, visual loss, fever, night sweats, weight loss, anorexia, proximal hip and shoulder pain, jaw claudication, posterior neck pain in a patient older than 50 years of age
SUSPECT giant cell arteritis Treat with oral or IV corticosteroids Biopsy temporal artery
Positive
Negative
Continue corticosteroid treatment
Continue treatment Biopsy other side
Negative biopsy Headache persists while taking steroids Headache better and PMR symptoms gone
Negative biopsy Positive biopsy
Headache goes away on steroids; systemic symptoms improve
Continue corticosteroid treatment Biopsy negative GCA
Discontinue corticosteroids and investigate for infection, inflammatory disease, or tumor
Continue oral corticosteroids Follow ESR, CRP, and symptoms
Figure 2 -1 Rarely is the diagnosis of giant cell ar teritis so open and shut. Asymptomatic cases or subtly symptomatic cases with normal sedimentation rates and even normal C-reactive protein (CRP) may confound the picture. Patients younger than age 50 years are rare, with only a small number having been repor ted over many years. CRP = C-reactive protein; ESR = er ythrocyte sedimentation rate (Westergren method); GCA = giant cell ar teritis; IV = intravenous.
25
expensive, acute-phase reactants. Thus, a sedimentation rate and CRP test should be performed on any patient suspected of having GCA. Other laboratory tests that may be abnormal include liver function studies, which may show elevated enzymes but no change in bilirubin. Blood counts may be low, and a modest microcytic, hypochromic anemia is common.
TEMPORAL ARTERY BIOPSY To Biopsy or Not To Biopsy? 1,3,8
GCA is a chronic disease.1 The exact reasons that move a physician to treat the patient with corticosteroids are often lost in the mists of time and are further obscured by patients, who may be persistent and insistent in their desire to be taken off the corticosteroids. It is reassuring to the physician to have a positive temporal artery biopsy in the records that justies such treatment.8 There may be scars of old arteritis rather than active arteritis, and it has been shown that these arteritic remnants have the same diagnostic signicance as acute active arteritis. The issue of whether to treat does not rest entirely on the biopsy results. A positive biopsy is a relief and justication, but a negative biopsy performed on one side may be followed by a positive biopsy performed on the opposite side. Furthermore, a negative biopsy with an elevated ESR may suggest diabetes mellitus, infection, or malignancy as an alternative diagnosis.14
26
When To Biopsy
It is obvious that a biopsy should be done as soon as possible. However, in the event that the performance of a biopsy is delayed, there should be no delay in beginning corticosteroid treatment if you are serious about the diagnosis.There is little or no risk of masking the biopsy evidence of arteritis by treatment.4,9 Furthermore, prompt improvement of symptoms with the use of corticosteroids is evidence in favor of the diagnosis of GCA.Ten to 15% of patients with negative biopsies are subsequently found to have GCA. Biopsy is not a risk factor for scalp necrosis or brain ischemia. Treatment of GCA consists of oral corticosteroids.2,3 It has been suggested that patients with GCA who present with transient visual loss or arteritic anterior ischemic optic neuropathy should be treated with high-dose corticosteroids (1,000 mg intravenous methylprednisolone daily for a week) rather than oral corticosteroids.Although this has not been subjected to a prospective randomized treatment trial, the potential for blindness as an end point with GCA makes it unlikely that any such study will ever be carried out.
How To Treat GCA
The corticosteroid dosage regimen remains controversial, but two things are clear. First, the dose of corticosteroid (usually prednisone) should be adequate to relieve all symptoms and to rapidly lower the ESR and CRP to normal. Second, every other day steroids are not effective in the
27
treatment of GCA and should never be used either initially or in the tapering phase.10 Initially, the patient should be seen monthly, and ESR and CRP should be done at each visit. Review the patients symptoms and begin a very slow taper only after the patients ESR, CRP, and symptoms have been stable for 2 to 3 months.3,11 You may want to turn the patient over to the care of a physician who is familiar with the treatment of patients with GCA. The long-term treatment and management of GCA with nonsteroidal alternative medications are not within the scope of a neurologic emergency text. Consider GCA to be a chronic disease and that it may need to be treated for 2 or more years.11 Clearly, the treatment of other diseases may be affected adversely by the chronic use of corticosteroids. Furthermore, these are older patients who are at risk of osteoporosis and hip and vertebral fractures that may develop rapidly after being treated with oral corticosteroids.
TYPICAL CASE
Figure 2 shows the optic discs of an 83-year old woman who had abrupt onset of painless visual loss (left eye) with normal vision (right eye). She complained of trash in the eye. She had no pain in her shoulders or hips and no fever, night sweats, or weight loss. She had, however, recent onset of pain in the neck and pain in the jaws when she chewed meat. She had been given COX-2 inhibitors for arthritis. Despite a normal erythrocyte sedimentation rate of 13, a temporal artery biopsy was done. The results of the biopsy were positive.
28
OD
A OS
B Figure 2-2A and 2-2B Typical appearance of ischemic optic neuropathy caused by giant cell arteritis. The left disc is pale and swollen, and there are a few splinter hemorrhages. Of special note in the right eye are the nerve ber layer infarcts superiorly and nasally from the disc. This is a sign of retinal ischemia in the nonaffected right eye and the infarcted disc in the left eye. The lack of clarity of both discs and vessels is due to cataracts.
29
CONCLUSION
The key to prevention of crippling visual loss owing to GCA is immediately starting the patient on oral or intravenous corticosteroids.Treatment should be begun before the temporal artery biopsy; even if the ESR is normal, the patient should be given corticosteroids if the clinical picture is strongly in favor of the diagnosis. Furthermore, if the patient has transient monocular visual loss or anterior ischemic optic neuropathy, round the clock, four times per day, intravenous 250 mg doses of methylprednisolone should be used to prevent infarction or to prevent the second eye from being infarcted.15
REFERENCES 1. Caselli RJ, Hunder GG,Whisnant JP. Neurologic disease in biopsy-proven giant cell (temporal) arteritis. Neurology 1988;38:3529. 2. Corbett JJ, Melms A. Giant cell arteritis and polymyalgia rheumatica. In: Brandt T, Caplan LR, Dichgans J, et al, editors. Neurological disorders: course and treatment. Academic Press; 2003. p. 47581. 3. Goodwin J.Temporal arteritis. In: Pinken PJ, Bruyn G, editors. Handbook of clinical neurology. Vol. 39. New York: American Elsevier Co. p. 31342. 4. Guevara RA, Newman NJ, Grossniklaus HE. Positive temporal artery biopsy 6 months after prednisone treatment. Arch Ophthalmol 1998;116:12523. 5. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998;125: 50920.
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6. Desmet GD, Knockaert DC, Bobbaers HJ.Temporal arteritis: the silent presentation and delay in diagnosis. J Intern Med 1990; 227:23740. 7. Ghanchi FD, Dutton GN. Current concepts in giant cell (temporal) arteritis. Surv Ophthalmol 1997;42:99123. 8. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123:28595. 9. Beevers DG, Harpur JE,Turk KAD. Giant cell arteritis.The need for prolonged treatment. J Chron Dis 1973;26:57184. 10. Caselli RJ, Daube JR, Hunder GG,Whisnant JP. Peripheral neuropathic syndromes in giant cell (temporal) arteritis. Neurology 1988;38:6859. 11. Caselli RJ. Giant cell (temporal) arteritis: a treatable cause of multi-infarct dementia. Neurology 1990;40:7535. 12. Hall S, Hunder GG. Is temporal artery biopsy prudent? Mayo Clin Proc 1984;59:7936. 13. Achkar AA, Lie JT, Hunder GG, et al. How does previous corticosteroid treatment affect the biopsy ndings in giant cell (temporal) arteritis? Ann Intern Med 1994;120:98792. 14. Hunder GG, Sheps SG,Allen GL, Joyce JW. Daily and alternate day regimens in treatment of giant cell arteritis: comparison in a prospective study. Ann Intern Med 1975;82: 6138. 15. Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 1998; 125:5216.
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CHAPTER 3
APPR OACH TO THE COMATOSE PATIENT

Michael De Georgia, MD, and John Andrefsky, MD CASE
. P. is a 47-year-old woman who suddenly developed left hemiplegia. On examination, she was alert and oriented and her eyes tended to the right, but she was able to cross midline. There was a dense left facial weakness, left hemiplegia, and profound neglect of the left side.A Babinskis sign was present on the left.A noncontrast head computed tomographic (CT) scan showed hypodensity of the right frontal and parietal lobes with edema, and a toxicology screen revealed the presence of cocaine. Transcranial Doppler ultrasonography demonstrated markedly reduced mean ow velocities of the right middle cerebral artery (MCA) and reversal of ow in the right anterior cerebral artery suggestive of a carotid occlusion, which was conrmed by carotid ultrasonography.The following day, she was lethargic but still arousable and able to follow simple commands. That evening, a second CT scan of the head showed a massive right MCA territory infarct. She was moved into the neurologic intensive care unit, where at 4:00 am she was minimally responsive. Examination revealed her right pupil to be dilated to 6 mm and not reactive to light; her left pupil was dilated to 4 mm and sluggishly reactive to light. She withdrew her right arm and leg normally to pain, adducted and exed her left arm, and showed a triple exion response of the left leg. Both toes were upgoing. She was intubated, hyperventi-
32
Appro a ch t o the Comat os e Pa t ient
lated, and treated with mannitol.A head CT scan demonstrated a massive right MCA territory infarct with 1.8 cm of anterior septal shift and temporal lobe herniation. A decompressive right hemicraniectomy was done immediately. Postoperatively, she was arousable but followed no commands.
INTRODUCTION
Consciousness is difcult to dene but may be thought of as the awareness of self and the environment. Physicians are often called on to evaluate reduced level of consciousness, the extreme of which is coma or no awareness of self or environment. Coma is not a disease in itself but is always a symptom of an underlying disorder. Sometimes the underlying disorder is obvious (eg, severe head trauma). More often the patient is found comatose, and little information is available. The evaluation must be approached methodically, leaving none of the common and treatable causes of coma unexplored.The following is a review of the anatomy of consciousness, terms used to describe consciousness, and a general approach to the comatose patient, including a review of brain herniation.
ANATOMY OF CONSCIOUSNESS
The ascending reticular activating system is a poorly dened group of neurons that make up the central core of the brainstem, extending from the lower medulla to the upper midbrain and diencephalon.These neurons project widely to the entire cerebral cortex. Consciousness comes from the cortex (Figure 3-1). To cause coma, there must
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Figure 3-1 The ascending reticular activating system.
be bilateral and diffuse cortical disease or brainstem disease that disrupts the ascending reticular activating system (Table 3-1). Bilateral and diffuse cortical disease can occur from a number of different causes, for example, bilateral infarcts (cardiac sources of emboli) or bilateral hemorrhages (subdural hemorrhages following trauma or associated with anticoagulation). Patients with metabolic disorders are included in this category of bilateral disease because both hemispheres are subjected to the chemical alteration. Patients with bilateral and diffuse cortical disease often do not have focal or lateralizing neurologic signs.
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Table 3-1 Two Mechanisms of Coma: Bihemispheric versus Brainstem Bihemispheric disease Bilateral or diffuse lesions Directly affect both hemispheres (including metabolic and systemic disorders) Unilateral lesions Directly extend into the diencephalon or indirectly cause lateral and downward displacement of the diencephalon Brainstem disease Directly impair the ascending reticular activating system
Large space-occupying unilateral lesions of the hemispheres (ischemic infarcts with edema, hemorrhages, tumors) can impair consciousness by directly extending into the diencephalon or by causing horizontal and downward displacement of the diencephalonupper brainstem structures.This displacement may occur with or without actual herniation of brain tissue (see Brain Herniation Syndromes). Patients with unilateral hemispheric lesions do have lateralizing neurologic signs. A number of lesions that directly affect the ascending reticular activating system in the brainstem (infarct, hemorrhage) can result in coma. In this group of patients, the focality of signs, such as
35
abnormal pupillary reactions and eye movements, points to the presence of a serious brainstem structural lesion.
GRADING LEVELS OF CONSCIOUSNESS
Terms such as confusion, lethargy, obtundation, and clouding of consciousness can be ambiguous. Although there are innite degrees of depressed consciousness, it is simplest to use four categories: alert, somnolent, stuporous, and comatose. Somnolent patients are sleepy and apathetic and often have difculty cooperating with the examination. Stupor denotes the inability to sustain a wakeful state without some external stimulation. Comatose patients cannot be aroused even by strong, painful stimuli.
DIAGNOSIS AND MANAGEMENT OF COMA General Medical Examination
When evaluating a comatose patient, the physician must always begin by doing a quick general medical examination: airway, breathing, and circulation (Figure 3-2). Does the patient have an adequate airway? Is the patient breathing on his/her own? Endotracheal intubation should be done in patients without an adequate airway to prevent upper airway obstruction or aspiration. Mechanical ventilation is needed in those with no spontaneous respiration or ineffective respiration (shallow breathing). Does the patient have a pulse and an adequate blood pressure? Ensuring hemodynamic stability takes precedence over determining the cause of coma in the rst few minutes.
36
Patient is comatose Does patient have an airway?
No
Yes
Create an airway
Is patient breathing?
No
Yes
Begin rescue breathing
Does patient have a pulse?
No
Yes
Begin cardiopulmonary resuscitation
Draw blood and start IV Thiamine 12 mg/kg IV push D50W 1 amp IV push Naloxone 0.01 mg/kg IV push
Neurologic examination
Figure 3-2 General medical examination. IV= intravenous.

37
The head should be inspected for any signs of trauma. Basilar skull fractures may be accompanied by periorbital ecchymoses (raccoon eyes), ecchymosis behind the ear (Battles sign), hemotympanum, and cerebrospinal uid (CSF) rhinorrhea or otorrhea. Examination of the optic fundi may demonstrate papilledema with increased intracranial pressure or subhyaloid hemorrhages in the setting of subarachnoid hemorrhage. Common reversible causes of coma include hypoglycemia and drug intoxication. Signs of meningeal irritation (neck stiffness on forward bending, Kernigs and Brudzinskis signs) can be seen in both bacterial meningitis and subarachnoid hemorrhage but may be absent in deeply comatose patients. Patients in the emergency department about whom you know little should receive a bolus of 50% glucose (always drawing off a blood sample before) and thiamine; glucose infusion in the setting of thiamine deciency (such as in an alcoholic patient) can precipitate Wernickes encephalopathy. Naloxone (Narcan) can be used to reverse opiates if a narcotic overdose is a possibility, and umazenil (Romazicon) can be used to reverse benzodiazepines.
Neurologic Examination
The neurologic examination is critical and should be directed at differentiating between the two main mechanisms of coma: bihemispheric disease and brainstem disease (Figure 3-3). Simply watching the patient for a minute yields considerable information. The brainstem sets posture: the position of the head and eyes; the rate, depth, and rhythm of respiration; and postures of the limbs
38
and body. Therefore, patients who look comfortable and are moving spontaneously and breathing easily likely do not have signicant brainstem involvement. Patients who look uncomfortable and have unnatural posturing movements and abnormal breathing patterns are likely to have brainstem disease. The state of responsiveness should be estimated by noting the patients reaction to calling his/her name, simple commands, or noxious stimuli. Focal lesions can usually be detected, even in comatose patients. A lack of restless movements on one side, for example, suggests hemiparesis. With hemispheric lesions, the eyes may be turned away from the paralyzed side (toward the lesion), and with brainstem lesions, the eyes may be turned toward the paralyzed side (away from the lesion).The most useful indicators of brainstem function are pupillary size and reactivity, eye movements, and breathing patterns. These functions are largely dependent on the integrity of the midbrain and upper pons and can be used, when combined with motor responses, to differentiate between bihemispheric disease, in which they will be normal, and brainstem disease, in which they will be abnormal.
Pupils
Pupil reactivity to light, symmetry, and size should be observed. Pupil size is a balance between parasympathetically mediated constriction and sympathetically mediated dilation. Pupils that are reactive to light, symmetric, and of normal size (roughly 35 mm in diameter) in a comatose patient generally suggest bihemispheric disease. Pupillary
39
40
Neurologic examination: is the brainstem working? Yes Pupils Reactive to light Symmetric Normal size
Eye movements and other brainstem reflexes
Spontaneous eye movements (roving) Conjugate Normal oculocephalic or oculovestibular reflexes Blink to corneal touch Cough/gag present Normal or Cheyne-Stokes respiratory pattern
Spontaneous movement Motor examination Withdrawal or flexion Brainstem is working (bihemispheric cause of coma)
Figure 3-3 Neurologic examination.
Neurologic examination: is the brainstem working? No Pupils Not reactive to light Asymmetric Abnormal size (very large or very small)
Eye movements and other brainstem reflexes
No spontaneous eye movements Dysconjugate Abnormal oculocephalic or oculovestibular reflexes No blink to corneal touch No cough/gag present Abnormal respiratory pattern (central neurogenic hyperventilation, apneustic breathing, or ataxic breathing)
No spontaneous movement Motor examination Flexion or extension Brainstem is not working (Brainstem cause of coma)
Figure 3-3 Continued.
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reactions are usually normal with coma owing to drug intoxications, but important exceptions include opiates, which cause pinpoint pupils, and barbiturates, which cause small pupils, around 1 to 2 mm in size. Poisoning with atropine or atropine-like drugs (including tricyclic antidepressants) is characterized by dilated and xed pupils. Pupils that are not reactive to light or are asymmetric in size, very large, or very small are likely to occur in patients with brainstem disease. A unilaterally enlarged pupil (> 5 mm diameter) is the most important and localizing sign of brainstem involvement, usually signifying progressive displacement of the midbrain and stretching or compression of the oculomotor nerve (see Brain Herniation Syndromes). With massive midbrain lesions that disrupt both parasympathetic and sympathetic bers, both pupils become xed at about 4 mm (midposition). Pontine tegmental lesions cause extremely small pupils (< 1 mm), with only a slight reaction to strong light.
Eye Movements and Other Brainstem Reflexes
Eye movements come from the brainstem.Therefore, if the eyes are moving, the brainstem (from the vestibular nuclei in the upper medullalower pons to the oculomotor nucleus in the midbrain), at least to some degree, must be intact. Eyes that spontaneously rove back and forth point to a bihemispheric cause of coma. Lateral and downward deviation of one eye suggests an oculomotor nerve palsy, and medial deviation suggests an abducens nerve palsy. Commonly, latent strabismus can be unmasked in stuporous patients, and the eyes may appear dysconjugate
42
(wall-eyed). Conjugate deviation of the eyes away from the paralyzed limbs can be seen with large hemispheric lesions and toward the paralyzed limbs with unilateral pontine lesions.The eyes turn toward the convulsing side of the body during a seizure (pushed away from the seizure focus) and may be turned down and inward (looking at the tip of the nose) with thalamic lesions and upper midbrain lesions (Parinauds syndrome). If the eyes are not moving on their own, then the physician should try to make them move reexively.The oculocephalic reex (dolls-eyes maneuver) is elicited by quickly turning the head and consists of conjugate movement of the eyes in the opposite direction. This demonstrates the integrity of all the ocular motor nerves and brainstem structures and loss of cortical inhibition that normally suppresses these movements. Remember to never rotate the neck of an unconscious patient unless you are absolutely sure that there is no cervical fracture. If the eyes do not move with head turning or if a cervical fracture has not been excluded, a stronger stimulus, such as instilling cold water into the ears (oculovestibular reex or ice-water cold calorics), may be used. After making sure that the tympanic membrane is intact, the oculovestibular reex is elicited by irrigating each ear canal with 10 mL of ice water.This will normally cause slow conjugate deviation of the eyes toward the irrigated ear and compensatory nystagmus (fast component) away from the irrigated ear. In coma from bihemispheric disease, the fast corrective phase of nystagmus is lost, and the eyes remain tonically deviated toward the side irrigated with cold water. In coma from brainstem disease, no eye movement occurs and the eyes remain straight ahead.
43
The presence of other brainstem reexes (blink at the pontine level and cough/gag at the medullary level) and normal or Cheyne-Stokes respiration suggests an intact brainstem. Cheyne-Stokes respiration is characterized by a crescendo-decrescendo pattern of periodic breathing regularly alternating with periods of apnea.This pattern usually indicates bilateral deep hemispheric or diencephalic disease and has been attributed to an increased ventilatory response to carbon dioxide causing hyperventilation. As a result, the carbon dioxide concentration drops below that required to stimulate the forebrain respiratory center and breathing stops. Carbon dioxide then reaccumulates until it exceeds the respiratory threshold, and the cycle repeats itself. Cheyne-Stokes respiration is a complicated respiratory pattern, and its presence generally indicates an intact brainstem. The absence of these brainstem reexes or the presence of abnormal breathing patterns (such as central neurogenic hyperventilation, apneustic breathing, or ataxic breathing) suggests brainstem disease. Central neurogenic hyperventilation is characterized by an increase in the rate and depth of respiration, which, at times, can seem mechanical. Central neurogenic hyperventilation localizes to the lower midbrainupper pontine tegmentum and is thought to represent a release of respiratory control. Mild degrees of hyperventilation are common after any acute neurologic event and in the setting of medical illness (pneumonia, atelectasis, metabolic acidosis and severe liver failure) so that the diagnosis of central neurogenic hyperventilation is always one of exclusion.Apneustic breathing, characterized by a few rapid deep breaths followed by a
44
2- to 3-second pause at full inspiration, is usually seen in low pontine lesions. Ataxic or Biots breathing, characterized by chaotic and irregularly interrupted breathing with varying rate and depth, is usually seen in medullary lesions.
Motor Responses
Spontaneous movements or normal withdrawal and abduction of the limbs to pain generally suggest an intact brainstem. No spontaneous movement or abnormal extension and adduction of the limbs to pain (so-called decerebrate posturing) suggest brainstem disease. In its full form, decerebrate posturing consists of opisthotonos, tight clenching of the jaws, stiff extension and internal rotation of the arms and legs, and plantar exion of the feet. Bilateral midbrain or pontine lesions cause decerebrate posturing. Abnormal stereotypical flexion and adduction of the arms with extension and internal rotation of the legs (so-called decorticate posturing) are less localizing but generally occur in hemispheric disease or upper midbrain lesions (classically above the red nucleus). Essentially, this is the same as spastic hemiplegia.
BRAIN HERNIATION SYNDROMES
When bilateral hemispheric mass lesions develop within the cranium, such as diffuse cerebral edema, bilateral subdural hematomas, or bilateral infarcts, the only available direction of expansion, given the symmetry of pressures between the two sides, is downward toward the tentorial opening (Figure 3-4A). The thalamus and upper
45
midbrain are then forced, en bloc, through the tentorial opening.This is referred to as central herniation (Figure 3-4B). Conversely, when a unilateral hemispheric mass develops within the cranium, such as an intracerebral hemorrhage or massive infarct, the direction of expansion is toward the opposite hemicranium through the subfalcial window. The more anterior structures are relatively free to move, but the more posterior structures, close to the tentorial opening, are conned; a shift of only a few millimeters results in midbrain compression against the unyielding tentorial edge.With continued expansion of the mass, eventually the medial temporal lobe (uncus) can slip down through the tentorial opening to lie next to the midbrain. This is referred to as uncal herniation (Figure 3-4C). In both cases, actual herniation of brain tissue is probably a relatively late event. Similarly, an infratentorial mass, such as a hemorrhage or tumor in the cerebellum, can expand upward and push the cerebellum up through the tentorial opening. In patients with central herniation, there is often a rostral-caudal deterioration of function. Early, there is confusion, poor concentration, and drowsiness and either normal or Cheyne-Stokes respiration from compression of the diencephalon. The pupils become small and poorly reactive to light. Eye movements and other brainstem reexes, however, are generally preserved initially. Bilateral Babinskis signs and increased muscle tone can be detected, and, later, patients may develop decorticate posturing. These signs then give way to more threatening signs of brainstem disease: coma; xed, midposition pupils; loss of oculocephalic and oculovestibular reexes; central
46
Figure 3-4 Brain herniation syndromes. A, Normal; B, central herniation; C, uncal herniation.
neurogenic hyperventilation; decerebrate posturing; ataxic breathing; and death. Uncal herniation differs in that early unilateral pupillary dilatation (as the oculomotor nerve becomes trapped or compressed) accompanies or even precedes drowsiness. Subtle anisocoria with a sluggish light reaction or an oval pupil can sometimes be seen hours before other signs
47
appear. Eventually, consciousness worsens, and the upper midbrain, particularly the cerebral peduncle, may be pushed against the opposite side of the tentorium, causing a Babinksis sign ipsilateral to the hemispheric lesion (the Kernohan-Woltman phenomenon).
MANAGEMENT OF THE COMATOSE PATIENT
The main goal is to determine the mechanism of coma (bihemispheric versus brainstem) and underlying cause (eg, infarct, hemorrhage, metabolic). Diagnosis and treatment must proceed concurrently (Figure 3-5).The management of airway and blood pressure takes precedence over all other diagnostic and treatment measures. Shallow and irregular respirations, upper airway obstruction, and hypoxia require the establishment of a clear airway and delivery of oxygen. Arterial blood gases and pulse oximetery should be done in all patients. Comatose patients should be placed on their side to prevent aspiration of secretions and emesis.The inability to protect against aspiration and the presence of hypoventilation or hypoxia are reasons for endotracheal intubation and mechanical ventilation.There is sometimes a tendency to delay intubation as long as possible in the hope that it will not be necessary or to not lose the neurologic examination. It is always better to intubate early rather than later, after the patient has aspirated. Two large-bore intravenous lines should be placed early. In patients with tenuous venous access, a central venous catheter should be inserted (the femoral vein is the
48
quickest and safest route). A medical history should be obtained if possible, and blood samples should be drawn for the determination of glucose, electrolytes, renal and liver function tests, coagulation studies, arterial blood gas, and a drug toxicology screen. Naloxone (Narcan), 0.4 mg, should be given intravenously if a narcotic overdose is suspected and umazenil (Romazicon), 0.2 mg, if a benzodiazepine overdose is possible. Infusion of 50% glucose (1 ampule or 50 mL of D50W) should be done empirically for hypoglycemia; this must be supplemented with thiamine. Once the patient is hemodynamically stable, a brief neurologic examination should be able to differentiate patients with a bihemispheric mechanism of coma, in whom brainstem function will be normal, from those with a brainstem mechanism of coma, in whom brainstem function will be abnormal. Patients with bihemispheretype coma should undergo a CT scan as soon as possible. Abnormal scans will fall into one of two categories: abnormal with operable lesions (such as a large intracerebral hemorrhage with mass effect amenable to evacuation; Table 3-2 and Figure 3-6) and abnormal with nonoperable lesions (such as diffuse cerebral edema without mass effect; Table 3-3 and Figure 3-7). If the CT scan is normal, a lumbar puncture should be performed to exclude meningitis and subarachnoid hemorrhage. If the CSF is normal, further workup, including electroencephalography, may be necessary to exclude nonconvulsive status epilepticus (Table 3-4 and Figure 3-8; see Chapter 4, Approach to Status Epilepticus).
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Brainstem is working (bihemispheric cause of coma)
CT scan* Abnormal Normal
Operable lesion(s) consult neurosurgery

Ischemic infarct(s) with mass effect (unilateral or bilateral) Intracerebral hemorrhage(s) with mass effect (unilateral or bilateral) Subdural or epidural hemorrhage(s) with mass effect (unilateral or bilateral) Abscess(es) with mass effect (unilateral or bilateral) Hydrocephalus Subarachnoid hemorrhage
Bihemispheric coma with normal CT scan

Meningoencephalitis Bilateral ischemic infarcts Subarachnoid hemorrhage Head trauma Venous sinus thrombosis Hypoxic/ischemic injury Drugs and toxins Electrolyte disturbances Postictal state or nonconvulsive status epilepticus
Inoperable lesion(s) medical therapy

Bilateral ischemic infarcts Diffuse cerebral edema Multiple abscesses without mass effect *If CT scan is abnormal, then *If CT scan is normal, then further appropriate action should be taken investigation is warranted, including (consult neurosurgeon, start lumbar puncture for cerebrospinal antibiotics or corticosteroids, etc) fluid analysis, toxicology screen, and electroencephalogram. The cause may still be bihemispheric disease, but the physician should re-examine the patient to make sure that brainstem function is indeed normal.
Figure 3-5 Diagnosis and treatment algorithm. CT = computed tomography; MRI = magnetic resonance imaging.
50
Brainstem is not working (Brainstem cause of coma)
Yes
Signs of herniation?
1. Call neurosurgeon 2. Intubate and hyperventilate to Pco2 2530 mm Hg 3. Mannitol 20% 1 g/kg IV
No
CT scan* MRI Abnormal Operable lesion(s) consult neurosurgeon

Ischemic infarct (basilar artery occlusion) Abscess(es) with mass effect Tumor Hydrocephalus
Normal Brainstem coma with normal CT scan

Early ischemic infarct (basilar artery occlusion) Meningoencephalitis Subarachnoid hemorrhage Diffuse axonal injury
Inoperable lesion(s) medical therapy

Ischemic infarcts Intracerebral hemorrhage Head trauma *If CT scan is abnormal, then *If CT scan is normal, then further appropriate action should be taken investigation is warranted, including (consult neurosurgeon, start lumbar puncture for cerebrospinal antibiotics or corticosteroids, etc) fluid analysis, toxicology screen, and electroencephalogram. The cause may still be bihemispheric disease, but the physician should re-examine the patient to make sure that brainstem function is indeed normal.
51
Table 3-2 Bihemispheric Cause of Coma: CT Scan Abnormal with Operable Lesion
Disease Ischemic infarct(s) with mass effect (unilateral or bilateral) Etiology Action to Take May be cardioembolic Dene source and or large artery disease treat accordingly (anticoagulation, antiplatelet agent) Consult neurosurgery for possible ICP; monitor placement and/or possible decompressive craniectomy
Intracerebral Multiple causes Dene cause and treat hemorrhage(s) with including hyperaccordingly (manage mass effect (unilateral tension, arteriovenous hypertension, correct or bilateral) malformation, coagulopathy) aneurysm, amyloid If sinus venous thromangiopathy, bosis considered, coagulopathy, obtain MRI/MRV or trauma catheter angiography Consult neurosurgery for possible evacuation Subdural or epidural Most often from hemorrhage(s) with trauma or mass effect (unilateral coagulopathy or bilateral) Dene cause and treat accordingly (correct coagulopathy) Consult neurosurgery for evacuation and drainage Dene cause and treat accordingly (antibiotics) Consult neurosurgery for possible drainage and resection Dene cause Consult neurosurgery for ventriculostomy and drainage Consult neurosurgery for management
Abscess(es) with mass effect (unilateral or bilateral) Hydrocephalus
Multiple causes, including bacterial, fungal, tuberculous, parasitic May have multiple causes
Subarachnoid hemorrhage
Most often from aneurysm or trauma
CT = computed tomography; ICP = intracranial pressure; MRI = magnetic resonance imaging; MRV = magnetic resonance venography. 52
Figure 3-6 Subdural hematoma with mass effect.
Table 3-3 Bihemispheric Cause of Coma: CT Scan Abnormal with Nonoperable Lesion
Disease Bilateral ischemic infarcts Etiology Most often from cardiac source; diffuse large artery disease (vasculitis) or hypercoagulable state May have multiple causes (infarct, infection, trauma, anoxia, rapid correction of hyperosmolar state) Multiple causes, including bacterial, fungal, tuberculous, parasitic Action to Take Dene source and treat accordingly (anticoagulation, antiplatelet agent) Dene cause and treat accordingly (intubation, mannitol, corticosteroids)
Diffuse cerebral edema
Multiple abscesses without mass effect
Dene cause and treat accordingly (antibiotics)
CT = computed tomography. 53
Figure 3-7 Diffuse cerebral edema.
Table 3-4 Bihemispheric Cause of Coma: CT Scan Normal

Disease Meningoencephalitis Etiology Bacterial, fungal, tuberculous, viral, carcinomatous, lymphomatous Most often from cardiac or hypercoagulable state. CT scan may be normal early in course Action to Take Dene cause and treat accordingly
Bilateral ischemic infarcts
Dene source and treat accordingly (anticoagulation, antiplatelet agent). CT scan may be normal early. Diffusion-weighted MRI more sensitive Continued
54
Table 3-4 (continued)

Subarachnoid hemorrhage Most often from aneurysm CT scan can be or trauma. CT scan my be normal. Requires normal lumbar puncture and CSF analysis for diagnosis Consult neurosurgery for management Consult neurosurgery for management Most often hypercoagulable Conrm diagnosis state with MRI/MRV or catheter angiography Consult cerebrovascular specialist and/or interventional neuroradiologist and treat accordingly (eg, anticoagulation, local thrombolysis) Hypoxix/ischemic injury Drugs and toxins Most often after cardiac arrest Multiple drugs Supportive care Dene cause (history, toxicology screen) and treat accordingly Action to Take Dene cause (laboratory tests) and treat accordingly EEG necessary for diagnosis
Head trauma Venous sinus thrombosis
Disease Electrolyte disturbances Postictal state or nonconvulsive status epilepticus
Etiology Most common hyponatremia, hypo- and hyperglycemia Multiple causes
CSF = cerebrospinal uid; CT = computed tomography; EEG = electroencephalogram; MRI = magnetic resonance imaging; MRV = magnetic resonance venography.
55
Figure 3-8 Nonconvulsive status epilepticus.
If the brainstem is abnormal (asymmetric, nonreactive pupils, dysconjugate eyes, irregular breathing, extensor posturing), then the cause is most likely related to brainstem involvement. Brain herniation is a life-threatening emergency, and any sign of herniation (eg, a unilaterally dilating pupil) should prompt immediate treatment and a call to neurosurgery. The patient should be intubated (if not already) and hyperventilated to a carbon dioxide partial pressure of 25 to 30 mm Hg. Mannitol, 20% solution, should be given at a dose of 1 g/kg intravenously over 10 to 20 minutes.The patient should then undergo a CT scan (or magnetic resonance imaging [MRI]) as soon as possible.As with bihemispheric causes of coma, abnormal
56
Table 3-5 Brainstem Cause of Coma: CT Scan Abnormal with Operable Lesion
Disease Ischemic infarct Etiology Most often from cardiac source or vertebrobasilar large artery disease (basilar occlusion) Action to Take Dene source and treat accordingly (local intraarterial thrombolysis for basilar occlusion, anticoagulation, antiplatelet agent) Consult cerebrovascular specialist and/or interventional neuroradiologist for possible intraarterial thrombolysis
Abscess
Bacterial, fungal, tuberculous, Dene cause and treat parasitic accordingly Consult neurosurgery for possible drainage and resection Multiple types Consult neurosurgery for management Corticosteroids for swelling Dene cause Consult neurosurgery for ventriculostomy and drainage
Tumor
Hydrocephalus
May have multiple causes
CT = computed tomography.
scans will fall into one of two categories: abnormal with operable lesions (pontine infarct from basilar artery occlusion amenable to thrombolysis;Table 3-5 and Figure 3-9) and abnormal with nonoperable lesions (such as a large
57
Figure 3-9 Pontine infarct.
Table 3-6 Brainstem Cause of Coma: CT Scan Abnormal with Nonoperable Lesion
Disease Ischemic infarct Etiology Most often from cardiac source Action to Take Dene source and treat accordingly (anticoagulation, antiplatelet agent) Dene cause and treat accordingly (correct coagulopathy) Care is usually supportive Care is usually supportive
Intracerebral hemorrhage
Most often from hypertension
Head trauma
CT = computed tomography.
58
Figure 3-10 Pontine hemorrhage.
hypertensive hemorrhage; Table 3-6 and Figure 3-10). Identifying the CT scan appearance of brain herniation is crucial in the evaluation of a comatose patient (see Figure 3-7). If the CT scan or MRI does not disclose any abnormality, then a lumbar puncture should be performed to exclude meningitis and subarachnoid hemorrhage. It is important, however, in patients who are comatose with a brainstem-type coma and a normal CT scan, that basilar artery occlusion is not missed. This diagnosis, which is treatable with thrombolysis, must be denitively excluded with vascular imaging (Table 3-7).
59
Table 3-7 Brainstem Cause of Coma: CT Scan Normal

Disease Early ischemic infarct Etiology Action to Take
Most often from cardiac CT scan may be normal source or vertebroearly. If possible basilar basilar atherosclerotic occlusion must be disease (basilar denitively excluded occlusion) with vascular study (TCD, MRA, or angiogram) Empirically, bolus with heparin if suspicion is high Bacterial, fungal, tuberculous, viral, carcinomatous, lymphomatous Most often from aneurysm or trauma. CT scan may be normal Dene cause and treat accordingly
Meningoencephalitis
Subarachnoid hemorrhage
CT scan can be normal. Requires lumbar puncture and CSF analysis for diagnosis Consult neurosurgery for management Care is usually supportive
Diffuse axonal injury
Most often from head trauma
CSF = cerebrospinal uid; CT = computed tomography; MRA = magnetic resonance angiography;TCD = median tissue culture dose.
CONCLUSION
Coma is often mysterious, frightening, and catastrophic. Because the anatomy of consciousness is relatively straightforward, the evaluation of coma should also be
60
straightforward. Consciousness comes from the cerebral cortex. Disruption of the cortex or the reticular activating system ascending from the brainstem is necessary to produce coma. With a brief neurologic examination, one should be able to differentiate between these two main mechanisms of coma: bihemispheric disease or brainstem disease. Brain imaging studies (CT scan or MRI) are needed to dene the exact cause within each category. Scans will be either abnormal with operable lesions, abnormal with nonoperable lesions, or normal. It is important to act quickly when stabilizing the patient, obtaining and acting on the scan, and continuing the evaluation until the exact cause has been identied and treatment started.
RECOMMENDED READINGS Fisher CM. The neurological examination of the comatose patient. Acta Neurol Scand Suppl 1969;356. Fisher CM. Acute brain herniationa revised concept. Semin Neurol 1984;4:41722. Fisher CM. Brain herniation: a revision of classical concepts. Can J Neurol Sci 1995;22:8391. Plum F, Posner JB. Diagnosis of stupor and coma. 3rd ed. Philadelphia: F. A. Davis Company; 1980.
61
CHAPTER 4
APPR OACH TO STATUS EPILEPTICUS

Michael De Georgia, MD, and John Andrefsky, MD
tatus epilepticus is a medical emergency that must be recognized and treated quickly to prevent brain injury and death. Status epilepticus is the extreme end of a spectrum of seizure durations and frequencies, and cumulative neuronal damage develops with increasing duration or frequency of seizure activity. By denition, however, a seizure lasting longer than 30 minutes or two or more seizures within 30 minutes without the patient regaining consciousness between seizures constitutes status epilepticus. Status epilepticus occurs most frequently in the very young and old.The annual incidence of status epilepticus is about 50 cases per 100,000 per year, with one-third of episodes occurring in patients with known epilepsy in which withdrawal of antiepileptic medication or poor compliance is the precipitating factor. Other causes include alcohol withdrawal, primary brain tumors, head injury, ischemic and hemorrhagic stroke, meningitis, encephalitis, and metabolic factors such as rapid and marked shifts in serum electrolyte concentrations.The following is a review of the clinical features of status epilepticus and a rational approach to this most feared type of seizure.
CLINICAL FEATURES
Generalized tonic-clonic status epilepticus is the most common and potentially damaging form. A generalized
62
A ppro a ch t o St a t us Epilept icus
tonic-clonic seizure starts with a tonic contraction of the limbs that lasts about 10 to 20 seconds (the tonic phase). The patient may violently arch the back and neck and scream as air is forced through the closed vocal cords.This is followed by repetitive relaxation of tone (the clonic phase). The clonic jerks gradually decrease in amplitude and frequency over several minutes.Autonomic activity is high, and patients are usually hypertensive and tachycardic. Electroencephalography (EEG) demonstrates bilaterally symmetric ictal discharges. Usually, a period of apnea then begins, ending with a deep inspiration and subsequent unconsciousness for minutes to hours (the postictal phase), followed by regaining of consciousness. Patients in status epilepticus either continue to convulse or have intermittent seizures without regaining consciousness between seizures. After about 20 to 30 minutes, electromechanical dissociation may occur, that is, continuous electrographic sezuires with few clinical manifestations except subtle lip or eyelid twitching (so-called nonconvulsive status epilepticus). During this phase, systemic acidosis may result in reduced cardiac output, hypotension, and reduced cerebral blood ow. Neuronal damage probably results from glutamate-mediated excitotoxicity and the additive effects of impaired cerebral perfusion, hypoxemia, hyperthermia, and acidosis. Distinguishing the patient who is postictal from the one who is in nonconvulsive status epilepticus can be difcult clinically. The previous convulsive activity may not have been witnessed, or only a brief seizure may have been seen. Difculty arises in the intensive care unit, where patients often have several reasons for altered conscious63
ness. A recent study showed that up to 10% of comatose patients in an intensive care unit have nonconvulsive status epilepticus.When there is uncertainty, an EEG should be done at the bedside. Other forms of status epilepticus include absence status, focal motor status, and complex partial status. The patient with absence status may be confused or somnolent, with continuous or intermittent spike and slow-wave discharges on EEG. The patient with focal motor status has continuous jerking of certain muscle groups (epilepsia partialis continua), whereas the patient with complex partial status often appears dazed and has automatisms (lip smacking, repetitive hand movements).
APPROACH TO THE PATIENT WITH GENERALIZED TONIC-CLONIC STATUS EPILEPTICUS General Management
Immediate intervention is crucial within the rst minutes after seizure onset.The rst priority is airway management because many patients develop airway obstruction or aspirate secretions (Figure 41). Airway obstruction can also worsen after antiepileptic medications are given (eg, benzodiazepines).The head should be positioned, the airway suctioned, and, if needed, an oral airway inserted. Oxygen should be administered by nasal cannula or face mask. Endotracheal intubation and mechanical ventilation should be done in patients without an adequate airway and those with no spontaneous respiration or ineffective respiration (shallow breathing).Two large-bore peripheral
64
Time 0
Patient is in status epilepticus
Does patient have an airway?
Yes No
Is patient breathing? Create an airway
Yes No
Does patient have adequate pulse and blood pressure? Begin rescue breathing (Ambu bag), intubate
No Stabilize
Draw blood for electrolytes, renal and liver function tests, anticonvulsant medication levels, toxicology screen. Start two peripheral IV lines or central line. Administer thiamine 12 mg/kg IV push, D W 1amp IV push 50
1 minute
65
Figure 4-1 The tonic phase. IV = intravenous.
intravenous lines should be inserted as soon as possible. In patients with tenuous venous access, a central venous catheter should be inserted (the femoral vein is the quickest and safest route).A medical history should be obtained if possible. Blood should be withdrawn for a complete blood count and measurement of serum glucose, sodium, calcium, magnesium, blood urea nitrogen, anticonvulsant medication levels, and a toxicology screen. Pulse oximetry or an arterial blood gas analysis should be done to ensure adequate oxygenation. If hypoglycemia is documented or suspected, intravenous glucose (50 mL of 50% glucose) should be given (preceded by intravenous thiamine 100 mg). All electrolyte abnormalities should be corrected cautiously, being careful not to overcorrect. For example, most patients with seizures develop metabolic acidosis. Bicarbonate should not be given, however, unless the pH is less than 7.0 because the risk of overcorrection and alkalosis may be greater than the risk of the acidosis itself. Patients should be adequately hydrated with normal saline because they often become dehydrated and there is a risk of rhabdomyolysis after vigorous muscle contraction. Patients with new-onset seizures should undergo computed tomographic scanning or magnetic resonance imaging. A cerebrospinal uid analysis to exclude meningitis or encephalitis should be done if no cause of status has been identied.
Specific Treatment Plan
There are an innite number of algorithms in the literature for treating status epilepticus. Sticking rigidly to one spe66
cic algorithm is less important than simply having a clear plan that one follows. Most patients with status epilepticus will respond to therapy with a single antiepileptic drug. The longer seizures persist, however, the more difcult they are to control. Benzodiazepines are the rst line of therapy. There is little difference in the effectiveness of seizure control between the benzodiazepines (lorazepam, diazepam, and midazolam). Lorazepam is started at a dose of 0.1 mg/kg and a rate of 2 mg per minute until seizures stop or a total dose of 10 mg is reached. Diazepam is usually started at a dose of 0.2 mg/kg at 4 mg per minute until seizures stop or a total dose of 20 mg is reached. Lorazepam is more lipid soluble than diazepam and has a smaller distribution phase, a slightly longer onset of action (2 to 3 minutes instead of 1 to 2 minutes), and a longer duration, on average 6 hours compared with less than an hour with diazepam (Table 4-1 and Figure 4-2). Benzodiazepines should be followed immediately with phenytoin or fosphenytoin given as a 20 mg/kg loading dose to achieve a total level greater than 25 to 30 mg/dL. The maximal rate of phenytoin delivery is 50 mg/min (25 mg/min in elderly patients). Intravenous phenytoin is limited by complications such as infusion-site reactions (phlebitis, tissue necrosis) and cardiovascular effects (hypotension, cardiac arrhythmias). If signicant hypotension develops, the infusion should be slowed or stopped. Fosphenytoin, a water-soluble prodrug of phenytoin written as phenytoin equivalents, can be safely administered by rapid intravenous infusion (up to 150 mg/min) or by intramuscular injection if there is no venous access.
67
68
Table 4-1 Antiepileptic Drugs for Status Epilepticus
Drug 824 h 2050 h 1.5 3.5 h 22 h (oral); 1015 h (IV) 1030 1224 h 15 15 h 95 9095 13 1560 min 95 23 212 h 90 1.3 0.82.6 0.86.6 0.60.7
Loading Dose IV (mg/kg) Rate Serum Halflife
Time to Stop Status (min) Not established 0.50.8 Not established 1020
TheraDurapeutic tion Protein Serum of Binding Vol level Action (%) (L/kg) ( g/mL)
Lorazepam (Ativan)
0.1
2 mg/ min
Diazepam (Valium)
0.2
4 mg/ min
Midazolam (Versed)
0.2
2 mg/ min
Phenytoin (Dilantin)
20
50 mg/ min
Continued
Table 4-1 (Continued)
Drug 1030 530 1020 0.5 10 h 0.510 h 2045 3555 1224 h 9095
Loading Dose IV (mg/kg) Rate Serum Halflife 0.60.7 0.5 1
Time to Stop Status (min) 1020 1040 2050
TheraDurapeutic tion Protein Serum of Binding VD level Action (%) (L/kg) ( g/mL)
Fosphenyoin (Cerebyx) 53 140 h 35 50 h 40 750 min 510
20
150 mg/ 1015 h min
Phenobarbital
20
100 mg/min
Pentobarbital (Nembutal)
510
0.5 3 mg/ kg/h
Propofol (Diprivan)
510 mg/ kg/h
Not 9799 established
60
Not established
69
IV = intravenous; Vol = volume dose.
70
Administer lorazepam 0.1 mg/kg IV at a rate of 2 mg/min (until seizures stop or maximum 10 mg).
If the precipitating cause is not known, patients should undergo a head CT; if bacterial meningitis is considered, lumbar puncture should be performed.
510 minutes
Administer phenytoin 20 mg/kg IV (rate mg/min).
Blood pressure should be closely monitored. If hypotension develops, provide bolus with IV fluids and decrease the rate of infusion.
15 minutes
Figure 4-2 The clonic phase. CT = computed tomography; IV = intravenous.
One of the most common mistakes made in the treatment of status epilepticus is administering repeated doses of benzodiazepines without treating the underlying precipitating cause or starting a longer-acting antiepileptic drug. Another common mistake is not giving enough phenytoin or fosphenytoin.The usual loading dose of 1 g of phenytoin is usually insufcient for seizure control. When seizure activity persists, another 5 to 10 mg/kg of phenytoin or fosphenytoin may be given.The next drug to use after that is controversial, and a neurologist, if not already involved, should be consulted. Many recommend phenobarbital given as a loading dose of 10 to 20 mg/kg at a maximal rate of 100 mg/min to achieve a level of 40 to 50 g/mL. Phenobarbital is often used instead of phenytoin in patients allergic to phenytoin and those with abnormal conduction patterns on electrocardiography. Several studies have shown intravenous midazolam, a short-acting benzodiazepine commonly used for sedation in intensive care units, to be effective. Midazolam is given as a loading dose of 0.15 mg/kg followed by an infusion of 0.05 to 4 mg/kg/h and is generally well tolerated. Recently, propofol, a very short-acting sedative agent, has also been shown to be effective. Propofol is given as a bolus of 2 mg/kg followed by an infusion of 5 to 10 mg/kg per hour (Figure 4-3). Many centers proceed directly to pentobarbital, given as a 5 to 10 mg/kg loading dose over an hour followed by a continuous infusion rate of 0.5 to 3 mg/kg per hour.The infusion rate should be adjusted to achieve a burst suppression pattern on bedside EEG (roughly aiming for 3 to 10 bursts per minute).The main side effects of pentobar71
72
30 minutes 45 minutes
If seizures continue, administer additional phenytoin 510 mg/kg PE IV. Obtain bedsde EEG.
If seizures continue, intubate patient (if not done already). Make sure that venous access is adequate and place arterial line.
Administer phenobarbital 20 mg/kg IV (rate 100 mg/min).
Blood pressure should be closely monitored. If hypotension develops, provide bolus with IV fluids and decrease the rate of infusion.
If hypotension does not improve with fluid challenge, begin vasopressor drips (dopamine 230 mg/kg/min or phenylephrine 20200 mg/min)
Bedside EEG should be hooked up and running.
Figure 4-3 The clonic jerks gradually decrease. EEG = electroencephalogram; IV = intravenous; PE = phenytoin equivalents.
If seizures continue, administer pentobarbital 515 mg/kg loading dose followed by continuous infusion rate 0.53 mg/kg per hour.
Increase infusion rate to achieve burst suppression pattern on EEG.
Monitor blood pressure continuously with arterial line. Treat hypotension with fluids, vasopressor agents, or both as indicated.
60 minutes
Maintain pentobarbital for 24 hours, then decrease dose gradually, observing for recurrent seizures. If necessary, increase dose again for another 24 hours.
Follow phenytoin and phenobarbital levels, maintaining them at high range.
Continue every 12 to 24 hours to wean pentobarbital, looking for underlying seizure activity.
During this phase, meticulous intensive care management is required including maintaining hemodynamic stability and adequate oxygenation and ventilation. Patients should receive prophylaxis against deep venous thrombosis and gastric ulcers. Pulmonary infections are common: patients should be suctioned frequently.
73
Figure 4-4 The postictal phase. EEG = electroencephalogram.
bital are respiratory and myocardial depression.All patients need to be intubated and mechanically ventilated. Patients should have central venous access and, ideally, an arterial catheter for continuous blood pressure monitoring. Intravascular volume should be maintained with intravenous uids. Vasopressor agents (dopamine or phenylephrine) are almost always required in patients in burst suppression with pentobarbital (Figure 44).
CONCLUSION
The clinical outcome of status epilepticus largely depends on the underlying cause of seizures. Prompt and appropriate treatment, however, signicantly reduces mortality and morbidity. Therapeutic and diagnostic measures are done simultaneously to stop the seizure as quickly as possible. Most importantly, a predetermined specic treatment plan is needed.
RECOMMENDED READINGS DeLorenzo RJ, Pellock JM, Toen AR, Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol 1995;12:31625. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:4838. Meldrum B. Metabolic factors during prolonged seizures and their relation to nerve cell death. Adv Neurol 1983;34: 26175. Meldrum B. Excitotoxicity and epileptic brain damage. Epilepsy Res 1991;10:5561. Parent JM, Lowenstein DH.Treatment of refractory generalized status epilepticus with continuous infusion of midazolam.
74
Neurology 1994; 183740. Proposal for revised clinical and electroencephalographic classication of epileptic seizures: from the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:498501. Treiman DM, Meyers PD,Walton NY, et al.A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998;339:7928.
75
CHAPTER 5
SPINAL CORD EMER GENCY CONDITIONS

Rober t M. Herndon, MD
cute and rapidly progressive lesions of the spinal cord constitute a medical emergency. Failure to recognize and rapidly treat lesions compressing the spinal cord often leads to permanent paralysis and, especially in the case of cervical injuries, death. The signs and symptoms of cord compression, whether by trauma, tumor, or abscess, consist of (1) pain localized to the area of cord involvement or in a root distribution related to the level of involvement, (2) limb weakness at and below the level of the lesion, (3) paresthesias in the distribution of a nerve root, and (4) bladder and bowel dysfunction.
CORD TRAUMA
The occurrence of cord trauma is often hidden because cord trauma is only part of multiple injuries in 75 to 80% of cases. Persons with head injury and persons with multiple trauma from motor vehicle accidents or falls frequently also sustain neck or other spine trauma, and unless precautions are made to prevent movement of the spine until it is clear that the spine is intact, further serious cord damage may occur.1 Persons involved in motor vehicle accidents who are dazed or unconscious should have their neck and spine immobilized if possible before they are moved, and immobilization should be maintained until it is established that major spine injury has
76
Spinal Cord Emergency Condi t ions
not occurred. Over half of spine injuries are cervical, and because these are the most serious, special attention to this region is important. Spine immobilization procedures are taught to paramedics, and this has resulted in a very signicant decrease in the number of cases in which further cord injury has been done following an accident. Most cervical fractures in the young and middle-aged are in the mid to lower cervical spine; however, in those over 70 years who fall and fracture the cervical spine, the majority are high cervical or odontoid in location.2 Most cervical fractures are visible on cervical radiographs, but, if in doubt, computed tomography (CT) will usually show them. Magnetic resonance imaging (MRI) is good for showing cord damage but is relatively poor for showing damage to the vertebrae.3 High cervical cord and craniocervical junction injuries are particularly dangerous because they often result in respiratory paralysis. Even small movements of the neck when facing a high cervical or odontoid fracture can lead to respiratory arrest. Remember that C3, 4, and 5 keep the diaphragm alive, and, of course, the intercostal muscles are supplied by the thoracic cord, so high cervical cord injury leads not only to quadriplegia but also to respiratory failure. Intubation and management of respiratory collapse in patients with fractured spines must be in the hands of very experienced anesthesiologists and should not be undertaken by the novice. It is possible to maintain respiration with an Ambu bag until competent qualied personnel take over. In lower cervical cord injury, proximal arm function may remain. Lesions in the thoracic or upper lumbar cord
77
lead to paralysis below the level of the lesion and rarely cause respiratory problems, although high thoracic lesions can result in reduced pulmonary capacity owing to intercostal muscle paralysis. Hemisection of the cord leading to Brown-Squards syndrome (Figure 5-1) can occur with cord trauma owing to stab wounds or gunshot wounds and occasionally owing to rotational fractures of the cervical spine. This results in weakness or paralysis and loss of position and vibration ipsilateral to the lesion and loss of pinprick and touch on the opposite side beginning two to three segments below the level of injury. This is because the pain bers cross just anterior to the central canal one to three segments above the point of entry to ascend in the ventrolateral cord on the opposite side. Anterior spinal artery occlusion is only rarely directly related to trauma. It occurs more commonly owing to thrombosis of the great radicular artery of Adamkiewicz and may be seen following aortic surgery. This leads to infarction of the anterior two-thirds of the spinal cord with paraplegia and loss of pain and temperature sensation with preservation of position and vibration below the lesion. In cases of spinal cord injury, if the patient is conscious, in most cases, a pinprick sensory level will provide fairly accurate information regarding the level of the injury. In some cases, particularly with inammatory and chronic cord lesions, the sensory level may simply set a lower limit on the area of involvement, but in trauma, local root involvement will usually indicate the level of the lesion quite accurately. If you nd a sensory level, the
78
Figure 5-1 Example of Brown-Squards syndrome from hemisection of the left side of the spinal cord at about T9. Hatch marks indicate an area of pain and temperature loss; crosshatch indicates an area of upper motoneuron paralysis and proprioceptive loss.
79
lesion will be at or above that level. It is important to realize that the pain bers cross to the other side just ventral to the central canal within about three segments from their point of dorsal root entry. It is also important to remember that the vertebral level and the cord level are not the same in the lower thoracic and lumbar regions because the cord ends at about L2.Thus, lesions below this level compress the cauda equina, not the cord itself, and lesions at T12 and L1 will injure the lowermost segments of the lumbar cord. Traumatic spinal injury is treatable, and with proper management, considerable improvement can be expected. Rapid stabilization of the neck or back with rapid surgical decompression when indicated will minimize the longterm disability. Currently the standard of care, Methylprednisolone, at a dose of 30 mg/kg as a bolus followed by an infusion at 4 mg/kg/h for 23 hours, has been recommended4 but is somewhat controversial.5
TUMORS AND METASTASES AFFECTING THE SPINAL CORD
With the increasing longevity of patients with malignancies, the incidence of spread of tumor to involve vertebrae and the spinal canal has increased. Signs and symptoms of spinal metastases are easy to miss in cancer patients with generalized weakness and diffuse pain.The occurrence of new spinal or neck pain in these patients, which persists even while lying down, even if relieved by analgesics, deserves investigation. If the patient develops limb weakness, bowel or bladder incontinence, or paresthesias in a
80
nerve root distribution, it is an oncologic emergency. Depending on the level of the lesion, such patients can become paraplegic or quadriplegic extremely rapidly. Physical examination, plain lms of the spine that will show lytic or blastic lesions in vertebrae, and an MRI directed to the spinal level found by clinical examination or on the plain lms will lead to denition of the lesion. If MRI is unavailable, CT will usually dene the lesion. CT myelography and lumbar puncture should be avoided because they can greatly aggravate the injury by removing the protection provided by the cerebrospinal uid pressure, which helps protect the cord from compression and spinal cord herniation (Table 5-1).6 In most cases, rapid institution of radiotherapy at the time of discovery of the lesion will shrink the lesion and preserve cord function. If the patient worsens after radiation therapy or the tumor is radioresistant, surgical decompression is indicated.This is urgent because failure of radiation to decompress the cord can lead to major permanent decits. Of those patients who are diagnosed and appropriately treated while still ambulatory, 94% remain ambulatory until terminally conned. Primary extramedullary tumors involving the cord present with signs and symptoms essentially the same as those with metastases, except the onset is usually much less dramatic and may occur over many months or years. Pain that is unrelieved by lying down and radicular pain are very common complaints. Table 5-2 lists the most common primary extramedullary tumors affecting the cord. It should be evident that a diagnosis or family history of neurobromatosis should provide a high index of sus81
Table 5-1 Frequency of Metastatic Tumors Compressing the Spinal Cord Tumor Carcinoma of the breast Carcinoma of the lung Lymphoma Sarcoma Carcinoma of the prostate Hypernephroma Carcinomas of the gastrointestinal tract Multiple myeloma Unknown primary Miscellaneous
Adapted from Schutta H.6
% 25.5 22.4 7.8 7.5 7.2 6.8 5.0 4.4 7.8 5.6
picion for neurobroma as the source when there is evidence of cord compression.
INTRAMEDULLARY CORD TUMORS
Primary intramedullary cord tumors often extend over many segments. If the tumor is conned to a few segments, the symptoms will usually be similar to those of
82
Table 5-2 Most Common Primar y Extramedullar y Tumors Affecting the Spinal Cord Tumor Neurobroma and schwannoma Meningioma Ependymoma Miscellaneous Astrocytoma Metastatic and other
Adapted from Schutta H.6
% 29 26 13 12 7 13
extramedullary tumors except that they may be painless. The more common presentation is with a mixed sensory loss. Pain may be a symptom if there is root entry zone involvement, but many are painless. Intramedullary metastases to the spinal cord can occur but are rare.They present like primary intramedullary tumors but usually progress more rapidly and are much rarer than extramedullary metastases. Involvement of the pain bers that cross just anterior to the central canal will often give pain and temperature loss over several segments similar to that seen in syringomyelia.As the tumor expands, the long motor and sensory tracts may become involved, but the dorsal column sensory bers from the sacral area are very peripheral in the cord and are often spared.This so-called
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sacral sparing is a good indication of an intramedullary cord lesion. Syringomyelia, which is a uid-lled cavity generally found in the cervical cord, behaves in a manner very similar to intramedullary tumors, with loss of pain and temperature in the upper extremities, muscle wasting, usually in the intrinsic hand muscles, and reex asymmetry and loss. Intramedullary metastases, usually from lung or breast carcinoma in advanced stages, behave like primary intramedullary tumors except that they tend to grow much faster. The prognosis for most intramedullary cord tumors is poor.They are generally not amenable to surgical therapy and usually are relatively resistant to radiation and chemotherapy. In the case of metastatic disease, they may be relatively radiosensitive, but the majority of such patients have multiple metastases, and the survival rate is poor. Nevertheless, radiation may preserve function long enough to be worthwhile in some cases.
INFLAMMATORY AND INFECTIOUS DISORDERS OF THE SPINAL CORD
Transverse myelopathy (transverse myelitis) is an inammatory demyelinating condition of the spinal cord. It may be either painful or painless and typically involves two to ve cord segments, although much longer regions of involvement can occur.There are multiple etiologies. Many cases of multiple sclerosis begin with a transverse myelitis. It also can be seen as a manifestation of a systemic disease, such as lupus erythematosus. It is marked by weakness and sensory loss below the level of the lesion, usually with a clear sensory
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level to pinprick.The lesion may be partial or complete. It is typically fairly symmetric and usually evolves over a period of a few hours to a few days, although, in rare cases, it can progress slowly for a week or two. Cerebrospinal uid examination may reveal an increase in white cells, predominantly lymphocytes, and there may be an increase in protein or gammaglobulin G. Rarely, cord swelling will be so severe that a cerebrospinal uid block will occur and the cerebrospinal uid protein will be very high. In such cases, cord necrosis from compromise of the blood supply secondary to compression may be seen. An MRI of the spine will show a high signal on T2-weighted images usually extending over several segments.Treatment with high-dose steroids, such as 1 g of methylprednisolone daily for 3 to 10 days, is warranted. Additionally, a search for underlying systemic disease is indicated.Transverse myelopathy is generally seen in the second to fth decades and is rare in children and older adults. Epidural and paraspinal abscesses extending into the epidural space are rare but, if not recognized and treated, can cause cord compression or infarction and will often result in paraplegia or quadriplegia.7,8 Paraspinal abscesses may be acute or chronic.They are usually seen on a background of chronic illness with impaired immunity or following surgery, epidural anesthesia, or epidural catheter placement for analgesia.9 Causes of impaired immunity include human immunodeciency virus (HIV) infection, diabetes, chronic leukemias, lupus, and alcoholism. Epidural abscesses are more common in the thoracic and lumbar spine than in the cervical spine. They typically present as severe localized spinal pain requiring narcotics
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for pain control, and, initially, this may be the only indication of the presence of an abscess.The source of infection may be an abscess elsewhere, including dental abscess, osteomyelitis, decubitus ulcer, or skin infection. Paraspinal abscesses can occur at any age. They are marked by back pain, fever, malaise, neck stiffness, and headache accompanied or followed by radicular pain. There is usually local tenderness over the spine. Neurologic signs are similar to those seen with extradural tumors.The cerebrospinal uid is cloudy and may be xanthochromic with increased white cells, usually a mixture of polymorphonuclear leukocytes and lymphocytes, but the sugar content is normal. The protein may be elevated. CT or MRI will reveal the lesion, although the full extent of involvement is best seen on contrasted MRI.10 Prompt recognition and treatment are essential if permanent paralysis, which can occur abruptly and without warning, is to be avoided.The mortality rate is about 30% in acute cases, but with prompt recognition and treatment before paraplegia has occurred, excellent recovery is possible. Surgical decompression should be carried out as soon as possible because neurologic decits can occur very rapidly and may lead to permanent decits. Chronic paraspinal abscess is usually due to tuberculosis, although cases of fungal paraspinal abscesses are rarely reported.They typically begin with a dull ache in the back that resembles the pain of disk disease.The pain gradually increases in intensity. The initial infection is often in the disk space, which accounts for the pain. It spreads along the ligaments and often extends over two or three segments. Diagnosis can be difcult, although the abscess will
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usually show on a spinal MRI. Contrast enhancement often provides additional information.10,11 If the abscess is untreated, vertebral collapse with gibbus formation frequently occurs.Treatment is with antibiotics and surgical decompression.
REFERENCES 1. Anderson S, Biros MH, Reardon RF. Delayed diagnosis of thoracolumbar fractures in multiple-trauma patients. Acad Emerg Med 1996;3:8329. 2. Ryan MD, Henderson JJ.The epidemiology of fractures and fracture-dislocations of the cervical spine. Injury 1992;23: 3840. 3. Klein, GR,Vaccaro AR,Albert TJ, et al. Efcacy of magnetic resonance imaging in the evaluation of posterior cervical spine fractures. Spine 1999;24:7714. 4. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. N Engl J Med 1990; 322:140511. 5. Hugenholtz H, Cass DE, Dvorak MF, et al. High-dose methylprednisolone for acute closed spinal injuryonly a treatment option. Can J Neurol Sci 2002;29:22735. 6. Schutta H. Spinal tumors. In: Joynt RJ, Griggs RC, editors. Bakers clinical neurology. Philadelphia: Lippincott Williams and Wilkins; 1998. p. 1750. 7. Schutta H. Diseases of the dura mater. In: Joynt RJ, Griggs RC, editors. Bakers clinical neurology. Philadelphia: J. B. Lippincott Co.; 1994. p. 1137. 8. Baker AS, Ojemann RG, Swartz MN, Richardson EP. Spinal epidural abscess. N Engl J Med 1975;293:4638.
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9. Wang LP, Hauerbert J, Schmidt JF. Incidence of spinal epidural abscess after epidural analgeisa. Anesthesiology 1999;91:192836. 10. Sadato N, Numaguchi Y, Ragamonti D, et al. Spinal epidural abscess with gadolinium enhanced MRI: serial follow-up studies and clinical correlations. Neuroradiology 1994;36: 448. 11. Fam AG, Rubenstein J. Another look at spinal tuberculosis. J Rheumatol 1993;20:173140.
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CHAPTER 6
RE SPIRATORY FAILURE DUE TO NEUR O MUSCULAR DISEASE

Rober t M. Pascuzzi, MD
euromuscular disorders may produce life-threatening weakness of the diaphragm (resulting in hypoventilation) or weakness of the oropharyngeal and upper airway muscles (leading to aspiration or obstruction). Patients with known or previously undiscovered neurologic disease may present with respiratory failure as a logical sequel of a chronic progressive neuromuscular condition such as amyotrophic lateral sclerosis (ALS) or muscular dystrophy. In addition, patients with acute or subacute acquired disorders may present to the emergency department with respiratory failure as an early or presenting manifestation (without an established diagnosis), as in the case of GuillainBarr syndrome (GBS), botulism, and some patients with myasthenia gravis (MG). Ventilatory performance depends on three factors: inspiratory effort, expiratory effort, and airway patency. Mainly the chest wall muscles and the diaphragm drive inspiratory effort. The abdominal muscles are important for expiratory function, including cough. Poor expiratory function is often overlooked as a feature of neuromuscular weakness. A weak cough leads to a failure to clear secretions, aspiration, mucus plugging, and pneumonia. Muscles of the upper airway, including those of the mouth, tongue, palate, and larynx, largely maintain airway patency. These structures affect airway resistance and air89
ow and are critical for effective pulmonary function. Combined weakness of inspiratory and expiratory effort and of the upper airway muscles leads to a critical spiral of decreasing respiratory function.
GENERAL ISSUES REGARDING NEUROMUSCULAR RESPIRATORY FAILURE Respiratory Muscle Weakness and Fatigue
Respiratory muscle weakness and fatigue are frequent contributors to ventilatory failure in the patient with neuromuscular disease. Progressive muscle weakness and fatigue lead to low lung volume, hypoventilation, hypercarbia, and, ultimately, hypoxemia. Life-threatening respiratory failure usually occurs when pulmonary function drops below 30% of predicted values.
Patient Evaluation
Symptoms of neuromuscular respiratory failure may be straightforward, with patients complaining of subjective dyspnea and shortness of breath. On the other hand, the patients symptoms may be more nonspecic, such as restlessness, inability to sleep, and altered mental status (from hypoxemia or hypercarbia). Sleep is an important factor in patients with neuromuscular respiratory insufficiency. Patients with diaphragm weakness have better pulmonary function when awake and sitting upright, ostensibly because gravity works to enhance downward movement of the diaphragm dur90
Respirat or y Failure due t o Neuromus cular Dis eas e
ing inspiration.When lying at, hypoventilation increases in severity, leading to hypercarbia and hypoxemia. In addition, if the patient has a degree of upper airway obstruction or oropharyngeal weakness leading to aspiration, respiratory status and pulmonary function are most severely compromised during sleep. Therefore, patients with chronic or subacute respiratory failure may describe symptoms consistent with nocturnal or sleep-associated hypoventilation, including headaches on awakening (owing to high carbon dioxide partial pressure [PCO2]), daytime fatigue, and daytime sleepiness. Patients who have signicant weakness of oropharyngeal muscles may complain chiey of intermittent choking or difculty clearing secretions from the throat or may present with a history of new or recurrent aspiration pneumonia.
Examination
The experienced clinician will recognize the presence of bifacial, tongue, and palatal weakness in patients with oropharyngeal weakness.The speech may be slurred and, when the palate is weak, may have a nasal quality sounding like someone talking with a cleft palate. Dysphonia (raspy voice) may present from an abrupt onset of cough owing to weakness of the epiglottis. Look for the use of accessory muscles and the presence of tachycardia as other helpful signs to indicate respiratory insufciency.
Assessing Diaphragm Function at the Bedside Asking the patient to provide a vigorous sudden sniff will give the clinician a sense of diaphragm power.
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Cough
Asking the patient to take a huge breath and cough can lead to impressive and, at times, unexpected insight into the severity of a patients neuromuscular respiratory function.A very weak cough should alert the clinician that the patient is at high risk for rapid respiratory decompensation.
Observe for Paradoxical Abdominal Wall Movement
Normally, with inspiration as the diaphragm contracts, the abdomen is forced down, leading to protrusion of the belly. In severe diaphragm weakness, inspiration may be more dependent on the intercostal and accessory muscles, in which case, the weak diaphragm muscle may be drawn up into the chest with inspiration, leading to a sunken or scaphoid appearance to the abdomen.The astute clinician will watch the abdominal wall movement with inspiration. If the movement is inward, then one should conclude that there is severe diaphragm muscle weakness.
Counting Test
At the bedside, ask the patient to take a huge breath and to begin to count aloud. Determine how high the patient can count in one breath. If the patient can count to 10 in one breath, he or she has a forced vital capacity (FVC) of about 1,000 mL; if the patient can count to 25, the FVC can be estimated to be about 2,000 mL.
Spirometry FVC and peak inspiratory pressure are readily available measures in most medical facilities. Occasionally, patients will demonstrate stable or adequate function by these tests, but during nighttime sleep, they will have
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more profound hypoventilation. Such patients may require nighttime oximetry to detect serious hypoventilation. FVC is a readily obtainable measure of pulmonary function that reects clinically important respiratory muscle weakness.When the FVC falls below 15 to 20 mL/kg, respiratory failure will follow. In an average-sized adult, 15 to 20 mL/kg equals about 1,000 mL. Peak inspiratory force less than 25 cm H2O is typically associated with precarious respiratory function and impending respiratory failure. In the acute setting, the FVC should be monitored at least every 4 hours and perhaps more often if the FVC drops below 20 mL/kg.
Arterial Blood Gas
Arterial blood gas changes tend to occur relatively late in the course of respiratory failure owing to neuromuscular weakness and therefore are not the optimal tool for monitoring the patient.Thus, arterial blood gas analysis is not a particularly good measure to follow in the patient with progressive respiratory failure. Similarly, oxygen saturation falls late only in neuromuscular respiratory failure and is an insensitive measure in the acute setting. Every time you do an arterial blood gas analysis, you wake the patient up and do a painful stick that stimulates respiration and gives a falsely elevated pulmonary function test, as reected in the blood gases.
When Should You Intubate?
You should begin invasive/mechanical ventilation in the following cases:

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1. In the patient with acute or subacute weakness, when the FVC is < 15 mL/kg (about 1,000 mL in the averagesized adult) 2. Poorly protected airway (oropharyngeal weakness): the patient cannot handle oral secretions (choking); intermittent aspiration; upper airway obstruction 3. Signicant hypoxemia 4. If the patient just looks bad or appears to be struggling to breathe, it is best to intubate. In general, it is best to have a low threshold for hospitalization, for placement in the intensive care unit (ICU), and for the use of ventilatory support, whether it is noninvasive or endotracheal intubation with mechanical ventilation 5. The bottom line: when in doubt, intubate the patient! 6. The top priority: when evaluating any patient with respiratory failure, including those with neuromuscular disorders, it is imperative to secure the patients respiratory status as the top priority. Intubate the patient, protect the airway, and provide adequate supportive mechanical ventilation, and once the respiratory status is secure, then focus on clarication of the underlying diagnosis and precipitating factors
Precipitating Factors
Neuromuscular patients often have acute precipitating factors that lead to respiratory failure. Upper airway obstruction and acute aspiration should be suspected in patients with bulbar dysfunction (as is common in ALS and in MG). Bronchiolar mucus plugging and atelectasis commonly develop in patients with poor diaphragm function
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and can lead to pneumonia. Patients with paralytic disorders are at increased risk of developing aspiration and are also prone to deep vein thrombosis with pulmonary emboli. Both scenarios are important to consider in the neuromuscular patient who has undergone acute respiratory decline. Patients with MG may decompensate in the setting of a superimposed infection or the use of a new medication. Often identication and treatment of the precipitating factor are crucial to a successful outcome.Additionally, metabolic and electrolyte abnormalities, such as hypophosphatemia and hypokalemia, as well as hyperglycemia, may exacerbate muscle weakness and precipitate respiratory dysfunction.
CLINICAL PATTERNS OF NEUROMUSCULAR CONDITIONS THAT MAY PRESENT WITH RESPIRATORY FAILURE Myasthenia Gravis
MG is an autoimmune disorder of neuromuscular transmission in which there are autoantibodies that are directed against the nicotinic acetylcholine (ACh) receptor (AChR). AChR antibodies are detectable in the serum of 80 to 90% of patients with MG.The prevalence of MG is about 1 in 10,000 people.Women are affected about twice as often as men. Symptoms may begin at virtually any age, with a peak in women in the second and third decades, whereas the peak in men occurs in the fth and sixth decades. Autoimmune diseases such as rheumatoid arthritis, lupus, and pernicious anemia are present in about 5% of
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patients. Thyroid disease occurs in about 10%, often in association with antithyroid antibodies. About 10 to 15% of patients with MG have a thymoma, whereas thymic lymphoid hyperplasia with a proliferation of germinal centers occurs in 50 to 70% of cases. In most patients, the cause of autoimmune MG is unknown. However, there are three iatrogenic causes of autoimmune MG: D-penicillamine (used in the treatment of Wilsons disease and rheumatoid arthritis), interferon- therapy, and bone marrow transplantation, which can, in some patients, be the cause of MG.
Clinical Features
The hallmark of MG is uctuating or fatigable weakness. The presenting symptoms are ocular in half of all patients (25% of patients initially present with diplopia, 25% with ptosis); within 1 month into the course of the illness, 80% of patients have some degree of ocular involvement. Presenting symptoms are bulbar (dysarthria or dysphagia) in 10%, leg weakness in 10%, and generalized weakness in 10%. Respiratory failure is the presenting symptom in 1% of cases. Patients usually complain of symptoms from focal muscle dysfunction such as diplopia, ptosis, dysarthria, dysphagia, inability to work with arms raised over the head, or disturbance of gait. In contrast, patients with MG tend not to complain of generalized weakness, generalized fatigue, sleepiness, or muscle pain. In the classic patient, uctuating weakness is worse with exercise and improved with rest. Symptoms tend to progress later in the day. Many different factors can precipitate or aggravate weakness, such as
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physical stress, emotional stress, infection, or exposure to medications that impair neuromuscular transmission.
Indications for Hospitalization Patients with severe MG can deteriorate rapidly over a period of hours.Therefore, patients with dyspnea should be hospitalized immediately in a constant observation or ICU setting. Patients with moderate or severe dysphagia, weight loss, and rapidly progressive or severe weakness should be admitted urgently. This will allow close monitoring and early intervention in the case of respiratory failure and will also expedite the diagnostic work-up and initiation of therapy. Diagnostic Conrmation of MG The diagnosis is based on a history of uctuating weakness with corroborating ndings on examination.There are several different ways to validate or conrm the diagnosis. Edrophonium Test (Tensilon Test)
To perform the test, one or two clearly clinically weak muscles must be selected for monitoring. Eyelid ptosis, dysconjugate gaze, and other cranial decits provide the most reliable end points.The test should be administered in a clinical setting in which hypotension, syncope, or respiratory failure can be managed because occasional patients decompensate during the test. In patients with severe dyspnea, the test should not be performed until the airway is secure. An intravenous line should be placed.Atropine 0.4 mg should be readily available in the event of bradycardia or extreme gastrointestinal side effects. Edrophonium 10 mg (1 mL) is
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drawn up in a syringe, and 1 mg (0.1 mL) should be given as a test dose while checking the patients heart rate for bradycardia (to ensure that the patient is not supersensitive to the drug). If no adverse side effects occur after 1 minute, another 3 mg is given. Many patients with MG will show improved power within 30 to 60 seconds of giving the initial 4 mg, at which point, the test can be stopped. If after 1 minute there is no improvement, an additional 3 mg is injected; if there is still no response, 1 minute later the nal 3 mg is administered. If the patient develops muscarinic symptoms or signs at any time during the test (sweating, salivation, gastrointestinal symptoms), one can assume that sufcient edrophonium has been provided to see improvement in strength, and the test can be stopped.When a placebo effect or examiner bias is of concern, the test should be performed in a doubleblind, placebo-controlled fashion. The 1.0 mL control syringe may contain saline, 0.4 mg atropine, or 10 mg nicotinic acid.When improvement occurs, it typically lasts for about 5 minutes and then quickly abates. When improvement is clear-cut, then the test is positive. If the improvement is borderline, it is best to consider the test negative. In some patients, the edrophonium test should be repeated because the response may be inconsistent. The sensitivity of the edrophonium test is estimated as 80 to 90%. The specicity is difcult to determine because improvement following intravenous edrophonium has been reported in other neuromuscular diseases, including Lambert-Eaton syndrome, botulism, GBS, and motoneuron disease (including ALS), and in some patients with neoplasm or aneurysm affecting the cranial nerves.
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Caveat: Some patients with MG with severe bulbar or respiratory weakness may decompensate during or immediately following the test.The test should be performed in a setting in which the patients respiratory status is secure. Overall, AChR binding antibodies are present in about 80% of all myasthenic patients (50% of patients with pure ocular MG, 80% of those with mild generalized MG, 90% of patients with moderate to severe generalized MG, and 70% of those in clinical remission). The level of AChR antibodies does not predict the severity or clinical course of the patient.
Serologic Testing Electrophysiologic Testing Using electromyography (EMG), repetitive stimulation testing of the limb muscles is widely available and has variable sensitivity depending on the number and selection of muscles studied and various provocative maneuvers. In general, about 50% of patients with MG will have a decrement to repetitive stimulation. If there is weakness of the muscles undergoing study, the sensitivity is higher. A minority of patients with pure ocular or slight generalized weakness have a decrement to repetitive stimulation. Single-ber electromyography (SFEMG) is a highly specialized technique, usually available in major academic centers, with a sensitivity of about 90%.Abnormal singleber results are common in other neuromuscular diseases; therefore, the test must be used in the correct clinical context. The specicity of SFEMG is an important issue in that mild abnormalities can clearly be present with a variety of other diseases of the motor unit, including
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motoneuron disease, peripheral neuropathy, and myopathy. Disorders of neuromuscular transmission other than MG can have substantial abnormalities on SFEMG. In contrast,AChR antibodies are not present in patients without MG. In summary, the two highly sensitive laboratory studies are SFEMG and receptor antibodies; nonetheless, neither test is 100% sensitive.
Treatment First-Line Therapy: Cholinesterase Inhibitors
Cholinesterase inhibitors (CEIs) are generally safe and effective and represent rst-line therapy in all patients. Inhibition of acetylcholinesterase reduces the hydrolysis of ACh, increasing the accumulation of ACh at the postsynaptic membrane. The CEIs used in MG bind reversibly (as opposed to organophosphate CEIs, which bind irreversibly) to acetylcholinesterase. These drugs cross the blood-brain barrier poorly and tend not to cause central nervous system side effects. Absorption from the gastrointestinal tract tends to be inefcient and variable, with oral bioavailability of about 10%. Muscarinic autonomic side effects of gastrointestinal cramping, diarrhea, salivation, lacrimation, and diaphoresis may occur with any of the CEI preparations. Parenteral CEI can occasionally lead to bradycardia. A feared potential complication of excessive CEI use is skeletal muscle weakness (cholinergic weakness). Patients receiving parenteral CEI are at the greatest risk of cholinergic weakness. It is uncommon for patients receiving oral CEI to develop signicant cholinergic weakness even while experiencing muscarinic cholinergic side effects.
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Pyridostigmine (Mestinon) is the most widely used CEI for long-term oral therapy. Onset of effect is within 15 to 30 minutes of an oral dose, with peak effect within 1 to 2 hours and wearing off gradually at 3 to 4 hours postdose. The starting dose is 30 to 60 mg three to four times per day depending on symptoms. Optimal benet usually occurs with a dose of 60 mg every 4 hours. Muscarinic cholinergic side effects are common with larger doses. Some patients require and tolerate over 1,000 mg per day, dosing as frequently as every 2 to 3 hours. Patients with signicant bulbar weakness will often time their dose about 1 hour before meals to maximize chewing and swallowing. Of all of the CEI preparations, pyridostigmine has the fewest muscarinic side effects. Pyridostigmine may be used in a number of alternative forms to the 60 mg tablet. The syrup may be necessary for children or for patients with difculty swallowing pills. Sustained-release pyridostigmine 180 mg (Mestinon Timespan) is sometimes preferred for nighttime use. Unpredictable release and absorption limit its use. Patients with severe dysphagia or those undergoing surgical procedures may need parenteral CEI. Intravenous pyridostigmine should be given at about one-thirtieth of the oral dose. For patients with intolerable muscarinic side effects at CEI doses required for optimal power, a concomitant anticholinergic drug such as atropine sulfate (0.40.5 mg orally) or glycopyrrolate (Robinul 1 mg orally) on an as needed basis or with each dose of CEI may be helpful. Patients with mild disease can often be managed adequately with CEIs. However, patients with moderate, severe, or progressive disease will
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usually require more effective therapy. Cholinergic weakness (cholinergic crisis) is uncommon with oral drug use but more likely when parenteral CEIs are used.
Corticosteroids
For patients with severe MG, it is best to begin with high-dose daily therapy of 60 to 80 mg/d orally. Early exacerbation occurs in about half of patients, usually within the rst few days of therapy and typically lasting 3 or 4 days. In 10% of patients, the exacerbation is severe, requiring mechanical ventilation or a feeding tube (thus the need to initiate therapy in the hospital). Overall, about 80% of patients show a favorable response to corticosteroids (with 30% attaining remission and 50% marked improvement). Mild to moderate improvement occurs in 15%, and 5% have no response. Improvement begins as early as 12 hours and as late as 60 days after beginning prednisone, but, usually, the patient begins to improve within the rst week or two. Improvement is gradual, with marked improvement occurring at a mean of 3 months and maximal improvement at a mean of 9 months. Of those patients with a favorable response, most maintain their improvement with gradual dosage reduction at a rate of 10 mg every 1 to 2 months. More rapid reduction is usually associated with a are-up of myasthenic weakness. Although many patients can eventually be weaned off corticosteroids and maintain their response, the majority cannot. Such patients usually require a minimum dose (5 to 30 mg alternate day) to maintain their improvement. Complications of long-term high-dose prednisone therapy are substantial, including weight gain, swelling, hyper-
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tension, diabetes, osteoporosis, and cataracts, just to name a few. Alternative immunosuppressive drug therapy is commonly used in severe or refractory patients, but most drugs, including azathioprine, mycophenolate mofetil, and cyclosporine, require several months of therapy before clinical improvement is expected.
Plasma Exchange Plasma exchange (plasmapheresis) removes AChR antibodies and results in rapid clinical improvement. The standard course involves removal of 2 to 3 L of plasma every other day or three times per week until the patient improves (usually a total of ve or six exchanges). Improvement begins after the first few exchanges and reaches its maximum within 2 to 3 weeks. The improvement is moderate to marked in nearly all patients but usually wears off after 4 to 8 weeks owing to the reaccumulation of pathogenic antibodies. High-Dose Intravenous Immunoglobulin High-dose intravenous immunoglobulin (IVIg) administration is associated with rapid improvement in MG symptoms. The mechanism is unclear but may relate to down-regulation of AChR antibody production or to the effect of antiidiotype antibodies. The usual protocol is 2 g/kg spread out over 5 consecutive days (0.4 g/kg/d). Different IVIg preparations are administered intravenously at different rates (contact the pharmacy for guidelines).The majority of patients with MG improve, usually within 1 week of starting IVIg. The degree of response is variable, and the
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duration of response is limited, like plasma exchange, to about 4 to 8 weeks.

Drugs to Avoid in MG
Avoid using botulinum toxin, D-penicillamine, interferon- , chloroquine, quinine, quinidine, and procainamide. Aminoglycoside antibiotics should be avoided unless needed for a life-threatening infection. Neuromuscular blocking drugs such as pancuronium and vecuronium can produce marked and prolonged paralysis in patients with MG. Depolarizing drugs such as succinylcholine can also have a prolonged effect and should be used by a skilled anesthesiologist who is well aware of the patients MG. Iodinated intravenous contrast is occasionally associated with exacerbation of MG and should be avoided unless absolutely necessary.
Myasthenic Crisis
Myasthenic crisis (Table 6-1) is a medical emergency characterized by respiratory failure from diaphragm weakness or severe oropharyngeal weakness leading to aspiration. Crisis can occur in the setting of surgery (postoperatively), with acute infection, or following rapid withdrawal of corticosteroids (although some patients have no precipitating factors). In some patients, the use of a new medication may precipitate crisis (Table 6-2). Patients should be placed in an ICU setting and have FVC and forced expiratory volume at 1 second checked every 2 hours. Changes in arterial blood gases occur relatively late in neuromuscular respiratory failure. There should be a low threshold for intubation and mechanical ventilation. Criteria for intubation include a drop in the FVC below 15 mL/kg, severe aspiration from oropharyn-
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Table 6-1 Acutely Deteriorating Myasthenic Patients Myasthenic crisis Respiratory distress Respiratory arrest Cyanosis Increased pulse and blood pressure Diaphoresis Poor cough Inability to handle oral secretions Dysphagia Weakness Improves with edrophonium Cholinergic crisis Abdominal cramps Diarrhea Nausea and vomiting Excessive secretions Miosis Fasciculations Diaphoresis Weakness Worse with edrophonium
geal weakness, or labored breathing regardless of the measurements. If the diagnosis is not clear-cut, it is advisable to secure the airway with intubation and stabilize ventilation and only then address the question of the underlying diag105
Table 6-2 Medications That May Exacerbate Myasthenia Gravis Botulinum toxin Chloroquine Quinine Quinidine Procainamide Aminoglycoside antibiotics Ciprooxacin Recent high-dose corticosteroids (50% of MG patients have an early exacerbation)
D-Penicillamine
(causes MG)
Interferon- (causes MG) Neuromuscular blocking drugs (eg, pancuronium, vecuronium) can produce marked and prolonged paralysis in MG patients Depolarizing drugs (succinylcholine) can also have a prolonged effect Iodinated intravenous contrast is occasionally associated with exacerbation of MG
MG = myasthenia gravis. For a more extensive list and discussion of adverse drug effects on neuromuscular transmission, see the Myasthenia Gravis Foundation of America Web site (<www.myasthenia.org>).
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nosis. If the patient has been taking CEIs, the drug should be temporarily discontinued to rule out the possibility of cholinergic crisis. The development of respiratory failure in MG may occur suddenly or gradually for several reasons. Oropharyngeal or neck muscles may become weak, leading to collapse of the airway. Vocal cord abductor muscles may become weak, leading to obstruction of the larynx and a presentation of stridor. Sustained coughing may weaken the diaphragm muscles and thereby prevent the airway from being cleared of secretions. When the diaphragm, intercostal, and abdominal muscles are sufciently weak, inspiration may be critically reduced. Patients with MG are complex; bifacial weakness may limit their expression of discomfort or distress. Patients with weakness of the diaphragm, abdominal, and intercostal muscles may appear to be taking rapid shallow breaths.The presence of paradoxical wall motion, in which an inspiration leads to a more scaphoid appearance of the abdomen (sunken as opposed to protrusion of the abdomen), should be a telltale sign of serious diaphragmatic weakness. For the treatment of myasthenic crisis, the steps are as follows: 1. Protect the airway with an endotracheal tube. 2. Clear oropharyngeal pulmonary secretions with suctioning. 3. Use mechanical ventilation as needed to secure respiration. 4. Look for factors that may be identied as precipitants of crisis.
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Screen for and correct any underlying medical problems, such as systemic infection, metabolic problems (such as diabetes), and thyroid disease (hypo- or hyperthyroidism can exacerbate MG), and screen the patients medication list (see Table 6-2).
Cholinergic Crisis Cholinergic crisis is relatively uncommon compared with myasthenic crisis. It is particularly unlikely in the patient taking oral CEIs.Thomas and colleagues, in a retrospective review of 73 episodes of crisis from 1983 to 1984, found none in which cholinergic crisis was the culprit.1 However, with the use of parenteral CEIs, cholinergic weakness is, in fact, a real entity that should be considered and addressed. Precipitating factors of acute or subacute weakness with respiratory failure in MG include infection, fever, aspiration, hyperthyroidism, and the adverse effects of a variety of medications (including prednisone). Additional steps in management, in general, for the patient in crisis are as follows:
1. It is reasonable to withhold CEIs for several days following intubation and stabilization while potential precipitating factors are pursued. 2. Once the airway and ventilation are secure, it is appropriate to treat the patients with one of a variety of options, including high-dose corticosteroids, plasmapheresis, and IVIg.
Recent Observations on the Role of Plasma Exchange and IVIg in Severe MG and Myasthenic Crisis Regarding treatment with
high-dose IVIg compared with plasma exchange, Ronager

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and colleagues reported clinical effect of high-dose intravenous immunoglobulin compared to plasma exchange in patients with moderate to severe myasthenia gravis,2 comparing the two treatments in patients with moderate to severe MG. The study was a randomized, crossover study.Twelve patients with generalized moderately severe MG were on immunosuppressive therapy for at least 3 months, either azathioprine, prednisone, or both, with a stable dose for 1 month prior to randomization. One group of patients received IVIg 400 mg/kg/d for 5 consecutive days and was then observed for 16 weeks. The second group of patients was treated initially with plasma exchange and later with IVIg.The patients were evaluated using a quantified myasthenia gravis clinical score (QMGS) and were evaluated at 1, 4, 8, and 16 weeks after the end of each treatment. Additional measures included immunoglobulin concentrations, titers of AChR antibodies, and, at baseline and 1 week after each treatment, repetitive stimulation studies. The Ronager study showed that 1 week after treatment, those who received plasma exchange had signicantly improved QMGS, whereas such improvement could not be shown 1 week after IVIg treatment.2 Four weeks after treatment, there was signicant improvement in QMGS in both the plasma exchange and IVIg groups; 1 week and 4 weeks after treatment, no signicant difference between the two treatments was found. A higher number of adverse events was noted during and after IVIg treatment, but the adverse events were relatively minor and transient. Conversely, with plasma exchange, there were fewer adverse events, but those that occurred
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included some that were judged to be more serious, including one patient with septicemia and another patient with arterial bleeding.There were no signicant changes in the EMG studies (repetitive stimulation). The authors concluded that both treatments have clinically signicant benets in patients with chronic stable MG. In this limited study, the authors felt that improvement was more rapid after plasma exchange compared with IVIg but that the side effects observed with IVIg were more benign than those seen with plasma exchange. Gajdos and colleagues reported on the clinical trial of plasma exchange and high-dose IVIg in MG.3 Eightyseven patients with exacerbation of MG were randomized to one of two treatment groups. Group 1 received plasma exchange (n = 4), three exchanges in total. The second group received IVIg (n = 46), 0.4 g/kg/d for either 3 days (n = 23) or 5 days (n = 23). The primary end point was the myasthenic muscular score (MSS), with the change in score from time of randomization to day 15. The results showed that the MSS variation was similar in both the plasma exchange and IVIg patient groups, with an improvement in score of 18 points in the plasma exchange group and of 15.5 points in the IVIg group (p = .65).The two different schedules of IVIg administration provided a similar degree of improvement, but there was a trend toward reduced improvement in the 5-day group compared with the 3-day group. Regarding side effects, the plasma exchange group had eight patients with side effects, whereas only one patient in the IVIg group had side effects.The authors concluded
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that although there was no difference in the efcacy of both treatments, the less frequent side effects in the IVIg group suggest that this is an important therapy for treatment of myasthenic crisis. Qureshi and colleagues reported a retrospective multicenter chart review comparing the tolerance and efcacy of plasma exchange and IVIg in 54 episodes of myasthenic crisis.4 The decision to treat with plasma exchange or IVIg was at the discretion of the physician. In this retrospective review, the authors found that plasma exchange was somewhat more effective than IVIg, as dened as the ability to extubate the patient at 2 weeks and the 1-month functional outcome. However, patients in the plasma exchange group had more adverse complications than those receiving IVIg. The complications tended to be hemodynamic in the plasma exchange group.The authors concluded that IVIg provided a good alternative treatment, particularly in patients at risk of hemodynamic complications or in those who did not adequately respond to plasma exchange, and suggested a formal, prospective, randomized trial. Thomas and colleagues retrospectively reviewed the records of 53 patients with 73 myasthenic crises at Columbia Presbyterian Medical Center from 1983 to 1994.1 Age at the time of crisis was 20 to 82 years, with a median age of 55 years.Women were more often affected than men at a ratio of 2:1, and the average interval from initial myasthenic symptoms to initial episode of crisis was 8 months. Precipitating factors were headed by infection, typically pneumonia or an upper respiratory infection, which occurred in 38%, whereas in 30% of patients, there was no
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clear-cut precipitating event. In 10% of patients, aspiration seemed to precipitate the myasthenic crisis. Twenty-ve percent of patients were extubated by 7 days, 50% by 13 days, and 75% by 1 month, with the longest duration of intubation over 5 months. There were three independent predictors of prolonged intubation over 5 months, including a preintubation serum bicarbonate level 30 mg/dL, a peak FVC on day 1 to 6 of postintubation at < 25 mL/kg, and age over 50 years. None of those with no risk factors, 21% of those with one risk factor, 46% of those with two risk factors, and 88% of those with three risk factors remained intubated longer than 2 weeks. Complications in this series of prolonged intubation were atelectasis, anemia, Clostridium difcile gastrointestinal infection, and congestive heart failure.Three episodes were fatal, for an overall mortality rate of 4% (3 deaths in 73 crises). Four other patients died following extubation.All deaths were apparently related to multiple medical complications. Of those who survived, half were functionally dependent at home or in a facility at the time of discharge. The authors emphasized that not only are immunotherapies important in addressing myasthenic crisis, but the prevention and management of multiple medical complications are central to optimal outcome for myasthenic crisis. These authors defined crisis as respiratory failure requiring mechanical ventilation. Berrouschot and colleagues recently reported on therapy of myasthenic crisis, reviewing their experience with the causes, course, and outcome of 63 myasthenic crises treated by their group over a 26-year period
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(19701995), with an interest in the effect of the following different therapeutic modalities: myridostigmine intravenous, pyridostigmine plus prednisolone, and plasma exchange.5 Of 235 patients with MG treated at the University of Leipzig, the following observations were made. Forty-four patients experienced myasthenic crisis, for a total of 63 presentations.The average annual incidence of myasthenic crisis over this time period in these patients was 2.5%, a gure that was fairly consistent throughout the 26-year monitoring period. The 44 patients with crisis included 26 women and 18 men, with a mean age of 43 years. Twenty-five patients had a single crisis, 14 patients had two episodes, 4 patients had three episodes, and 1 patient had four episodes.The precipitating factors included myasthenic weakness alone in 32%, respiratory infection in 27%, post-thymectomy in 17%, start of corticosteroid therapy in 5%, overdose of cholinergic drugs in 3%, underdose of cholinergic drugs in 2%, emotional stress in 2%, and no specic cause in 12%.The average time from onset of MG to the occurrence of crisis was a mean of 37 months, with a broad range. Fourteen (22%) crises preceded thymectomy, whereas 46% followed thymectomy, and 20% occurred in patients who never had thymectomy. Precrisis treatment included pyridostigmine in 33%; pyridostigmine plus azathioprine in 25%; pyridostigmine, azathioprine, and prednisolone in 16%; pyridostigmine and prednisolone in 11%; and neostigmine in 2%. In 8 patients (13%), crisis was the rst manifestation of MG.The evolution of crisis was 1 to 3 days from onset of deterioration to requiring mechanical ventilation in
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68%, 4 to 7 days in 22%, and 14 to 21 days in 10%. Precrisis treatment included increasing medication dosage in 40%, plasma exchange in 1 patient, and an unchanged regimen in 58% of patients.The mean duration of mechanical ventilation was 9 days, with a range of 2 to 51 days. With regard to treatment of crisis, 24 patients received pyridostigmine as a continuous intravenous infusion, from 1 to 2 mg/h. Eighteen patients received pyridostigmine at 1 to 2 mg/h continuous intravenous infusion, along with 100 mg of prednisolone over 5 days, with a subsequent decrease in dosage.Two patients were given azathioprine, and one received IVIg. Twenty-one patients received plasma exchange every 2 days.A variety of other immunosuppressive drugs were administered in some of these patients as well. Overall, the three treatment groups showed no significant overall differences in the interval between the start of crisis and ventilation, and the outcome in the three groups was similar. After 3 months, all but two patients reached their precrisis status. Eight patients died during crisis (13%), with the causes being cardiac arrhythmia in six patients, cardiac arrest in ve patients, debrillation in one patient, and infection with pneumonia and sepsis after long-term ventilation in two patients. Autopsy was performed on seven of the eight patients, and four of them were found to have malignant thymoma. One patient had evidence of a viral myocarditis; otherwise, the heart autopsy was normal.The authors emphasized the importance of general support for the patient in crisis with early intubation, mechanical ventilation, and treatment of infection when present.
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Guillain-Barr Syndrome
GBS is usually a postinfectious illness. With the prevention of acute paralytic polio, GBS has become the most common cause of acquired nontraumatic generalized paralysis in adults. One of every 1,000 individuals will develop GBS at some point in their lifetime. GBS is classically an acute inammatory demyelinating polyneuropathy. Antecedent viral infection is identiable in about 66% of cases.Viral infection occurs 1 to 6 weeks prior to GBS. Documented viral infections have included cytomegalovirus, Epstein-Barr virus, other herpesviruses, and human immunodeciency virus. Other antecedent infections include Campylobacter jejuni (severe diarrhea) and Mycoplasma. Some patients develop GBS in the setting of lymphoma, surgery, and vaccinations. Clinical diagnostic critieria require progressive motor weakness in more than one limb and global hyporeexia or areexia.Weakness usually progresses over several days to 3 weeks in a relatively symmetric fashion. Although motor signs predominate at the time of diagnosis, pathologic and EMG evidence supports equivalent involvement of sensory and motor nerve bers eventually. The cerebrospinal uid classically exhibits elevated protein in the absence of pleocytosis. Another diagnosis is likely if there are > 50 white blood cells/mm3. The presence of a high white blood cell count in the cerebrospinal uid should trigger a search for sarcoidosis, human immunodeciency virus, cytomegalovirus, and West Nile virus as an associated or precipitating condition. EMG studies provide evidence of acquired demyelination in the form of conduc115
tion block, multifocal and asymmetric slowing, or prolonged distal motor latencies in warmed limbs.With supportive care, recovery is excellent in about 85% of patients. Usual recovery requires 4 to 6 months, but gradual further improvement may occur over as long as 2 years. Acute motor axonal neuropathy occurs in epidemics during the summer in China and is often associated with C. jejuni infection. Motor involvement with distal predominance and sparing of cranial nerves is the usual pattern. Recovery is more guarded than in acute inammatory demyelinating polyneuropathy because axonal loss is prominent. Acute motor sensory axonal neuropathy has a presentation similar to acute motor axonal neuropathy except that sensory involvement is also prominent. Recovery from acute motor sensory axonal neuropathy is often incomplete. Miller Fisher syndrome consists of ophthalmoplegia, ataxia, areexia, facial weakness, and bulbar weakness. The clinical syndrome of Miller Fisher is associated with anti-GQ1b antibodies in 90% of patients acutely. The differential diagnosis of GBS includes several less common but important conditions that are often overlooked or misdiagnosed (Table 6-3): tick paralysis; heavy metal poisoning, in particular arsenic and thalium; medication neurotoxicity from nitrofurantoin; solvent toxicity (hexane); thiamine deciency; and acute intermittent porphyria.All of these conditions should be considered in the patient who presents with GBS.
Treatment Treatment of all of these conditions consists of supportive medical care and, when necessary, IVIg or
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Table 6-3 Guillain-Barr Syndrome Look-alikes Tick paralysis Heavy metal poisoning (in particular arsenic and thallium) Medication neurotoxicity from nitrofurantoin Solvent toxicity (hexane) Thiamine deciency Acute intermittent porphyria
plasmapheresis. Supportive medical care may include management in the ICU for adequate ventilation, airway protection, and management of autonomic insufficiency. Early tracheostomy, enteral or parenteral feeding, subcutaneous heparin, and passive range of motion help prevent the complications of prolonged, severe illness.The North American Trial of Plasmapheresis (ve treatments over 7 to 10 days) demonstrated that the time to improve one clinical grade, time to independent walking, improvement at 4 weeks, and outcome at 6 months were all improved in the plasmapheresis group.6 A subsequent Dutch study demonstrated an equivalent response between IVIg and plasmapheresis (Table 6-4).7
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Table 6-4 Summar y of Guillain-Barr Syndrome Acute/subacute ascending paralysis Legs then arms Proximal = distal Evolves over 13 wk (occasionally days) 50% maximum by 1 wk 80% maximum by 3 wk Predominantly motor peripheral neuropathy Symmetric loss of reexes About one-third have respiratory involvement Recovery begins 24 wk after progression stops By 6 mo, 85% are ambulatory Recurrence in 3% Outcome 25% mortality Half have some residual abnormality 15% have signicant handicap 5% are severely disabled Laboratory Elevated CSF protein; often takes 519 d Normal CSF cell count (cytoalbuminologic dissociation), but 510% have up to 100 WBCs; in those patients, consider GBS associated with HIV, Lyme disease, sarcoidosis, CMV,West Nile virus About 5% abnormal LFTs Occasional increased muscle enzymes (acute denervation)
Continued
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Severe or sudden cases: stool culture for Camplylobacter jejuni; many of these are associated with GM1 antibodies Electrophysiology Demyelinating neuropathy Very slow conduction velocities Dispersed CMAPs Conduction block Look for prolonged F waves Needle examination with relatively little brillation In the rst few days, the NCS may be normal or only mildly abnormal NCS and EMG abnormalities lag behind the clinical examination Severe reduction of CMAP amplitude predicts outcome Management FVC below 15 mL/kg FVC falls below 1 L Patient dyspneic or looks bad Err on the side of early intubation Bedside counting estimate: 25 = 2 L, 10 = 1 L
Continued
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Immunotherapy of GBS Corticosteroids Prospective trials show no benet PE Several large randomized trials show benet (North American GBS study group, French, Swedish)6 GBS study group: total volume 200 mL/kg over 12 wk (45 exchanges of 3.54 L)7 No difference in complications Time to improve 1 clinical grade (come off vent, walk) decreased by 50% in the PE group (19 vs 40 d) Percentage of patients improved at 1 mo and average clinical grade 1520% better in PE group Time to independent walking decreased 40% in PE group (53 vs 85 d) No benet when PE started later than 2 wk after onset 10% rebound rate; may respond to repeat exchange IVIg Dutch randomized trial showed 0.4 g/kg/d for 5 d as good as plasma exchange7
CMAP = compound muscle action potential; CMV = cytomegalovirus; CSF = cerebrospinal uid; EMG = electromyography; FVC = forced vital capacity; GBS = Guillain-Barr syndrome; GM = gangliosidosis; HIV = human immunodeciency virus; IVIg = intravenous immunoglobulin; LFT = liver function test; NCS = nerve conduction study; PE = plasma exchange;WBC = white blood cell.
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Botulism
Consumption of sausage spoiled by Clostridium botulinum resulted in an outbreak of this paralytic illness in the 1700s in Germany, leading to the name botulism, derived from the Latin term for sausage, botulus. Botulinum toxin blocks ACh release at the presynaptic motor nerve terminal (and causes dysautonomia by blocking muscarinic autonomic cholinergic function as well).The intracellular target of botulinum toxin appears to be a protein of the ACh vesicle membrane. The toxin is a zinc-dependent protease that cleaves protein components of the neuroexocytosis apparatus.
Classic Botulism Classic botulism occurs after ingestion of food contaminated by botulinum toxin. Eight different toxins have been identified, but disease in humans is caused by types A, B, and E.Type E is associated with contaminated seafood.All types produce a similar clinical picture, although type A may produce more severe and enduring symptoms. In all three types, the condition is potentially fatal. Most cases result from ingestion of bottled or canned foods that have not been properly sterilized during preparation, especially home-canned foods.Todays tomatoes used in home canning may have a low acid content compared with the tomatoes of the good old days and therefore may be more vulnerable to contamination. Foods cooked on an outdoor grill and then wrapped in foil for a day or two, creating an anaerobic environment, can lead to toxin production. Home-bottled oils should also be considered; in the case of children, honey may be the contaminated food.
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Clinical Features Clinical features begin 12 to 48 hours after ingestion of tainted food. Bulbar symptoms, including diplopia, ptosis, blurred vision, dysarthria, and dysphagia, occur initially and are followed by weakness in the upper limbs and then in the lower limbs. In contrast to the typical patient with GBS, botulism is sometimes said to produce an acute descending paralysis. Severe cases result in respiratory failure, requiring mechanical ventilation. Botulism produces autonomic dysfunction, including constipation, ileus, dry mouth, and dilated pupils (some of these signs are seen in most but not all patients; normal pupils do not rule out the diagnosis of botulism). Diagnosis The compound muscle action potential amplitudes are typically low on motor nerve conduction studies. Repetitive stimulation studies before and following exercise may show a decrement to low rates of repetitive stimulation and postexercise facilitation of the compound muscle action potential amplitude. It is wise to send both stool and serum specimens to the laboratory for detection of the toxin. The specimen is injected into the peritoneum of a mouse, whereas neutralized or inactivated specimen is injected in the control. If the mouse becomes paralyzed and dies, the diagnosis is secure.Toxin is found in blood samples 30 to 40% of the time, whereas stool samples have a somewhat higher yield (thus the need to send both samples). Newer polymerase chain reaction tests for the organism have been used to screen for the bacteria in food. Management
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Management involves placement of the patient in the ICU and assiduous monitoring of pul-
monary function every few hours. When the FVC falls below 15 mL/kg or 1 L or if the patient appears to be having respiratory difculty, intubation and mechanical ventilation are necessary. There is a trivalent botulinum antitoxin, but its use is controversial, in part because of adverse side effects that occur in about 20% of patients. There is some evidence that the antitoxin shortens the course of the illness, especially that associated with type E. If one can make the diagnosis early, it may be worth using the antitoxin.
Clinical Course With aggressive support, the overall mortality remains about 5 to 10%, usually the result of respiratory or septic complications. Other patients improve over a period of several weeks to several months. In those who survive, the eventual level of recovery is usually nearly complete. Several years after the illness, some patients have subjective fatigue and autonomic symptoms, including constipation, impotence, and dry mouth. Clinical recovery results from brisk sprouting of new motor axons from the nerve terminal with reinnervation of denervated muscle bers.
Infant botulism is probably the most frequent form of botulism.The infant ingests the spores of C. botulinum, which lodge in the intestinal tract, germinate there, and produce botulinum toxin in the gut. Honey has often been implicated as the contaminated food in infant disease. In adults, the small amount of C. botulinum in honey appears inadequate to colonize the gastrointestinal tract. The typical presentation is an infant between the ages of 6 weeks and 6 months of age who exhibits generInfant Botulism
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alized weakness and constipation.The weakness may start in the cranial muscles and then descend, causing a weak suck, a poor cry, and reduced spontaneous movement.The cranial muscles are weak, with poor extraocular movements, reduced gag reex, and drooling. Finding C. botulinum in feces validates the diagnosis.The toxin is usually not detectable in the serum. EMG studies can point to the diagnosis in 80 to 90% of cases. Infantile botulism can range from mild to severe. Management centers on observation and general support (including respiratory stability).The recovery is usually excellent and runs a course of several weeks to several months.
Wound Botulism Wound botulism occurs when toxin is produced from C. botulinum infection of a wound. The symptoms are similar to those of classic botulism except that the onset may be delayed for up to 2 weeks after contamination of the wound. The diagnosis is supported by EMG studies, demonstration of toxin in the patients blood, or nding the organism in the patients wound. Wounds that lead to botulism include direct trauma, surgical wounds, and wounds associated with drug use (such as intravenous and intranasal cocaine). Acute Weakness in the Critically Ill Intensive Care Patient
Prolonged paralysis from neuromuscular blockers may occur on occasion in patients without neuromuscular junction disease. Factors that may inuence the duration of neuromuscular blockade include dosage and duration of
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therapy, concurrent drug use (including muscle relaxants, corticosteroids, magnesium, and cimetidine), severity of underlying disease, electrolyte abnormalities, and renal insufciency (which may lead to high drug concentrations). Patients with metabolic acidosis, high serum magnesium levels, renal failure, and high blood levels of 3-desacetyl-vecuronium appear more likely to experience prolonged paralysis. Prolonged neuromuscular blockade can be severe enough to produce neurogenic muscle atrophy. Corticosteroids may potentiate the effects of muscle relaxants (see Acute Quadriplegic Myopathy). Prolonged weakness in intensive care patients can result from a multitude of causes, some leading to peripheral neuropathy, myopathy, junctional disturbance, or a combination thereof. In many patients, multiple concomitant factors contribute to prolonged paralysis.
Acute Quadriplegic Myopathy (Critical Illness Myopathy)
Patients on corticosteroids seem prone to development of acute and prolonged generalized weakness when exposed to neuromuscular blocking drugs (with days to weeks of weakness persisting after the neuromuscular blocker is stopped). This condition seems particularly common in patients treated for status asthmaticus. Creatine kinase may be normal or markedly elevated. The nerve conduction studies are usually normal, but the EMG needle examination can show some myopathic features and some neurogenic changes. Muscles may be electrically inexcitable, even with direct electrical stimulation. Muscle biopsy shows severe necrotizing myopathy, acute type II ber atrophy, and selective degeneration of myosin laments
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(on electron microscopy). Weakness typically develops over days, and muscle atrophy is often present.Weakness is symmetric, involving limbs proximal more than distal, often with respiratory compromise. Cranial muscles are relatively spared. Even when patients have severe weakness, recovery can be excellent, although it may take several weeks to several months.
Critical Illness Neuropathy
Acute quadriplegic myopathy is differentiated from critical illness neuropathy in that the latter is truly an axonal sensory/motor peripheral neuropathy.The sensory involvement can be established clinically or by nerve conduction studies. Both groups of patients are usually in the ICU with multisystem disease, severe generalized weakness, and difculty weaning from the ventilator.
Inflammatory Myopathies Diagnosis There are three common forms of myositis: polymyositis, dermatomyositis, and inclusion body myositis (they each account for roughly one-third of subacute or chronic myositis). Viral myositis is typically transient and lasts a week or two, and by the time the tests are arranged, the patients symptoms have resolved. Except for skin lesions, polymyositis and dermatomyositis are similar in their clinical presentation: proximal weakness in the neck exors/extensors and shoulders/hips.These patients do not tell us, Doctor, Im weak; rather, they complain of loss of a specic function: Im having trouble rising
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from a chair, going up or down stairs. Most patients with myositis have little or no pain!
Examination
The examination shows symmetric proximal weakness, normal sensation, preserved reexes, and not much cranial weakness except for dysphagia, which may be seen in about 25% of patients. Although uncommon, patients with acute severe myositis may have diaphragm involvement and respiratory failure. The skin lesions in dermatomyositis include the following: Heliotrope rash (violet rash on the eyelids, named after the heliotrope plant).The plant has pretty blue, violet, or pink owers and the fragrance of vanilla. The owers face the sunlight in the morning and follow the sun across the sky as the day progresseshence the name heliotrope. Red scaly lesions on the knuckles, elbows, and knees Buttery rash on the face Rash on the sun-exposed regions of the head/neck/trunk Periungual edema Systemic manifestations of dermato- and polymyositis can include fatigue, weight loss, arthralgias, and fever. Cardiac involvement can lead to arrhythmia, heart block, or congestive failure. Interstitial lung brosis can lead to a variety of respiratory problems. Dysphagia and other gastrointestinal motility abnormalities may occur.
Laboratory Findings
Laboratory ndings in dermatomyositis/polymyositis include elevated creatine kinase in

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90% of patients. EMG is abnormal in 90%, indicating the presence of a myopathy; brillation suggests an active component and may help distinguish inclusion body myositis and help select the muscle to biopsy. Muscle biopsy should distinguish the three common forms of inammatory myopathy (and help diagnose the uncommon forms as well): Polymyositis: muscle ber necrosis, cellular inltration Dermatomyositis: vasculopathy, vasculitis, perifascicular atrophy Inclusion body myositis: inammation and rimmed vacuoles on hematoxylin and eosin stain and oil red O stain; electronic microscopy (EM) shows lamentous inclusions
Issues in Respiratory Involvement with ALS
Because most patients with ALS die from complications of respiratory failure, the clinician should anticipate the signs and symptoms of hypoventilation. Whether the goal is prolonged survival, maximal comfort, or both, the management of respiratory failure in the patient with ALS should be a high priority. Often the earliest signs of respiratory weakness are those associated with disturbed sleep. Daytime spirometry and blood gases may appear stable, but at night, the patient may experience severe hypoventilation. In general, the PCO2 will not begin to rise until the FVC falls below 50% of predicted. Early on, the blood gases may show mild hypoxia and hypocapnea as patients hyperventilate to maintain oxygenation. As respiratory
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function deteriorates, the patient develops carbon dioxide retention from hypoventilation, and the serum bicarbonate levels become elevated as compensation for the respiratory acidosis. Signicant hypercapnia typically develops when the FVC is 30% of predicted, at which point, the patient is at major risk of acute respiratory decompensation. As the FVC falls to 50 to 60%, the patient with ALS begins to develop symptoms of hypoventilation, and the use of noninvasive positive pressure ventilation (bilevel positive airway pressure) should be pursued to improve symptoms (quality of life) and prolong survival.
PITFALL SCENARIOS
1. A patient is admitted for GBS with associated dyspnea. The patients blood gases are normal; therefore, the patient is stable and is admitted to a ward bed for observation. Four hours later, the patient has a respiratory arrest and dies. Comment: In patients with neuromuscular respiratory failure, the blood gas changes occur relatively late. Do not be fooled, especially with patients with GBS and MG. 2. A patient with ALS has chronic dyspnea owing to diaphragm weakness. In an effort to provide maximum comfort, she is given supplemental oxygen. Over the next hour, the patient appears much more comfortable and less short of breath. Two hours later, she appears more peaceful and is nally able to go to sleep. Several hours later, she has a respiratory arrest and dies. Comment: The problem here is that the patient with chronic hypoventilation may have a chronic elevation
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of PCO2, leading to hypoxic drive of respiration.The supplemental oxygen raises the oxygen partial pressure, and the patient loses the hypoxic drive.Therefore, the patient further hypoventilates, leading to increasing levels of carbon dioxide.The patient appears more comfortable, in part because of the sedating effects of hypercapnia. Such sedation becomes increasingly profound, and over the next few hours, the patient follows a vicious cycle of increased sedation leading to reduced ventilation, which, in turn, raises the PCO2 even further, producing increasing sedation and, ultimately, a respiratory arrest.The solution is to use noninvasive ventilation (such as bilevel positive airway pressure) prior to adding the supplemental oxygen. Also, starting with lower concentrations of supplemental oxygen may be prudent. 3. A patient hospitalized for myasthenia has an FVC measurement of 400 mL.The nurse calls, asking you if the patient should be intubated.The patient insists he is stable and not short of breath. Comment: Always see the patient and assess the situation rsthand.The FVC may be wrong. It is often difcult to seal patients with facial muscle weakness tightly around the mouthpiece, allowing air to escape when measuring the FVC.
REFERENCES 1. Thomas CE, Mayer SA, Gunger Y, et al. Myasthenia crisis. Clinical features, mortality complications and risk factors for prolonged intubation. Neurology 1997;48:125360.
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2. Ronager J, Raunborg M, Hermansen I, et al. Clinical effect of high-dose intravenous immunoglobulin treatment versus plasma exchange in patients with moderate to severe myasthenia gravis. Artif Organs 2001;25:96773. 3. Gajdos P, Chevert S, Clair B, et al. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in MG. Ann Neurol 1997;41:78996. 4. Qureshi AI, Choudry MA, Akbar MS, et al. Plasma exchange vs. IVIg treatment of myasthenic crisis. Neurology 1999;52:62932. 5. Berrouschot J, Baumann I, Kalischewski P, et al.Therapy of myasthenic crisis. Crit Care Med 1997;25:122835. 6. GBS Study Group. Plasmapheresis and acute GBS. Neurology 1985;35:1096104. 7. Dutch GBS Study Group.A randomized trial comparing IV gamma globulin and plasma exchange in acute GBS. N Engl J Med 1992;326:11239. RECOMMENDED READINGS Chalola JA. Pearls and pitfalls in the intensive care management of Guillain-Barr syndrome. Semin Neurol 2001;21: 399405. Cherington M. Botulism. Muscle Nerve 1998;10:2731. Hund E. Critical illness polyneuropathy. Curr Opin Neurol 2001;14:64953. Keesey JC. Crisis in myasthenia gravis: an historical perspective. Muscle Nerve 2002;26:13. Kissel JT. Misunderstanding, misperceptions, and mistakes in the management of the myopathies. Semin Neurol 2002;22: 4151. Lacomis D, Campellone JV. Critical illness neuromyopathies. Adv Neurol 2002;88:32535.
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Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensive care unit: a study of ninety-two patients. Muscle Nerve 1998;21:6107. Lacomis D, Zochodne DW, Bird SJ. Critical illness myopathy. Muscle Nerve 2000;23:17858. Lindenbaum Y, Kissel JT, Mendell JR.Treatment approaches for Guillain-Barr syndrome and chronic inammatory demyelinating polyradiculoneuropathy. Neurol Clin 2001;19: 187204. Pascuzzi RM. Pearls and pitfalls in the diagnosis and management of neuromuscular junction disorders. Semin Neurol 2001;21:42540. Pascuzzi RM.ALS, motor neuron disease, and related disorders: a personal approach to diagnosis and management. Semin Neurol 2002;22:7587. Watling SM, Dasta JR. Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Crit Care Med 1994;22:88493.
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CHAPTER 7
ISCHEMIC STR OKE

Patrick S. Reynolds, MD, and Terrence W. Bruner, MD, MBA
r. J. K. is a 57-year-old man with a history of hypertension, coronary artery disease, and cigarette smoking. On the day of admission, he was in his usual state of health and was out working in the elds on his tractor. He came in for lunch and was talking to his wife at the kitchen table.As he was getting ready to go back out, he suddenly began to slur his speech and could not get up out of the chair. His wife called their son, who practically carried Mr. K to the car, and they took him to the emergency department. He arrived at the emergency department approximately 1 hour after the onset of symptoms. The triage nurse suspected a stroke, and he was evaluated urgently. On examination in the emergency department, his vital signs were stable (blood pressure 158/72 mm Hg, pulse 110 bpm and irregular, respiratory rate 16 breaths per minute, temperature 99F). His general examination was notable for the following: no carotid bruits, equal radial and dorsalis pedal pulses, and an irregularly irregular heart rate without murmur. His neurologic examination was notable for an expressive aphasia, right homonymous visual eld decit, a left gaze preference, right facial weakness, moderate right hemiparesis, and right hemisensory loss. Quantication of his examination using the National Institutes of Health (NIH) Stroke Scale resulted in a score of 16, which indicates a large stroke. An emer133
gent head computed tomographic (CT) scan was obtained and was unremarkable (Figure 7-1). Electrocardiography (ECG) showed atrial brillation with no ST segment changes. Laboratory workup showed a normal metabolic prole, including a blood sugar of 104 mg/dL; prothrombin time (PT) and partial thromboplastin time (PTT) were normal, the complete blood count was normal, and the platelet count was normal. Serum creatine phosphokinase and troponin levels were not elevated.The patient had had no recent surgical procedures and had no history of gastrointestinal or genitourinary bleeding or trauma. The patient was felt to be a good candidate for thrombolytic therapy and met all laboratory and blood pressure parameters for the stroke thrombolytic protocol. The risks and benets of thrombolytic therapy were discussed with the patients wife and son, and informed consent was obtained
Figure 7-1 Initial head computed tomographic scan in the emergency depar tment approximately 1 hour, 45 minutes after the patients stroke.
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Is ch emic Stroke
for administration of intravenous tissue plasminogen activator (t-PA). Intravenous t-PA was administered per protocol, with the bolus begun 2:15 minutes after symptom onset. He was admitted to the acute stroke unit using the postt-PA protocol. His blood pressure remained stable on treatment with his usual blood pressure medications. Twenty-four hours after the t-PA infusion, he was neurologically much improved. He was speaking uently but continued to have some naming and paraphasic errors. He could repeat. His gaze preference and homonymous hemianopia had resolved. His facial droop and hemiparesis had dramatically improved. His NIH Stroke Scale score had improved from 16 to 6. He was participating well in physical, occupational, and speech therapy, and he had passed his swallowing evaluation and could eat safely without increased risk of aspiration pneumonia. Approximately 24 hours after the t-PA infusion was completed, a follow-up brain CT scan was performed to evaluate the size of the residual infarct and to look for intracranial hemorrhage. The CT scan (Figure 7-2) showed a moderate-sized residual infarct but no hemorrhage.The patient was ruled out for myocardial infarction with serial cardiac enzyme testing.The presumptive cause of his stroke was cardioembolism owing to atrial brillation; however, a further etiologic workup was nevertheless necessary. A transthoracic echocardiogram was performed to assess his ventricular performance and to determine if there had been any decreased cardiac function since his last echocardiogram. This echocardiogram showed mild left ventricular hypertrophy with an ejection fraction of 55% and no segmental wall motion abnormal135
Figure 7-2 Follow-up head computed tomographic scan approximately 30 hours after stroke.
ities.The left atrium was dilated, but no thrombus was seen on this examination.A carotid duplex sonogram was performed and showed mild, nonstenotic, atherosclerotic plaque in the patients internal carotid arteries bilaterally. After the follow-up CT scan showed no hemorrhage and only a small residual infarct, the patient was started on intravenous heparin and warfarin for long-term anticoagulation. When his international normalized ratio (INR) was therapeutic (> 2.0), the heparin was discontinued, and the patient was discharged home with outpatient therapy. For control of his blood pressure, he was continued on a -blocker, an angiotensin-converting enzyme (ACE) inhibitor, and a thiazide diuretic. He was continued on his statin medication (3-hydroxy-3-methylglutaryl coenzyme A inhibitor [statin]) for cholesterol therapy and was encouraged to stop smoking.
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The patient returned in follow-up to the stroke clinic 3 months after discharge. He was once again working as a farmer. His decits had almost completely resolved, with the only residual ndings on examination being a very mild right facial weakness and minimal clumsiness of his right hand. He had managed to quit smoking and was compliant with his medications.
DEFINITION
Stroke is a sudden, nonconvulsive, focal neurologic decit caused by a disorder of blood vesselsa vascular event. Ischemic stroke (or infarction) is the death of neurons and glia caused by lack of blood ow owing to an artery blockage or inadequate perfusion. Hemorrhagic stroke is bleeding into the brain parenchyma owing to a ruptured blood vessel. Subarachnoid hemorrhage is bleeding into the subarachnoid space. The diagnosis of stroke remains a diagnostic challenge as there are many potential nonvascular causes of acute neurologic decits, making good history and physical examination skills paramount in the evaluation of neurologically impaired patients. Some conditions that can mimic stroke are shown in Table 7-1.
EPIDEMIOLOGY INTRODUCTION
Stroke is the third leading cause of death in the United States and the leading cause of long-term disability. The
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Table 7-1 Conditions That May Mimic Stroke Condition Infections Seizure Metabolic Benign positional vertigo Cardiac Syncope Other
Adapted from Libman RB et al.36
% 20 17 13 6 5 5 19
American Heart Association (AHA) and the National Stroke Association estimate that there are approximately 700,000 new strokes each year and that approximately one-third of patients with new strokes will die. This equates to approximately one stroke every minute in the United States and one stroke death every 3 minutes.The prevalence of stroke in the general population is 500 to 700 in 100,000. The incidence increases with age from 200 in 100,000 around age 60 to 3,000 in 100,000 after age 85.There are estimated to be approximately 4 million stroke survivors in the United States.
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BACKGROUND
Ischemic stroke (infarction) accounts for 80 to 85% of strokes in the United States, and 15 to 20% of strokes are hemorrhagic: intraparenchymal or subarachnoid hemorrhage. A transient ischemic attack (TIA) is a focal neurologic decit caused by a temporary interruption of blood supply without permanent damage to brain tissue. By definition, a TIA is dened as a neurologic decit lasting less than 24 hours.This denition is outdated, and with modern imaging methods, we know that many patients with clinical decits lasting only a few hours will have imaging evidence of permanent damage to their brain. The usual duration of a TIA is from 5 to 20 minutes, and most attacks last less than 1 hour.TIAs should be considered analogous to unstable angina in heart disease and mandate urgent evaluation and treatment. Ten percent of patients who have a TIA will have a stroke within 3 months, but half of those (5%) will have a stroke within 48 hours of the TIA. The 5-year risk of stroke after a TIA is at least 30%.6
Risk Factors and Causes
A risk factor is a condition (disease, genetics, gender, age) that increases the likelihood of developing a disease process in the future. The cause of an ischemic stroke is what actually causes poor blood ow or blockage of the artery, leading to brain cell death. A risk factor is not the same as a cause, and a risk factor such as hypertension can, in fact, predispose a patient to multiple causes of stroke.1,2,712
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Causes of Ischemic Stroke
Atherosclerosis: hardening (lipid buildup) of large vessels causing distal thromboembolism or hypoperfusion Cardioembolism: blood clots originating in the heart and embolizing to brain arteries Small vessel disease: thickening of small intracranial arteries owing to hypertension, diabetes, smoking, atherosclerosis Hypercoagulable states: congenital or acquired abnormalities leading to excessive or inappropriate blood clotting Nonatherosclerotic vasculopathies: dissections (tearing of the inner layer of an artery, usually owing to trauma), vasculitis, fibromuscular dysplasia, collagen vascular disorders Hypoperfusion (usually owing to relative hypotension): inadequate blood ow to a brain region
Nonmodifiable Risk Factors
Age: the most important nonmodiable risk factor. Past the age of 55, the risk of stroke doubles with each succeeding decade Gender: men are at greater risk of stroke than women, but women have their strokes at an older age Race: the incidence of stroke in blacks is more than double that in whites, and the incidence is also higher in Hispanic Americans Family history: especially important if rst-degree relatives have strokes at a young age
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Modifiable Risk Factors
Prior stroke or TIA: knowing the cause allows antithrombotic therapy for prevention of recurrent strokes and allows aggressive treatment of all other risk factors Hypertension: the most important risk factor for both ischemic and hemorrhagic stroke. Hypertension causes endothelial damage to both large and small vessels Heart disease: leading to embolism of clots from the heart to the brain Atrial brillation: causes stasis of blood in the brillating atrium, leading to the formation of clots, which may then embolize Ischemic or nonischemic cardiomyopathies: cause severe left ventricular dysfunction, which leads to stasis of blood in the ventricle and the formation of clots, which can then embolize Mechanical heart valves: lead to embolism Cigarette smoking: accelerates atherosclerosis owing to endothelial damage, free radical formation, heavy alcohol use: greater than two drinks per day increases risk of hemorrhagic stroke Hyperlipidemia: directly related to atherosclerosis Heavy alcohol use: especially related to hemorrhagic stroke Asymptomatic carotid stenosis: may lead to thromboembolism in the future Diabetes: probably functions by accelerating atherosclerosis in large vessels by endothelial damage and contributes to lipohyalinosis in small vessels
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Sympathomimetic drug use (both legal and illegal): induces hypertension, may induce a vasculitis, accelerates atherosclerosis through endothelial damage, and may induce a hypercoagulable state
NEUROANATOMY Anatomic Division
The brain can be divided into three major anatomic areas: the cerebrum, the cerebellum, and the brainstem. The cerebrum can be further divided into the overlying cortex (computer, processing center) and connecting subcortical areas (wiring) and the two sides, or hemispheres, of the cerebrum. Each hemisphere controls movement and sensation from the other side of the body. Left cortex: in most people, the left hemisphere is dominant, meaning that the language center is in the left hemisphere Right cortex: the right hemisphere recognizes and pays attention to the left environment and is more responsible for spatial relations and artistic endeavors Subcortical areas: consist of the white matter (bundles of axons and nerves that connect the neurons), basal ganglia (gray matter that modulates movement), and the thalami (gray matter that serves as a sensory relay center and motor switchboard) Cerebellum: coordination center to control timing of motor movements. The cerebellar vermis controls truncal balance and the cerebellar hemispheres con142
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trol appendicular (arms and legs) coordination and balance Brainstem: connects and relays all information from the brain to the spinal cord and to the rest of the body, all in a cross-sectional area little bigger than a quarter
Arterial Territory
Middle cerebral artery: supplies most of the ipsilateral hemispheres and much of the deep white matter and basal ganglia through small, penetrating arteries Anterior cerebral artery: supplies most of the medial portion of the hemispheres and a portion of the basal ganglia and anterior thalamus Posterior cerebral artery: supplies the occipital cortex, large portions of the thalamus, and some of the temporal lobe Basilar artery: supplies the pons, midbrain, parts of the cerebellum, and the posterior cerebral arteries Vertebral artery: supplies the medulla and the inferior cerebellum
STROKE SYNDROME
The part of the brain affected by a stroke can be localized based on the patients signs and symptoms. All stroke patients have a sudden onset of a cluster of symptoms.The patient should be assessed for stroke risk factors, both by a history and physical examination and by laboratory markers.
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Stroke Signs by Brain Region Damaged
Left hemisphere (dominant) Cortical involvement: aphasia, right visual field decit, left gaze preference Cortical and/or subcortical involvement: right hemiparesis, right hemisensory loss Right hemisphere (nondominant) Cortical involvement: neglect (hemi-inattention), left visual eld decit, right gaze preference Cortical and/or subcortical involvement: left hemiparesis, left hemisensory loss Cerebellum: truncal or gait ataxia, limb ataxia, vertigo Brainstem: the hallmark is crossed ndings (signs on both sides of the body, usually cranial nerve ndings on one side and motor/sensory ndings on the other side of the body Hemiparesis or quadriparesis Sensory loss on one or both sides Diplopia, gaze palsies, nystagmus Altered consciousness Vertigo, hiccups, hoarseness, nausea, vomiting
Stroke Syndromes by Arterial Territory
Left middle cerebral artery stroke Language disturbance (aphasia) Right visual eld decit Left gaze preference Right hemiparesis (arm weaker than leg) Right hemisensory loss
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Right middle cerebral artery stroke Left-sided inattention (neglect syndrome) Aprosody (abnormalities involving the emotional content of speech) Left visual eld decit Right gaze preference Left hemiparesis (the arm weaker than the leg) Left hemisensory loss Posterior cerebral artery stroke Contralateral homonymous visual eld decit Contralateral sensory loss if thalamus involved Memory loss if temporal lobe involved Basilar artery stroke: brainstem ndings localizing to the pons or midbrain and possibly cerebellar ndings Vertebral artery stroke: brainstem ndings localizing to the medulla and usually cerebellar ndings Classic small vessel stroke syndromes (lacunar syndromes) Pure motor stroke (usually localizes to internal capsule or ventral pons) Contralateral hemiparesis with equal weakness of the face/arm/leg No sensory or cortical ndings Pure sensory stroke (localizes to the thalamus) Contralateral sensory loss to all modalities No motor or cortical ndings Clumsy handdysarthria syndrome (usually localizes to the subcortical white matter or pons) Mild, usually distal upper extremity weakness Severe dysarthria, but language function is intact No sensory loss or other cortical ndings
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Sensorimotor stroke (usually localizes to the subcortical white matter) Contralateral hemiparesis Contralateral hemisensory loss No aphasia or neglect
PRIMARY PREVENTION OF STROKE
The goal is to prevent a rst-ever stroke.13 Hypertension is the most important treatable risk factor. Even a modest reduction in blood pressure has important effects on stroke prevention.8 Identication of heart disease to prevent myocardial infarction.Anticoagulation in patients with atrial brillation dramatically reduces the risk of ischemic stroke. However, in many states, fewer than half of patients with known atrial brillation and without bleeding contraindications are placed on anticoagulation with warfarin.This is a public health problem, which needs better education of physicians.9 Drug therapy with ACE inhibitors in at-risk patients (patients with heart disease or diabetes) can reduce the risk of rst-time stroke.This effect is independent of the antihypertensive effect of these drugs, and this benecial effect is seen in patients without hypertension.12 Treatment of hypercholesterolemia in at-risk patients (with known heart disease) with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) reduces the risk of rst-ever stroke.11
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Carotid endarterectomy for patients with high-grade, asymptomatic internal carotid artery stenosis can prevent stroke in carefully selected patients who are operated on by surgeons skilled in the procedure and who have low complication rates.7 Lifestyle changes: patients must be educated to be active participants in their own health care. They should be encouraged and taught about the following important lifestyle changes10: Smoking cessation Prudent diet, exercise, and weight loss Stopping excessive alcohol use and sympathomimetic drug use Public education is needed regarding stroke signs and symptoms and the fact that stroke is a treatable emergency. Teach the public to call 911 and to go to the emergency department for treatment of the acute stroke.
EMERGENCY ISCHEMIC STROKE CARE
Rapid identication and treatment of stroke patients are essential to minimize complications and enhance recovery. Ischemic stroke patients who present to the emergency department within 3 hours of their symptom onset should be evaluated for potential therapy with t-PA, a thrombolytic drug that has been shown to enhance recovery from stroke. Patients who receive intravenous t-PA according to strict guidelines have an approximately 30 to 50% increase in their chance of having an excellent recovery from their stroke, with a 6% risk of severe
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intracranial hemorrhage as a potential side effect, but appropriate administration of t-PA does not increase mortality (Figure 7-3).
Rationale for Thrombolytic Therapy
In the rst few hours after a stroke, there is a central area (core infarction) of dead neurons and a surrounding zone (ischemic penumbra) of ischemic, nonfunctioning (stunned) neurons, which are still viable if the blood supply can be re-established.A patients symptoms are due to the combined effects of the core of ischemic damage plus the dysfunction of the penumbra tissue. The amount of salvageable penumbra tissue cannot be determined by clinical examination or as yet by neuroimaging. The amount of time that penumbra neurons can remain viable is also not known, but intravenous t-PA has been shown to be effective only when given within 3 hours of stroke. Direct intra-arterial delivery of lytic therapy to the middle cerebral artery can extend that time window to 6 hours with reperfusion and improved clinical outcome. The presumed method of action of t-PA is to cause lysis of an acute thrombus occluding an artery, thereby allowing reperfusion.This reperfusion allows the ischemic neurons to recover function.Thrombolytic therapy causes a signicant risk of intracranial hemorrhage, however, and there are strict clinical criteria that must be met to allow treatment with thrombolytic therapy to be as safe as possible. The most important parameters are accurate identication of the time of symptom onset and not giving t-PA to patients with a blood pressure greater than
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Figure 7-3 National Institutes of Health r t-PA study: par t 2 results. ICH = intracranial hemorrhage; NIHSS = National Institutes of Health Stroke Scale14; Plac = placebo; r tPA = recombinant tissue plasminogen activator. Adapted from National Institute of Neurological Disorders and Stroke (NINDS) r tPA Stroke Study Group.14
185/110 mm Hg, which increases the risk of intracranial hemorrhage. Patients with other potential risks for bleeding also should not receive thrombolytic therapy (Figure 7-4).1418
Figure 7-4 Ischemic penumbra. The penumbra is the ischemic area around the infarcted core. Courtesy of Dr. David Lee Gordon, Center for Research in Medical Education, University of Miami School of Medicine.
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Practical Emergency Stroke Care
Acute stroke is a treatable medical emergency.The American Heart Association has identied a Chain of Survival to promote thrombolytic therapy for stroke: The 7 Ds: Stroke Chain of Survival and Recovery (from ACLS Provider Manual, copyright 2001, American Heart Association)19: Detection of the onset of stroke signs and symptoms Dispatch through activation of the emergency medical service (EMS) system and prompt EMS response Delivery of the victim to the receiving hospital while providing appropriate prehospital assessment and care and prearrival notication Door (emergency department triage) Data (emergency department evaluation, including a CT scan) Decision about potential therapies Drug therapy There are three other Ds that should also be thought of as part of emergency care and should be considered as well even when the patient is initially being evaluated: Defeat the medical complications of stroke. Determine the cause of the stroke (etiologic evaluationthe patients type of stroke and risk factors should indicate to the physician the most likely cause of the stroke to allow initial workup to be directed at those causes).
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Deter the next stroke (initiate appropriate secondary prevention after the cause of the stroke has been determined).
Sample Checklist for Administration of recombinant tissue plasminogen activator (rt-PA) for Acute Stroke Thrombolysis (Table 7-2) Eligibility Criteria
Clinical diagnosis of acute ischemic stroke with onset determined to be within 3 hours of administration of bolus of rt-PA Age 18 years or older A noncontrast CT scan must be obtained prior to t-PA administration
Warnings
An increased risk of intracranial hemorrhage in very large strokes (NIH Stroke Scale > 22) An increased risk of intracranial hemorrhage if the CT scan shows major early signs of infarct
Administration of t-PA
0.9 mg/kg with a maximum total dose of 90 mg 10% of total dose administered as a bolus over 1 minute with the remaining 90% of the dose administered as continuous infusion over the next 60 minutes
Follow-up
Close monitoring of vital signs and neurologic examination

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Table 7-2
History No 1. Only minor or rapidly improving stroke symptoms 2. Clinical presentation worrisome for SAH 3. Active systemic bleeding 4. Major surgery or trauma in last 14 d 5. Head trauma, intracranial surgery, or prior stroke in the last 3 mo 6. Gastrointestinal or urinary tract hemorrhage in last 21 d 7. Recent arterial puncture at noncompressible site 8. Recent lumbar puncture 9. History suggestive of possible seizure at onset or after stroke 10. History of AVM or aneurysm 11. Any history of intracranial hemorrhage 12. Post-MI pericarditis Laboratory 1. Intracranial hemorrhage or SAH on CT scan 2. Blood pressure > 185/110 mm Hg on repeated measurements or requires aggressive treatment to maintain these limits 3. Abnormal blood sugar (< 50 or > 400 mg/dL) 4. Platelet count < 100,000 5. Elevated apt 6. INR > 1.5 Yes*
*Any check in the Yes column makes the patient ineligible for tissue plasminogen activator therapy. Adapted from Report of the Quality Standards Subcommittee of the American Academy of Neurology.20 apt = activated partial thromboplastin time; AVM = arteriovenous malformation; CT = computed tomography; INR = international normalized ratio; MI = myocardial infarction; SAH = subarachnoid hemorrhage.
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Maintain blood pressure < 185/110 mm Hg No anticoagulant or antiplatelet therapy for the rst 24 hours Avoid invasive lines and procedures if possible in the rst 24 hours
EMERGENCY STROKE CARE
The goal of acute stroke care, whether or not the patient is a candidate for an acute intervention such as intravenous t-PA therapy, is to maximize the chance of recovery of the penumbra, prevent medical complications, determine the cause of stroke, initiate appropriate secondary prevention based on the mechanism of stroke, and enhance functional recovery through rehabilitation.
Four Things to Avoid in Emergency Stroke Care (The 4 Donts!)
Avoid hypotension. Most stroke patients have an elevated blood pressure at the time of the stroke, usually owing to poorly controlled or unrecognized hypertension prior to the stroke, as well as a physiologic response to the stroke itself. Hypertension in the setting of an acute infarct may be benecial by increasing perfusion pressure to the ischemic penumbra and, in general, should not be aggressively treated in the setting of acute stroke. Exceptions would be in patients with concurrent illnesses such as acute myocardial infarctions or aortic dissections or in patients who received thrombolytic therapy and whose blood pressure must be lowered to
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below 185/110 mm Hg. Acute blood pressure therapy should, in general, be aimed at maintaining mean arterial pressure in the range of 120 to 130 mm Hg. Longterm control of blood pressure should be obtained over a period of several weeks. Short-acting nifedipine should never be used in stroke patients because it causes large, acute drops in blood pressure that can potentially worsen the stroke. Avoid giving glucose. Hyperglycemia is associated with worsened outcome in stroke patients; therefore, it is best to avoid giving glucose-containing solutions. Glucose should be given only if the patient has documented hypoglycemia. Avoid hyperthermia.An elevated body temperature has been shown to be associated with worse stroke outcomes. Fevers should be aggressively treated with antipyretics, and the cause of the fever should be determined and directly treated. Avoid aspiration pneumonia.Aspiration pneumonia is a major cause of morbidity and mortality in stroke patients. Most stroke patients (not just patients with brainstem strokes) potentially have weak oropharyngeal muscles and/or poor or absent gag response. Aspiration precautions include maintaining the head of the bed at 30 or higher at all times and to avoid all oral intake, including medications, until the patients ability to swallow safely can be fully evaluated. If there is any doubt, then a nasogastric tube should be placed for nutrition and medication until a formal swallowing evaluation can be performed.
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Some Dos! in Emergency Stroke Care
Begin aspirin therapy after a CT scan has ruled out hemorrhage and if the patient is not a candidate for thrombolysis. If the patient receives thrombolytic therapy with t-PA, then all anticoagulant and antithrombotic medications must be withheld and not administered for the rst 24 hours. Therapy with aspirin within 48 hours of stroke onset has been shown to be benecial to decrease the rate of recurrence. Initiate deep vein thrombosis prophylaxis if the patient has impaired mobility. Avoid hypotonic intravenous solutions, which could worsen brain edema. Prioritize early mobilization and discontinue invasive intravenous lines and Foley catheters as soon as possible Initiate physical, occupational, and speech therapy as soon as possible if clinically indicated.
Role of Heparin
In general, there is usually NO indication for intravenous heparin in acute ischemic stroke. Heparin has never been shown to be benecial and carries the risks of systemic and intracranial bleeding as well as the risk of heparininduced thrombocytopenia. Subcutaneous heparin is benecial for deep vein thrombosis prophylaxis. There are some accepted uses of intravenous heparin24: Crescendo TIA: more than one TIA in 24 hours or several TIAs in the last few days
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Stroke in evolution: progression of a patients clinical stroke decits thought to be from more ischemic damage to the brain owing to an increase in the size of the thrombus and worsened perfusion to that area of the brain Stroke owing to arterial dissection Stroke owing to intracranial venous thrombosis
ETIOLOGIC EVALUATION/SECONDARY PREVENTION Laboratory Evaluation
The laboratory evaluation of the stroke patient should be designed to conrm the clinical syndrome identied on examination, determine the cause of the stroke, and identify all potential stroke risk factors. Such a comprehensive workup allows determination of appropriate antithrombotic therapy for secondary prevention and maximum treatment for risk factor modication: Etiologic evaluation encompasses imaging of the brain to conrm the type of stroke syndrome and evaluation of the heart, blood vessels, and blood components to identify the cause of the stroke. In general, laboratory tests should be done in a sequence going from noninvasive to invasive testing until the cause is determined. Brain imaging consists of an emergent CT scan without contrast in the emergency department to rule out hemorrhage. Follow-up scanning is done by either CT without contrast or the far more sensitive magnetic resonance imaging to visualize the actual ischemic lesion.
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Blood vessel imaging can be done by duplex ultrasonography to evaluate the extracranial carotid and vertebral arteries, by transcranial Doppler ultrasonography to evaluate the intracranial vessels, and by magnetic resonance angiography or CT angiography, which can evaluate both extra- and intracranial vessels. Conventional angiography can be performed to denitively image the vasculature if the noninvasive studies do not provide an answer. Cardiac evaluation consists of ECG and rhythm strip, cardiac telemetry to monitor for arrhythmias, especially atrial brillation, and echocardiography, which can be either transthoracic or the more invasive but more sensitive transesophageal echocardiography. Blood workup consists of analysis of coagulation times (PT, activated PTT), hemoglobin and hematocrit, and platelet count. Hypercoagulation proles (including but not limited to protein C and S levels, antiphospholipid protein antibody titers, antithrombin III levels, and factor V Leiden mutation) should be performed in younger stroke patients or in patients with no clearly identied, more common cause. Young patients should also be screened for illicit drug use, especially sympathomimetic drugsmost importantly, cocaine. Risk factor evaluation consists of identifying and searching for the following modiable risk factors: Hypertension Hyperlipidemia Diabetes Tobacco use
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Excessive alcohol use Illicit drug use Hyperhomocysteinemia Heart disease, especially atrial brillation or cardiomyopathies
Secondary Prevention
Secondary prevention must be initiated early.Appropriate secondary prevention is based on identication of the cause of stroke and identication of all modiable risk factors and potential surgical intervention. Aggressively treat all identied risk factors (hypertension, diabetes, hyperlipidemia, hyperhomocysteinemia, heart disease, hypercoagulable states) and encourage changes in lifestyle and behavior, especially regarding medication compliance, diet and exercise, smoking and illicit drug cessation, and moderation of alcohol intake. Initiate antithrombotic therapy for secondary prevention based on an identied cause. Antithrombotic therapy is intended to decrease clot formation, which is the end result that causes arterial blockage in most ischemic strokes.Antiplatelet therapy with aspirin has been shown to decrease stroke recurrence by approximately 25%. Ticlopidine, clopidogrel, and combination therapy with aspirin plus extended-release dipyridamole have all been shown to be somewhat more effective at preventing recurrent strokes than aspirin, but at a much higher price. Antiplatelet therapy is generally thought to be most effective in high-ow states in which platelet
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aggregation is thought to be the initiating event for thrombus formation.Anticoagulation with warfarin has been shown to dramatically decrease cardioembolic strokes owing to atrial brillation and mechanical valves and in postmyocardial infarction cardiomyopathy.Warfarin is thought to be more effective than antiplatelet therapy in low-ow states in which activation of clotting factors is thought to be the more important mechanism of initial clot formation.23,2533 Carotid endarterectomy has been shown to be effective for stroke prevention in patients symptomatic with stroke or TIA in the setting of an internal carotid artery (ICA) stenosis of 50 to 99%.The benet increases with increasing severity of stenosis. The benet is much less with stenoses in the 50 to 69% range, especially so in diabetic women in that stenosis range because surgical complications almost cancel out benets in that subgroup of patients. A large clinical trial has shown that carcinoembryonic antigen (CEA) for asymptomatic patients with ICA stenosis of 60 to 99% reduces stroke rate, but the riskbenet ratio is much narrower than in symptomatic patients.
Sample Secondary Prevention Guidelines Based on Cause
Atherosclerosis Symptomatic ICA stenosis 70 to 99% = CEA followed by aspirin therapy

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Symptomatic ICA stenosis 50 to 99% = probable CEA but requires heightened risk-benet assessment and aspirin after CEA Extracranial carotid disease but less than 50% stenosis = antiplatelet therapy Intracranial disease: antiplatelet therapy unless possible very high-grade intracranial stenosis Cardioembolic source: warfarin, usually with a targetINR of 2.0 to 3.0. Lacunar syndrome: antiplatelet therapy Hypercoagulable state: warfarin, INR 2.0 to 3.0 Nonatherosclerotic vasculopathy: therapy dependent on cause Dissection: warfarin for 6 months then antiplatelet therapy Vasculitis: immune-modulating therapy with steroids, azathioprine, cyclophosphamide Hypoperfusion: treat anemia, increase blood pressure Treat hypertension aggressively after the acute stage of the stroke. ACE inhibitors are neuroprotective in addition to their antihypertensive effects. Consideration should be made for treatment of stroke patients with ACE inhibitors even in the setting of normal blood pressure. Aggressive treatment of hyperlipidemia should be considered, especially using statin medications, which likely reduce the incidence of recurrent stroke. Patients with hyperhomocysteinemia should probably be treated with folic acid. All risk factors should be aggressively screened for and treated!
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CONCLUSION
Stroke is a brain attack. Stroke is not an accident. Stroke is a treatable, preventable disease.
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26. CAPRIE Steering Committee.A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996;348:132939. 27. Diener HC, Cuhna L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143: 113. 28. Diener HC, Forbes C, Riekkinen PJ, et al. European Stroke Prevention Study 2: efcacy and safety data. J Neurol Sci 1997;151:S177. 29. Hass WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke. N Engl J Med 1989;321:5017. 30. Feinberg WM. Guidelines for the management of transient ischemic attacks. Heart Dis Stroke 1994;3:27583. 31. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001; 119:300S20S. 32. Yusuf S, Zhao F, Mehta SR, et al.The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494502. 33. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:144451. 34. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benecial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:44553. 35. Barnett H, Taylor D, Eliasziw M, et al. Benet of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339:141525.
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36. Libman RB, Wirkowski EA, Rao TH. Conditions that mimic stroke in the emergency department. Implications for acute stroke trials. Arch Neurol 1995;52:111922.
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CHAPTER 8
NEUR OLEPTIC MALIGNANT SYNDR O ME

Rober t L. Rodnitzky, MD
CASE
22-year-old man with a diagnosis of schizophrenia had been treated with risperidone and benztropine mesylate. Because of an exacerbation of his psychosis with resultant paranoid delusions, he was admitted to the hospital. He demonstrated severe agitation and aggressive behavior, which resulted in his antipsychotic therapy being changed from risperidone to parenteral haloperidol.Three days later, he was noted to be intermittently slightly less alert. On examination, there was signicant axial and appendicular rigidity. He had a heart rate of 112 bpm and a temperature of 103F. Laboratory evaluation revealed a white blood count of 13,200 without a left shift. The serum creatine kinase level was 3,140 U/L. Chest radiography and urinalysis were normal. A diagnosis of neuroleptic malignant syndrome (NMS) was made. Haloperidol was discontinued, and benztropine mesylate was tapered and discontinued over 3 days. Dantrolene was started in an initial daily dosage of 75 mg. He was placed under a cooling blanket and hydrated with intravenous uids. After 24 hours of therapy, there was only mild improvement in the rigidity and fever and no change in his level of alertness. The daily dosage of dantrolene was increased to 150 mg. On the third day, dantrolene was increased to 200 mg, and bromocriptine 2.5 mg three times daily was begun and then titrated up to 5 mg three times daily on the fourth
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day.The rigidity began to improve, and the body temperature normalized. Liver function tests were monitored while on dantrolene therapy. After 8 days of therapy, there was no further rigidity, mental alertness was normal, and blood pressure and pulse rate were normal and stable. Dantrolene therapy was continued orally for the next 7 days, and bromocriptine was continued for the next 5 days, with a subsequent 3-day taper to zero. Creatine kinase levels gradually normalized over the rst 7 days of therapy.
DEMOGRAPHICS
NMS is a rare but potentially lethal complication of therapy with dopamine receptor blocking agents (DRBAs). It can also occur in patients with Parkinsons disease after rapid withdrawal of dopaminergic medications. The reported incidence rate in patients receiving typical neuroleptic drugs has varied widely, but in one of the largest and most recent studies, an incidence of 0.15% was reported.1 This represented a signicant decline in the reported incidence of 1.4% at the same medical center a decade earlier.2 The authors suggested that this nearly 10fold decline in incidence reected both better recognition of risk factors and preemptive early recognition and treatment of the syndrome. In addition, declining use of depot agents and the use of lower overall dosages of neuroleptic drugs may have contributed to the declining incidence.3
CAUSATIVE AGENTS AND RISK FACTORS
NMS is most commonly associated with the use of typical neuroleptics, such as haloperidol and uphenazine. The
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Neurolept ic Malignant Syndrome
atypical antipsychotic agents, including clozapine,4 olanzapine,5 risperidone,6 and quetiapine,7 have all been reported to cause NMS. However, there is a lower incidence in patients receiving these atypical agents, and at least in the case of clozapine, a milder syndrome with less predominant fever and elevation of creatine kinase may result.4 It is important to remember that antiemetic DRBAs such as metoclopramide and prochlorperazine can also result in NMS. NMS can also occur in patients with Parkinsons disease after rapid withdrawal or reduction of dopaminergic drugs8 or, rarely, during a daily wearing-off episode at the end of a levodopa interdose interval. NMS has been reported to occur after therapy with a variety of drugs that do not have signicant dopamine blocking action, such as tricyclics, selective serotonin inhibitors, benzodiazepines, methylphenidate, and carbamazepine. Such cases are infrequent, and in some reports, the clinical presentation is very atypical or indistinguishable from serotonin syndrome. When caused by administration of neuroleptics, the onset of the syndrome is usually within 1 month after the initiation or increase in dosage of the offending agent, although as many as 16% of cases develop within the rst day of therapy and 30% appear within 2 days.9 The incidence rate is highest in young males and in patients who are agitated, dehydrated, or hyponatremic or who have received a large, rapidly administered dosage of the offending DBRA.1012 Elevation of serum levels of creatine kinase during nonNMS psychotic episodes has been found to increase the risk of NMS in the future.13 The syndrome can occur in children and in adults. A recent review of the literature identied 4 cases below the age of 6 years, 6 cases between
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the ages of 6 and 10 years, and 22 cases between the ages of 11 and 14 years.14 The relatively low number of case reports in childhood may reect the more limited use of DRBAs in this age group.
CLINICAL FEATURES
The cardinal clinical manifestations of NMS are similar irrespective of its causation (Figure 81).The symptomatology consists of fever, muscular rigidity, autonomic instability, and confusion or alteration in consciousness.15 The autonomic disturbance may consist of any combination of symptoms, including tachypnea, tachycardia, labile blood pressure, diaphoresis, and urinary retention. The most striking movement disorder is rigidity, which is often axial and sometimes results in an opisthotonic posture. In a review of 52 cases of NMS, other movement disorders that were moderately common included dystonia, chorea, and a parkinsonian appearance.16 Buccofacial dyskinesias, oculogyric crises, and blepharospasm can be noted but are much less frequent. In children, dystonia is more likely to be the predominant extrapyramidal feature.14 Other neurologic signs that are occasionally reported in these cases include sialorrhea, dysphagia, exor or extensor posturing, muscle stretch reex abnormalities, and Babinskis signs.A review of over 300 cases of NMS found that changes in either mental status or rigidity were the initial manifestation in 82% of cases and were much more likely to be observed before the onset of hyperthermia and autonomic dysfunction.17 In the same series, 70% of the cases followed a sequence of presentation consisting of mental status changes, rigidity, hyperthermia, and autonomic dys170
function. Fever is typically at least 38C and often higher. Creatine kinase levels are usually above 2,000 IU/L and often in the range of 15,000 to 20,000 IU/L. Diagnostic confusion is possible because milder forms of the syndrome may exist without all of the cardinal features of the illness. Cases that are otherwise typical except for absence of fever have been reported. 18 In some patients, even in those who ultimately die of the syndrome, classic features such as muscle rigidity may not be present.19 Accordingly, it has been suggested that only three of the four classic features of the illness, fever, rigidity, altered consciousness, and autonomic instability, need to be present within a period of 1 day to consider the diagnosis of NMS.20 Another potential source of diagnostic confusion in NMS is the fact that some neuroleptics, particularly those characterized as atypical, can result in adverse effects that overlap with the symptoms of NMS and are inappropriately attributed to NMS.21 Lastly, it must be kept in mind that there are other syndromes that can result in hyperthermia, including malignant hyperthermia, anticholinergic poisoning, reactions to sympathomimetics, and infection, particularly meningitis.22 The recent increase in the use of 3,4-methylenedioxymethamphetamine (Ecstasy) among adolescents and young adults at drug-inspired dance gatherings known as raves has introduced an important differential diagnosis consideration for NMS.23 Exposure to this street drug, especially after dehydration resulting from vigorous dancing, can result in a syndrome of hyperthermia, autonomic instability, and elevated creatine kinase resembling NMS.24
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Figure 8-1 An algorithm for the treatment of neuroleptic malignant syndrome beginning with the withdrawal of the dopamine blocking agent or reinstitution of the withdrawn dopaminergic agent followed by appropriate pharmacologic and suppor tive therapies. DRBA = dopamine receptor blocking agent.
It is sometimes difcult to distinguish NMS from the serotonin syndrome because these two conditions have several clinical features in common, such as hyperthermia and alteration in consciousness. Useful features for differentiating the two conditions include the predominance of shivering, myoclonus, and gastrointestinal symptoms such as diarrhea and nausea in serotonin syndrome as opposed to prominent rigidity, marked elevation of creatine kinase, and more prominent autonomic disturbances in NMS.
TREATMENT AND PROGNOSIS
The treatment of NMS should be considered emergent, especially in cases in which all of the clinical criteria are fullled. In these cases, serious morbidity and, occasionally, mortality are possible. Serious morbidity can occur, including cardiac failure and cerebellar degeneration.The most common complications affecting the prognosis are respiratory disturbances and renal failure, the latter of which is associated with disseminated intravascular coagulation and rhabdomyolysis. The rst therapeutic measure that must be taken to treat NMS is discontinuance of the offending neuroleptic or other causative drug, or, in the case of patients with Parkinsons disease, replacing the recently withdrawn dopaminergic drug. In addition, drugs that inhibit heat dissipation, such as anticholinergic agents, should be discontinued, preferably by tapering to avoid rebound phenomena. Supportive measures such as hydration and lowering of fever should be started early. Occasionally, respiratory support is needed because of severe rigidity of
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respiratory musculature. Arrhythmias and blood pressure abnormalities must be treated. The most commonly used specic medical therapies for NMS include bromocriptine and dantrolene followed by amantadine. Although the use of one or all of these therapies enjoys widespread acceptance, there are no rigorous objective studies to support their efcacy in NMS. This is in large part due to the absence of prospective blinded placebo- or comparator-controlled studies of the condition. Most large studies of therapy in NMS are retrospective case report analyses culled from the literature. One of the largest of these retrospective reviews evaluated 734 cases of NMS and concluded that therapy with either bromocriptine, dantrolene, or amantadine resulted in a lower mortality rate than supportive therapy alone.25 In contrast, a smaller nonblinded, nonrandomized prospective study of 20 consecutive patients concluded that patients receiving bromocriptine or dantrolene actually endured a longer duration of symptoms than those receiving supportive therapy alone.26 The possibility of bias in selecting specic therapies in all of these reported case studies is so great as to cast signicant doubt on the recommendations that they generate. The treatment recommendations that follow here represent a view that, even in the absence of scientic conrmation, has been elevated to the status of common practice. Bromocriptine therapy can begin at 2.5 mg every 6 hours. If there is no response after 24 hours, the dosage can be doubled and then be titrated further upward according to clinical need to a dosage of 50 mg/d. Dantrolene can be similarly titrated using dosages in the range of
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1 to 10 mg/kg/d in divided dosages. In most cases, dosages toward the lower end of this range will be required, especially as initial therapy.27 The question arises as to when to use these drugs and which of them to begin rst.The earlier therapy is begun, the greater the likelihood of altering the course of NMS. Circumstances that would suggest the use of bromocriptine rst include the presence of a severe alteration in the level of consciousness and preserved ability to receive medication by mouth or nasogastric tube (there is no parenteral dosage form of bromocriptine). Findings that suggest that dantrolene should be chosen as the initial therapy are severe muscle rigidity, marked hyperthermia, and an inability to safely administer medication orally or by tube (dantrolene can be administered intravenously). These recommendations are largely based on the notion that bromocriptine will be most effective for symptoms related to central nervous system dysfunction, whereas dantrolene is more likely to improve rigidity and symptoms that result from it, such as hyperthermia. In this regard, it should be noted that it is possible that dantrolene may have some central effects as well.28 If the clinical circumstances do not clearly favor one of these two drugs over the other, bromocriptine is the preferred initial treatment. Whichever therapy is started initially, the other medication may need to be added if there is no apparent improvement by 36 to 48 hours. Even after resolution of symptoms, treatment should be continued for 7 to 10 days and for twice that duration if depot neuroleptics had been administered. Several second-line therapies are also avail176
able.Amantadine was found to improve NMS mortality in a large meta-analysis, 25 and there are case reports of remarkable improvement after administration of carbamazepine.29 Apomorphine, a rapidly acting dopamine agonist that can be administered subcutaneously, shows promise of providing a more rapid and complete response than bromocriptine, which must be administered orally.30 Plasma exchange has been reported to be effective in a single case in which the procedure was used for removing a long-acting protein-bound neuroleptic drug from the peripheral circulation.31 Electroconvulsive (ECT) treatment should be considered in patients with an inadequate response to medical therapy. It may also be indicated in patients whose psychosis has seriously worsened owing to the required withdrawal of neuroleptics.32 It must be kept in mind that the autonomic dysfunction associated with NMS might increase the risk of serious cardiovascular problems during ECT. Recovery typically occurs over a 1- to 2-week period, the longer resolution occurring in those patients who received long-acting depot neuroleptics. Rechallenge with neuroleptics after recovery results in recurrence of NMS in less than 15% of cases and is less likely to occur if more than 2 weeks pass before the rechallenge and an atypical neuroleptic agent is used.33 During reintroduction, careful monitoring should be undertaken for premonitory signs of NMS, such as an elevation of creatine kinase or the white blood count, signs of autonomic instability, or any alteration in the level of consciousness. In cases in which a transition from a typical neuroleptic to an atypical antipsychotic agent is executed
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to prevent the primary occurrence of NMS or its reappearance, the risk of the syndrome may be increased if there is an overlap period during which both agents are being administered.34 The prognosis for rapid and complete recovery is improved by early recognition and early intervention, including discontinuance of the offending drug and early initiation of therapy. Untreated, the syndrome usually reaches peak severity within 3 days.With treatment, fever, rigidity, creatine kinase levels, and autonomic dysfunction usually improve within 1 to 3 days, and full resolution can be expected within 1 to 2 weeks or slightly longer if depot neuroleptics were used.29 Among those who recover from the acute hyperthermia, persistent symptoms such as a residual catatonic state can be seen in a small percentage of cases.31 In a small percentage of patients, there is a fatal outcome. Patients with severe rhabdomyolysis, myoglobinuria, and renal failure are most likely to succumb.25 Although mortality from NMS was reported to be as high as 76% in the 1960s,35 more recent studies suggest that with earlier recognition and better treatment, it is now in the range of 5 to 8%.
REFERENCES 1. Keck PE Jr, Pope HG Jr, McElroy SL. Declining frequency of neuroleptic malignant syndrome in a hospital population. Am J Psychiatry 1991;148:8802. 2. Pope HG Jr, Keck PE Jr, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry 1986;143:122733.
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3. Deng MZ, Chen GQ, Phillips MR. Neuroleptic malignant syndrome in 12 or 9,792 Chinese inpatients exposed to neuroleptics: a prospective study. Am J Psychiatry 1990; 147:114955. 4. Karagianis JL, Phillips LC, Hogan KP, LeDrew KK. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999;33:62330. 5. Filice GA, McDougall BC, Ercan-Fang N, Billington CJ. Neuroleptic malignant syndrome associated with olanzapine. Ann Pharmacother 1998;32:11589. 6. Bajjoka I, Patel T, OSullivan T. Risperidone-induced neuroleptic malignant syndrome. Ann Emerg Med 1997;30: 698700. 7. Stanley AK, Hunter J. Possible neuroleptic malignant syndrome with quetiapine. Br J Psychiatry 2000;176:497. 8. Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in Parkinsons disease after withdrawal or alteration of dopaminergic therapy. Arch Intern Med 1991;14:7946. 9. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull 1988;24:249. 10. Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry 1997;154:11568. 11. Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malignant syndrome.Acta Psychiatr Scand 1994;90: 4246. 12. Elizalde-Sciavolino C, Racco A, Proscia-Lieto T, Kleiner M. Severe hyponatremia, neuroleptic malignant syndrome, rhabdomyolysis and acute renal failure. Mt Sinai J Med 1998;65:2848. 13. Hermesh H, Manor I, Shiloh R,et al. High serum creatinine kinase level: possible risk factor for neuroleptic malignant syndrome. J Clin Psychopharmacol 2002;22:2526.
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14. Silva RR, Munoz DM, Alpert M, et al. Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38:187194. 15. Rodnitzky RL, Keyser DL. Neurologic complications of drugs.Tardive dyskinesias, neuroleptic malignant syndrome, and cocaine-related syndromes. Psychiatr Clin North Am 1992;15:491510. 16. Kurlan R, Hamill R, Shoulson I. Neuroleptic malignant syndrome. Clin Neuropharmacol 1984;7:10920. 17. Velamoor VR, Norman RM, Caroff SN, et al. Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis 1994;182: 16873. 18. Peiris DT, Kuruppuarachchi K, Weerasena LP, et al. Neuroleptic malignant syndrome without fever: a report of three cases. J Neurol Neurosurg Psychiatry 2000;69:2778. 19. Wong MMC. Neuroleptic malignant syndrome: two cases without muscle rigidity. Aust N Z J Psychiatry 1996; 30:4158. 20. Sachdev P. The diagnosis of neuroleptic malignant syndrome revisited. Aust N Z J Psychiatry 1996;30:8756. 21. Hasan S, Buckley P. Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry 1998;155:11136. 22. Chan TC, Evans SD, Clark RF. Drug-induced hyperthermia. Crit Care Clin 1997;13:785808. 23. Arria A, Yacoubian G, Fost E, Wish E. Ecstasy use among club rave attendees. Arch Pediatr Adolesc Med 2002;156:. 24. Demirkiran M, Jankovic J, Dean JM. Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome. Clin Neuropharmacol 1996;19: 15764. 25. Sakkas D, Davis JM, Hua J, Wang Z. Pharmacotherapy of neuroleptic malignant syndrome. Psychiatr Ann 1991;21: 15764.
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26. Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care? Br J Psychiatry 1991;159:70912. 27. Tsutsumi Y,Yamamoto K, et al.The treatment of neuroleptic malignant syndrome using dantrolene sodium. Psychiatry Clin Neurosci 1998;52: 4338. 28. Tanii H, Taniguchi N, Tsujio I, et al. Dantrolene sodium reverses the increase in cAMP response element and TPA responsive element DNA-binding activity in the rabbit brain following haloperidol administration and heat stress. Psychiatry Clin Neurosci 1997;51:4159. 29. Rosenberg MR, Green M. Neuroleptic malignant syndrome: review of response to therapy. Arch Intern Med 1989;149:192731. 30. Wang HC, Hsieh Y. Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy. Mov Disord 2001;16:76567. 31. Caroff SN, Mann SC, Keck PE Jr, Francis A. Residual catatonic state following neuroleptic malignant syndrome. J Clin Psychopharmacol 2000;20:2579. 32. Trollor JN, Sachdev PS. Electroconvulsive treatment of neuroleptic malignant syndrome: a review and report of cases. Aust N Z J Psychiatry 1999; 33:650. 33. Rosebush PI, Stewart TD, Gelenberg AJ.Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry 1989;50:2958. 34. Reeves RR, Mack JE, Torres RA. Neuroleptic malignant syndrome during a change from haloperidol to risperidone. Ann Pharmacother 2001; 35:698701. 35. Kellam AMP. The neuroleptic malignant syndrome, socalled: a survey of the world literature. Br J Psychiatry 1987;150:7529.
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CHAPTER 9
ENCEPHALITIS
Karen L. Roos, MD
ncephalitis is an acute infection of brain parenchyma characterized clinically by fever, headache, and an altered level of consciousness.There may also be focal or multifocal neurologic decits and focal or generalized seizure activity. Herpes simplex virus 1 (HSV-1) and the arthropodborne viruses are the major etiologic agents of viral encephalitis in immunocompetent individuals.
CASE
A 60-year-old gentleman presents with a 3-week history of fever, left hemicranial headache, and dysphasia. His daughter had taken him to the emergency department on two occasions during the last 3 weeks. During each visit, he had cerebrospinal uid (CSF) analysis, which demonstrated a lymphocytic pleocytosis with a normal glucose concentration and a slightly increased protein concentration. The daughter was told that her father had viral meningitis and would recover without antimicrobial therapy. She brings him for neurologic consultation because his difculty with nding words is getting worse.
DISCUSSION
The clinical presentation of HSV-1 encephalitis includes fever, hemicranial or generalized headache, confusion, and
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Enc ephali t is
behavioral abnormalities.These complaints may be associated with focal seizure activity or focal neurologic decits such as a disturbance of language or hemiparesis. Symptoms often take 2 to 3 weeks to reach maximal severity. The diagnosis of HSV-1 encephalitis is made by neuroimaging, electroencephalography (EEG), and examination of the CSF. Magnetic resonance imaging (MRI) is the neuroimaging procedure of choice (Figure 9-1).There is
Figure 9-1 The characteristic abnormality on magnetic resonance imaging of herpes simplex virus 1 encephalitis is a high signal intensity lesion on T2-weighted and uid-attenuated inversion recover y (FLAIR) images in the medial and inferior temporal lobes extending up into the insula.
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a distinctive EEG pattern in HSV encephalitis consisting of periodic, stereotyped, sharp- and slow-wave complexes that occur at regular intervals of 2 to 3 seconds and are expressed maximally over the involved temporal lobe. These discharges may be either unilateral or bilateral and are seen in two-thirds of pathologically proven cases of HSV encephalitis, typically between the second and the fteenth day of the illness. Examination of the CSF reveals an increased opening pressure, a lymphocytic pleocytosis of 5 to 500 cells/mm 3, red blood cells and/or xanthochromia reecting the hemorrhagic necrotic nature of the encephalitis, a mild to moderate elevation of the protein concentration, and a normal or slightly decreased glucose concentration. CSF viral cultures for HSV-1 are almost always negative.The availability of the polymerase chain reaction (PCR) for the detection of viral deoxyribonucleic acid (DNA) in CSF has increased the ability to make a diagnosis of HSV encephalitis. It generally takes from 1 to 4 days to obtain the results of PCR assay for HSV DNA. Red blood cells in the CSF will inhibit the PCR reaction; therefore, bloody CSF should never be sent for PCR to detect viral DNA. HSV DNA in CSF precedes the appearance of HSV antibodies by several days (Figure 9-2). CSF and serum samples should be obtained to determine if there is intrathecal synthesis of antibodies against HSV.Antibodies to HSV do not appear in the CSF until approximately 8 to 12 days after the onset of disease and increase signicantly during the rst 2 to 4 weeks of infection. A serum-to-CSF antibody ratio of 20:1 is considered diagnostic of HSV infection. Brain biopsy is generally reserved for those patients who fail to respond to
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Enc ephali t is
Encephalitis
Fever, headache, and an altered level of consciousness focal neurologic deficits seizure activity
Acyclovir plus ceftriaxone, cefotaxime, or cefepime plus vancomycin plus doxycycline (tick season)
MRI EEG Spinal fluid (CSF) analysis
Cell count with differential Glucose and protein concentration Gram's stain and bacterial culture PCR (HSV-1 and HSV-2) Herpes simplex virus antibodies IgM antibody titers Viral culture
Serum for herpes simplex virus antibodies Serum IgM antibody titers Acute convalescent sera for IgG antibody titers
Figure 9-2 CSF = cerebrospinal uid; EEG = electroencephalography; HSV = herpes simplex virus; Ig = immunoglobulin; MRI = magnetic resonance imaging; PCR = polymerase chain reaction.
acyclovir therapy and in whom MRI does not reveal an area of increased signal intensity on T2-weighted and uid-attenuated inversion recovery (FLAIR) images in the orbitofrontal and temporal areas, and/or the CSF PCR is
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negative for HSV DNA and there is no evidence of intrathecal synthesis of HSV antibodies. The empiric therapy of encephalitis in an immunocompetent patient should include intravenous acyclovir (child: 30 mg/kg/d every 8-hour dosing interval); adult: 30 mg/kg/d every 8-hour dosing interval); a third- or fourth-generation cephalosporin, either ceftriaxone (child: 100 mg/kg/d every 12-hour dosing interval; adult: 4 g/d every 12-hour dosing interval), cefotaxime (child: 200300 mg/kg/d every 4- to 6-hour dosing interval; adult: 12 g/d every 4-hour dosing interval), or cefepime (46 g/d every 12-hour dosing interval); and vancomycin (child: 60 mg/kg/d every 6-hour dosing interval; adult: 2 g/d every 6-hour dosing interval). Acyclovir is used for HSV-1 encephalitis, and the combination of a third- or fourth-generation cephalosporin and vancomycin is used for Streptococcus pneumoniae and Neisseria meningitidis, the most common causative organisms of communityacquired bacterial meningitis in children and adults and the leading disease in the differential diagnosis of encephalitis. In areas of the United States in which Rocky Mountain spotted fever is endemic, during tick season, doxycycline 100 mg twice daily is added to the empiric regimen.When HSV-1 is identied as the etiologic agent of the encephalitis, antimicrobial therapy is modied to intravenous acyclovir in a dose of 10 mg/kg every 8 hours for 3 weeks. Acyclovir-resistant strains of HSV-1 are rare but increasing; therefore, the patient with clinical characteristics typical of HSV-1 who is not responding to acyclovir should be treated with foscarnet (60 mg/kg every 8 hours) in addition to acyclovir.
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Enc ephali t is
The possibility that an arthropod-borne virus (arbovirus) is the etiologic agent of encephalitis should be considered in all cases of encephalitis occurring in late summer and fall.The geographic area in which the patient lives or where the patient has visited is important in identifying the arboviral etiologic agent of encephalitis (Table 9-1).The arboviruses are inoculated into the host subcutaneously by a mosquito bite and then undergo local replication at the skin site. A viremia follows, and if there is a large enough inoculum of virus, invasion and infection of the central nervous system occur. Infection of the central nervous system by an arbovirus may be asymptomatic, a mild febrile illness with headache, an aseptic meningitis, or an encephalitis.The onset of encephalitis symptoms is often preceded by an inuenza-like prodrome of malaise, myalgias, and fever.This is followed by symptoms of headache, nausea, vomiting, confusion, disorientation, and, occasionally, convulsions. Progressive deterioration in the level of consciousness may occur from lethargy to stupor to coma. Based on criteria established by the Centers for Disease Control and Prevention,1 a conrmed case of arboviral encephalitis is defined as a febrile illness with encephalitis during a period when arboviral transmission is likely to occur plus at least one of the following: (1) a fourfold or greater rise in viral antibody titer between acute and convalescent sera; (2) viral isolation from tissue, blood, or CSF; or (3) specic immunoglobulin M (IgM) antibody in CSF. A presumptive case is dened as a compatible illness plus either a stable elevated antibody titer to an arbovirus ( 320 by hemagglutination inhibition, 128 by complement xation, 256 by immunouorescent
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Table 9-1 Geographic Distribution of Arboviruses Virus La Crosse virus Geographic Area Midwestern United States (Indiana,Wisconsin, Minnesota, Illinois, Iowa) Central and southeastern United States, western and eastern Canada China, southeast Asia, northeast India, Napal, and Sri Lanka Northeastern and midwestern United States and Florida East and Gulf coast of the United States, Minnesota, Texas States west of the Mississippi River Venezuela,Texas, and Mexico Colorado, Utah, Montana, Wyoming, Idaho, California, South Dakota, Nevada, New Mexico Canada (Powassan, Ontario) and New York
St. Louis encephalitis virus Japanese encephalitis virus West Nile virus Eastern equine encephalitis virus Western equine encephalitis virus Venezuelan encephalitis virus Colorado tick fever virus
Powassan virus
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Enc ephali t is
assay, or 160 by plaque reduction neutralization test) or a specic IgM antibody in serum by enzyme immunoassay. Treatment of arbovirus encephalitis is primarily supportive care with management of the neurologic complications of seizures and increased intracranial pressure. Ribavirin is a synthetic nucleoside analogue that has been demonstrated in vitro to inhibit the replication of La Crosse virus. The differential diagnosis of a rash and encephalitis includes the following: (1) enteroviral encephalitis, (2) meningococcemia, (3) West Nile virus encephalitis, and (4) Rocky Mountain spotted fever. Empiric therapy should include a combination of penicillin G for meningococcemia and doxycycline for Rocky Mountain spotted fever while awaiting the results of diagnostic studies.The rash of Rocky Mountain spotted fever is initially a diffuse erythematous maculopapular rash that has an appearance similar to that of the rash of meningococcemia. It progresses to a petechial rash, then to a purpuric rash, and, if untreated, to skin necrosis or gangrene.The rash of Rocky Mountain spotted fever typically begins on the wrists and ankles, spreads distally and proximally within a matter of a few hours, and involves the palms and soles. Diagnosis is made by direct immunouorescence or immunoperoxidase staining of skin biopsies for detection of the bacteria Rickettsia rickettsii. Serologic diagnosis requires a fourfold rise in antibody titer between acute and convalescent sera. Rocky Mountain spotted fever is treated with doxycycline 100 mg twice daily. Doxycycline is used for a minimum of 5 to 7 days and until the patient has been afebrile for 2 days.
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REFERENCE 1. United States of America.Arboviral disease. MMWR Morb Mortal Wkly Rep 1995;44:6414.
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CHAPTER 10
BACTERIAL MENINGITIS
Karen L. Roos, MD
ever, headache, and stiff neck are the classic triad of symptoms and signs of bacterial meningitis. Nausea, vomiting, photophobia, and lethargy are also common complaints. The level of consciousness may deteriorate from lethargy to stupor to coma while the patient is being evaluated in the emergency department. Seizure activity occurs in approximately 40% of patients with bacterial meningitis and typically occurs at either the onset or within the rst few days of the illness. A stiff neck, or meningismus, is the pathognomonic sign of meningeal irritation. Meningismus is present when the neck resists passive exion. Brudzinskis sign is positive when passive exion of the neck results in spontaneous exion of the hips and knees. The most common causative organisms of communityacquired bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. Pneumonia may precede the symptoms of pneumonococcal meningitis in an adult. Meningococcal meningitis may be accompanied by a rash, which begins as a diffuse erythematous maculopapular rash that resembles a viral exanthem. The lesions of meningococcemia rapidly become petechial. The rash of meningococcemia begins on the trunk and lower extremities. Petechiae may also be found in the mucous membranes and conjunctiva and, occasionally, on the palms and soles.
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LABORATORY DIAGNOSIS
Examination of the cerebrospinal uid (CSF) is the gold standard for the diagnosis of bacterial meningitis.The classic CSF abnormalities in bacterial meningitis are as follows: (1) increased opening pressure, (2) a pleocytosis of polymorphonuclear leukocytes (10 to 10,000 cells/mm3), (3) a decreased glucose concentration (< 45 mg/dL and/or CSF-to-serum glucose ratio of < 0.31), and (4) an increased protein concentration. Opening pressure should be measured in the lateral recumbent position because the sitting position does not allow for accurate measurement of CSF pressure.The normal range of opening pressure for infants and children up to 6 years of age is 10 to 120 mm H2O and for children and adults is 10 to 200 mm H2O, and pressures of 200 to 250 mm H2O are indeterminate. In uninfected CSF in children and adults, the normal white blood cell (WBC) count ranges from 0 to 5 mononuclear cells (lymphocytes and monocytes)/mm3. In normal uninfected CSF in children and adults, there should be no polymorphonuclear leukocytes; however, with the use of a cytocentrifuge, an occasional polymorphonuclear leukocyte may be seen. If the total WBC count is < 5 mm3, the presence of a single polymorphonuclear leukocyte may be considered normal. The upper limit of normal value for CSF total WBC count is 22/mm3 in full-term neonates, 30/mm3 in infants 0 to 8 weeks, and 5/mm3 in those older than 8 weeks of age. In normal uninfected CSF in newborns, 60% of the cells are polymorphonuclear leukocytes and 40% are mononucleated cells. A normal CSF glucose concentration is between 45 and 80 mg/dL when the
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Ba cter ial M ening i t is
blood glucose concentration is between 70 and 120 mg/dL.Values below 45 mg/dL are abnormal, and a CSF glucose concentration of 0 mg/dL is not unusual in bacterial meningitis. Use of the CSF-to-serum glucose ratio corrects for hyperglycemia that may mask a decreased CSF glucose concentration. The CSF glucose concentration is low when the CSF-to-serum glucose ratio is < 0.5. A CSF-to-serum glucose ratio 0.31 is highly predictive of bacterial meningitis. It takes approximately 4 hours for the CSF glucose concentration to reach equilibrium with the blood glucose concentration after the administration of glucose; therefore, an ampule of D50 (50 mL of 50% glucose) prior to lumbar puncture, as commonly occurs en route to or in the emergency department, is unlikely to significantly alter the CSF glucose concentration unless more than a few hours have passed between glucose administration and lumbar puncture. Grams stain is positive in 70 to 90% of untreated cases of bacterial meningitis. The latex particle agglutination test for the detection of bacterial antigens of S. pneumoniae, N. meningitidis, Haemophilus inuenzae type b (Hib), group B streptococcus, and Escherichia coli K1 strains in the CSF is very useful for making a rapid diagnosis of bacterial meningitis and for making a diagnosis of bacterial meningitis in those patients who have been pretreated with oral or parenteral antibiotics in whom Grams stain and CSF culture are negative. It is important to emphasize, however, that a negative latex particle agglutination test for bacterial antigens does not rule out bacterial meningitis.The limulus amebocyte lysate assay
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is a rapid diagnostic test for the detection of gramnegative endotoxin in CSF and thus for making a diagnosis of gram-negative bacterial meningitis.To date, CSF polymerase chain reaction (PCR) tests are not as useful in the diagnosis of bacterial meningitis as they are in the diagnosis of viral central nervous sytem infections. A PCR assay is available for all of the common meningeal pathogens, but it often takes several days to obtain a PCR result, and by then Grams stain and/or culture have identied the etiologic organism. The necessity of obtaining either a cranial magnetic resonance image (MRI) or computed tomographic (CT) scan prior to lumbar puncture has been debated for years. If the neurologic examination demonstrates no focal decits, the level of consciousness is normal, and there is no evidence of papilledema, it is safe to perform lumbar puncture without imaging the brain rst. If the patient is being treated with antibiotics, there is no risk in delaying lumbar puncture until after neuroimaging is performed. Lumbar puncture should be performed with a 22- or 25gauge needle, and a minimum amount of CSF should be removed for analysis. Approximately 6 mL is sufcient to obtain cell count, glucose and protein concentrations, Grams stain and culture, and latex agglutination.An additional 1 mL of CSF can be sent to the PCR laboratory for viral deoxyribonucleic acid (DNA) analysis. Blood cultures should always be sent before or at the time of initiation of antimicrobial therapy in patients with suspected bacterial meningitis.Antibiotic therapy for several hours prior to lumbar puncture will not signicantly alter the CSF WBC count or glucose concentration, so
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that the possibility of bacterial meningitis is not suspected, and it is not likely to sterilize the CSF, so that the organism cannot be identied on Grams stain or grown in culture.The CSF WBC count increases after the initiation of antimicrobial therapy, and the glucose concentration remains low for several days. Grams stain and bacterial culture should be negative 24 hours after the initiation of antimicrobial therapy if the organism is sensitive to the antibiotic, but the etiologic organism can often still be identied by the latex agglutination technique, and it is expected that perfection of the PCR technique to detect bacterial DNA in CSF will also contribute to the diagnosis of bacterial meningitis in patients being treated with antimicrobial therapy at the time of or prior to lumbar puncture. MRI is preferred over CT because of its superiority in demonstrating areas of cerebral edema and ischemia.The meninges will diffusely enhance after the administration of gadolinium. This is a nonspecic abnormality, however, and it occurs with any process in which there is an increase in the permeability of the blood-brain barrier. Raised intracranial pressure is an expected complication of bacterial meningitis and is the major cause of obtundation and coma in this disease. Raised intracranial pressure may lead to cerebral herniation.The incidence of cerebral herniation caused by lumbar puncture in patients with acute bacterial meningitis is not known. Most of the articles written on this topic were written in the era before CT and MRI were available to demonstrate focal infectious mass lesions or cerebral venous sinus thrombosis. The risk of cerebral herniation from acute bacterial
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meningitis independent of lumbar puncture is approximately 6 to 8%.When the possibility of increased intracranial pressure exists because of a decreased level of consciousness, lumbar puncture should either be delayed until the increased intracranial pressure can be treated or performed with a 22-gauge needle 30 to 60 minutes after 1 g/kg of mannitol has been administered intravenously to reduce brain swelling.The patient can also undergo intubation and hyperventilation in addition to being treated with mannitol to decrease intracranial pressure prior to lumbar puncture. If lumbar puncture is delayed while increased intracranial pressure is treated, empiric antimicrobial therapy should be given.
EMPIRIC THERAPY
Empiric antimicrobial therapy is initiated when bacterial meningitis is suspected, before a diagnostic evaluation is pursued. Empiric therapy should be based on the possibility that penicillin- and cephalosporin-resistant pneumococci are the causative organisms of the meningitis and include a third- or fourth-generation cephalosporin, either ceftriaxone (pediatric dose: 100 mg/kg/d in a 12hour dosing interval; adult dose: 2 g every 12 hours), cefotaxime (pediatric dose: 300 mg/kg/d in a 4- to 6-hour dosing interval; adult dose: 3 g every 4 hours), or cefepime (adult dose: 2 g every 12 hours) plus vancomycin (pediatric dose: 40 to 60 mg/kg/d in a 6- or 12-hour dosing interval; adult dose: 500 mg every 6 hours or 1 g every 12 hours).Ampicillin plus gentamicin should be added to the empiric regimen for coverage of Listeria monocytogenes in
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individuals with impaired cell-mediated immunity owing to a chronic illness, organ transplantation, pregnancy, acquired immune deciency syndrome (AIDS), malignancies, or immunosuppressive therapy if they have not been on trimethoprim-sulfamethoxazole prophylactic therapy. Empiric therapy of neonatal bacterial meningitis should include a combination of ampicillin plus cefotaxime or ampicillin plus gentamicin to cover Streptococcus agalactiae, E. coli, L. monocytogenes, and Klebsiella pneumoniae. Acyclovir (10 mg/kg every 8 hours) is added to the empiric regimen for treatment of bacterial meningitis in infants, children, and adults because viral meningoencephalitis, specically herpes simplex virus encephalitis, is the leading disease in the differential diagnosis.
ORGANISM-SPECIFIC THERAPY
Once the results of bacterial culture and antimicrobial susceptibility tests are known, antimicrobial therapy can be modied accordingly (Table 101).
Meningococcal Meningitis
Penicillin G or ampicillin can be used for meningococcal meningitis. All CSF isolates of N. meningitidis should be tested for penicillin and ampicillin susceptibility. If antimicrobial susceptibility testing demonstrates that the isolate is a relatively penicillin-resistant strain of meningococci and in areas with a high prevalence of meningococci with decreased susceptibility to penicillin, cefotaxime or ceftri197
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Table 10-1
Antimicrobial Therapy of Bacterial Meningitis
Organism
Antibiotic Total Daily Dose (Dosing Interval) Adverse Effects Eosinophilia Biliary pseudolithiasis
Streptococcus pneumoniae
Ceftriaxone Adult dose: 4 g/d (q12h) Child dose: 200 mg/kg/d (q12h) or Cefotaxime Adult dose: 12 g/d (q4h) Child dose: 200300 mg/kg/d (q4h) or Cefepime Adult dose: 4 g/d (q12h) plus Vancomycin Adult dose: 2 g/d (q6 or q12h) Child dose: 4060 mg/kg/d (q612h)
Nausea, vomiting Diarrhea
Red man syndrome Leukopenia Eosinophilia

Continued
Table 10-1 (Continued) Rash
Neisseria meningitidis
Penicillin G Adult dose: 2024 million U/d (q4h) Child dose: 0.2 million U/kg (q4h) or Ampicillin Adult dose: 12 g/d (q4h) Child dose: 200300 mg/kg/d (q4h) Maculopapular rash Nausea, diarrhea
Staphylococci Rash Neutropenia
Methicillin sensitive
Methicillin resistant
Nafcillin Adult dose: 12 g/d (q4h) Child dose: 150200 mg/kg/d (q4h) Vancomycin Adult dose: 2 g/d (q6 or q12h) Child dose: 4060 mg/kg/d (q612h)
Leukopenia Eosinophilia
Continued
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200
Gram-negative bacilli (with the exception of Pseudomonas aeruginosa)
Cefotaxime or ceftriaxone
Nausea, vomiting, diarrhea Eosinophilia Biliary pseudolithiasis Transient in liver function tests
Pseudomonas aeruginosa
Celfazidine Adult dose: 8 g/d (q8h) Child dose: 150200 mg/kg/d (q8h)
Listeria monocytogenes
Maculopapular rash Nausea, diarrhea Nephro- and vestibulotoxicity
Ampicillin Adult dose: 12 g/d (q4h) Child dose: 200300 mg/kg/d (q4h) Gentamicin Adult dose: 6 mg/kg/d (q8h) Child dose: 6 mg/kg/d (q8h)
Streptococcus agalactiae
Penicillin G
Rash
axone should be used. A 7-day course of intravenous antibiotic therapy is adequate for most uncomplicated cases of meningococcal meningitis.The index case and all close contacts should receive chemoprophylaxis with a 2-day regimen of rifampin (600 mg every 12 hours for 2 days in adults and 10 mg/kg every 12 hours for 2 days in children older than 1 year of age). Rifampin should not be used in pregnant women. Adults can alternatively be treated with one dose of ciprofloxacin (750 mg) or azithromycin (500 mg). Close contacts are dened as those individuals who have had contact with oropharyngeal secretions either through kissing or through sharing toys, beverages, or cigarettes. The Advisory Committee on Immunization Practices recommends that college freshmen be vaccinated against meningococcal meningitis with a tetravalent (MenA, C, W-135,Y) meningococcal polysaccharide vaccine.1 MenC polysaccharide vaccine would also be effective. In the past few years, there has been an increasing incidence of meningococcal infection outbreaks on college campuses. Most of these have been caused by serogroup C N. meningitidis, which is potentially vaccine preventable. During an outbreak of meningococcal disease, individuals who have not been previously vaccinated should be treated with chemoprophylaxis. Up to 33% of secondary cases of meningococcal disease develop within 2 to 5 days of presentation of the index case.Vaccination is not a substitute for chemoprophylaxis to prevent secondary disease because there is an insufcient amount of time for the optimum effect of vaccination, which requires approximately 1 to 2 weeks for good antibody production.
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Pneumococcal Meningitis
Antimicrobial therapy of pneumococcal meningitis is initiated with a third- or fourth-generation cephalosporin and vancomycin. All CSF isolates of S. pneumoniae should be tested for sensitivity to penicillin and third- and fourthgeneration cephalosporins. Once the results of antimicrobial susceptibility tests are known, therapy can be modied accordingly.Vancomycin is initially by parenteral administration, but consideration should be given to using intraventricular vancomycin in patients who do not respond to parenteral vancomycin. Cefepime is a broad-spectrum fourth-generation cephalosporin with in vitro activity similar to that of cefotaxime or ceftriaxone against S. pneumoniae and N. meningitidis. In clinical trials, cefepime has been demonstrated to be equivalent to cefotaxime in the treatment of pneumococcal and meningococcal meningitis. Meropenem is a carbapenem antibiotic structurally related to imipenem but reportedly with less seizure proclivity than imipenem. Meropenem shows good activity against penicillin-resistant pneumococci in vitro, but the number of patients enrolled in clinical trials of meropenem in bacterial meningitis has not been sufcient to date to assess its efcacy against penicillin-resistant pneumococci or its epileptogenic potential. For pneumococcal meningitis, a repeat lumbar puncture should be performed 24 to 36 hours after the initiation of antimicrobial therapy to document eradication of the pathogen. A 2-week course of intravenous antimicrobial therapy is recommended for pneumococcal meningitis.
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Gram-Negative Bacillary Meningitis
Gram-negative bacilli (Actinetobacter calcoaceticus, E. coli, Klebsiella species, Pseudomonas aeruginosa, and Enterobacter species) cause meningitis in older adults, neurosurgical patients, alcoholics, and adults with underlying diseases, such as cancer, diabetes, congestive heart failure, chronic pulmonary disease, and hepatic or renal disease.The thirdgeneration cephalosporins, cefotaxime, ceftriaxone, and ceftazidime, are equally efcacious for the treatment of gram-negative bacillary meningitis, with the exception of P. aeruginosa. Ceftazidime is the drug of choice for P. aeruginosa meningitis. A 3-week course of intravenous antibiotic therapy is recommended for meningitis due to gram-negative bacilli.
Staphylococcal Meningitis
Staphylococcus aureus and coagulase-negative staphylococci are the predominant organisms causing meningitis as a complication of neurosurgical procedures, particularly shunting procedures for hydrocephalus, and as a complication of lumbar puncture for the administration of intrathecal chemotherapy. Meningitis due to S. aureus or coagulase-negative staphylococci is treated with nafcillin or oxacillin.Vancomycin is the drug of choice for methicillinresistant staphylococci and for patients allergic to penicillin.The CSF should be monitored during therapy, and if it continues to yield viable organisms after 48 hours of parenteral therapy, then either intrathecal or intraventricular vancomycin can be added.
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Streptococcus agalactiae Meningitis
S. agalactiae or group B streptococcus is a leading cause of bacterial meningitis and sepsis in neonates and is increasingly seen in two groups of adults: puerperal women and patients with serious underlying diseases. Meningitis due to this organism is treated with penicillin G.
Listeria monocytogenes Meningitis
L. monocytogenes is a causative organism of meningitis in individuals with impaired cell-mediated immunity from AIDS, organ transplantation, pregnancy, malignancy, chronic illness, or immunosuppressive therapy.The routine use of trimethoprim-sulfamethoxazole as a prophylactic agent to prevent Pneumocystis carinii pneumonia also reduces the risk of L. monocytogenes infection and therefore has had the added benet of decreasing the incidence of L. monocytogenes meningitis in immunosuppressed individuals. Present recommendations are that meningitis due to L. monocytogenes be treated with a combination of ampicillin and gentamicin.
Haemophilus influenzae Meningitis
Prior to the routine use of the Hib conjugate vaccine, Hib was the most common causative organism of bacterial meningitis in children.The incidence of Hib invasive disease among children 4 years of age and younger has declined 98% since the introduction of the Hib conjugate vaccine. Hib remains a causative organism of bacterial meningitis in older adults, immunocompromised patients, and patients with chronic lung disease, splenectomy,
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leukemia, and sickle cell disease. Meningitis owing to this organism is treated with a third-generation cephalosporin, either ceftriaxone or cefotaxime.
PATHOGENETIC MECHANISMS OF BRAIN DAMAGE OWING TO MENINGITIS AND THE RATIONALE FOR CORTICOSTEROID USE
The critical event in the pathogenesis of bacteria meningitis is the inammatory reaction in the subarachnoid space to the invading meningeal pathogen. It is not the pathogen itself that causes the neurologic complications. In bacterial meningitis, brain damage progresses long after the CSF has been sterilized by antibiotic therapy.The lysis of bacteria with the release of bacterial cell wall components in the subarachnoid space is the initial step in the induction of the inammatory process and the formation of a purulent exudate in the subarachnoid space. Components of bacterial cell walls, such as lipopolysaccharide molecules (endotoxins), cell wall components of gramnegative bacteria, and teichoic acid and peptidoglycan, cell wall components of pneumococcus, induce meningeal inammation by stimulating the production of inammatory cytokines and chemokines by microglia, astrocytes, monocytes, microvascular endothelial cells, and white blood cells in the CSF space. A number of pathophysiologic consequences result from the presence of the inammatory cytokines in CSF, including an increased permeability of the blood-brain barrier that allows for the leakage of serum proteins and other molecules into the CSF, resulting in the formation of a purulent exudate in
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the subarachnoid space. The purulent exudate obstructs the flow of CSF through the ventricular system and diminishes the resorptive capacity of the arachnoid granulations in the dural sinuses, leading to obstructive and communicating hydrocephalus. The inammatory cytokines recruit polymorphonuclear leukocytes from the bloodstream that degranulate and release toxic metabolites that contribute to cytotoxic edema, cell injury, and death. Dexamethasone exerts its benecial effect by inhibiting the synthesis of the inflammatory cytokines and by decreasing CSF outow resistance and stabilizing the blood-brain barrier. A meta-analysis of randomized, concurrently controlled trials of dexamethasone therapy in childhood bacterial meningitis published from 1988 to 1996 conrmed benet for Hib meningitis if begun with or before antibiotics and suggested benet for pneumococcal meningitis in children.The American Academy of Pediatrics recommends the consideration of dexamethasone for bacterial meningitis in infants and children 2 months of age and older.2 The recommended dose is 0.6 mg/kg/d in four divided doses (0.15 mg/kg/dose) given intravenously for the first 4 days of antibiotic therapy. Dexamethasone should be begun before or with the rst dose of antibiotic. There are presently ongoing clinical trials of dexamethasone therapy in adults with bacterial meningitis. Scientists working in the area of the molecular basis of neurologic injury in bacterial meningitis are in favor of the use of dexamethasone because of its benecial effect in inhibiting the synthesis of the inammatory cytokines. Figure 10-1 shows the management of the patient
206
Patient with headache, fever, stiff neck, altered level of consciousness
No rash Blood cultures, CBC Penicillin G or ampicillin Biopsy skin rash
Petechial or purpuric rash
Blood cultures, CBC
Dexamethasone (see text)
Ceftriaxone, cefotaxime, or cefepime plus vancomycin and acyclovir (doses of antibiotics in Table 10-1). For neonates, elderly, pregnant women, or immunosuppressed, add ampicillin
Head CT scan
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Figure 10-1 Recommended management of the patient with headache, fever, stiff neck, and an altered level of consciousness. CBC = complete blood count; CT = computed tomographic; HSV = herpes simplex virus; PCR = polymerase chain reaction; TB = tuberculosis.
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No signs of increased intracranial pressure
Signs of increased intracranial pressure: decreasing level of consciousness, poorly reactive pupils, papilledema
To reduce intracranial pressure: mannitol, hyperventilation
Analysis of cerebrospinal fluid cell count, chemistries, Grams stain and bacterial culture, latex agglutination, fungal smear and culture, cryptococcal antigen, PCR for HSV Deoxyribonucleic acid, TB smear or PCR and culture
Causative organism identified Modify antimicrobial therapy (Table 10-1)
If meningococcus, medicate index case and all close contacts with chemoprophylaxis
with headache, fever, stiff neck, and an altered level of consciousness and summarizes the above. In the gure, analysis of the CSF includes fungal smear and culture, cryptococcal antigen and tuberculosis smear, or PCR and culture.This information is included for the sake of completeness. Fungal meningitis and tuberculous meningitis have a much more insidious clinical presentation than bacterial meningitis, typically presenting with low-grade fever and headache of several weeks duration. In developed countries, meningitis due to fungi or Mycobacterium tuberculosis is not typically a neurologic emergency.
REFERENCES 1. Harrison LH. Preventing meningococcal infection in college students. Clin Infect Dis 2000;30:64851. 2. Committee on Infectious Diseases. Dexamethasone therapy for bacterial meningitis in infants and children. Pediatrics 1990;86:1303.
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CHAPTER 11
CEREBELLAR HEMORRHAG E AND INFAR CTION

John B. Selhorst, MD
CASE 1
54-year-old man with hypertension for 9 years complained of a sudden occipital headache and began to vomit.When he stood up to walk, he fell to the oor. In the emergency department, his blood pressure was 160/120 mm Hg. He was alert and coherent.There were no cranial nerve decits, and he moved all limbs on command. Sensation was intact in the limbs, and all reexes were normal. He was admitted to the hospital for control of his blood pressure. Four hours later, he became obtunded and slightly confused.A computed tomographic (CT) scan (Figure 11-1) showed a large hemorrhage in the right cerebellar hemisphere. The fourth ventricle was nearly obliterated, and the midbrain was compressed. Dilatation of the lateral ventricle and temporal horns indicated acute hydrocephalus (Figure 11-2).After immediate evacuation of the hematoma, the patient quickly improved.
CASE 2
A 68-year-old woman complained of dizziness. A mild headache and nausea followed. She required limited support to walk. CT scanning revealed a 2.0 cm hematoma in the
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Cereb ellar Hem orrhage and Infarct ion
Figure 11-1 Computed tomographic scan shows a large right cerebellar hematoma that nearly obliterates the four th ventricle (A) and compresses the dorsolateral midbrain (B) (Case 1).
anterior cerebellar vermis (Figure 11-3). Over the ensuing week, the headache and nausea remitted.After several more weeks, the patient was able to walk again unaided.
CASE 3
A 63-year-old truck driver developed transient, severe vertigo. The spinning sensation recurred 20 minutes later. A CT scan in an emergency department was normal. He was hospitalized overnight for observation.The next morning, he was found in a stuporous state. He was transferred to an acute stroke unit within the hour. He arrived in coma. Pupils were small and reacted poorly to light. Eye move211
Figure 11- 2 Computed tomographic scan through the lower cerebral hemispheres discloses the enlarged comma shape of dilated temporal horns (A) and expanded third and lateral ventricles (B) (Case 1).
ments were absent with rotation of the head or caloric stimulation with ice water. Decerebrate posturing occurred with pressure on the nail beds.A repeat CT scan showed obliteration of the fourth ventricle and dilated lateral ventricles, including the temporal horns.An immediate ventriculoperitoneal shunt was placed.Within the day, he was arousable and able to move each limb. Ten days later, he was independently ambulatory. His only neurologic decit was an inability to perform a tandem walk. Twelve years later, he remained in good health.
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Figure 11- 3 Computed tomographic scan shows a 2.0 cm hematoma in the anterior vermis (A) that impinges on the upper four th ventricle but does not result in obstruction of cerebrospinal uid or expand the temporal horns (B) (Case 2).
INTRODUCTION
Hemorrhage into the deep parenchyma of the cerebellum typically occurs in older hypertensive males.The situation presents several clinical challenges.The rst involves diagnosis, and the second deals with proper management.The following discussion outlines the requirements for timely recognition and discriminate treatment. Infarction of the cerebellum is a similar condition that differs by its slower, subacute evolution and softer mass effect.
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PATHOGENESIS
In patients with hypertension, cerebellar hemorrhage likely results from rupture of a small microaneurysm on a deep, penetrating arteriole. Hematomas are less often caused by vascular malformations and coagulopathies.The clinical picture varies by the size and location of the cerebellar mass. A small hematoma, usually less than 3.0 cm,1 causes symptoms and signs that are limited to the cerebellum. Larger hematomas directly compress the underlying brainstem and obstruct the fourth ventricle or aqueduct. Secondary compression of the brainstem and hydrocephalus are the chief causes of progressive neurologic deterioration.2 This progression is often due to swelling around the hematoma that occurs over several days or obstructed cerebrospinal fluid drainage and resulting hydrocephalus. Hydrocephalus reportedly occurs in twothirds of patients and, by increasing intracranial pressure, is another cause of progression.1 Cerebellar infarction results from obstruction of the superior, anteroinferior, or posteroinferior cerebellar arteries. If only the distal portion of a cerebellar artery is involved, infarction occurs only in the ipsilateral cerebellar hemisphere. If the occlusion is more proximal, near the origin from the basilar artery, ischemia of the lateral brainstem also occurs. Subsequent swelling of the cerebellar hemisphere varies in degree and occurs over several days to 1 week. Because the mass consists of soft necrotic tissue, compression of the underlying brainstem is less severe than from a hematoma, but obstruction of the fourth ven-
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tricle can result in acute, noncommunicating hydrocephalus with disastrous consequences (Case 3).
DIAGNOSIS
The acute expansion of a hematoma transmits pressure to pain fibers in the dura, producing a headache that is referred to the occiput.The increased tissue pressure stimulates the area postrema in the lower oor of the fourth ventricle and accounts for acute nausea and vomiting. Because the hematoma is usually deep within the cerebellar parenchyma, bers from the vermis for control of the lower limbs are commonly affected.Vestibular control of antigravity muscles in the trunk is also compromised by compression of vestibulocerebellar pathways. The acute truncal ataxia results in the inability to walk and, sometimes, the inability to sit up without assistance.3 Thus, the triad of headache, vomiting, and gait instability is considered diagnostic of an acute cerebellar mass. Complaints of dizziness also are common. Limb ataxia is present in hematomas in the lateral cerebellar hemisphere.As in Case 1, the preservation of consciousness and absence of hemiparesis and cranial nerve signs deceive many physicians and prevent them from recognizing this condition as a potential acute emergency. This pitfall is avoided by seeking an explanation for why every emergency department patient cannot walk. Failure to walk without assistance mandates that a CT scan is obtained to detect the high density of a hemorrhage or the hypodensity of infarction or impingement on the fourth ventricle
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Stable Brainstem Compression Surgical decompression Hydrocephalus Small < 3.0 cm Large > 3.0 cm Ventriculostomy Ventriculostomy Surgical decompression
Medical support
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Hemorrhage
Headache Vomiting Unstable gait
CT scan
Stable
Medical support
Infarction Hydrocephalus Ventriculostomy
Figure 11- 4. Acute cerebellar hemorrhage and infarction management algorithm. CT = computed tomography.
(Figure 11-4). If the CT scan is normal, magnetic resonance imaging may be necessary to show an infarction. Gaze paresis, loss of the corneal reflex, impaired oculovestibular responses, and altered levels of consciousness signal compression of the pons by the overlying hematoma.2 A systolic pressure greater than 200 mm Hg at admission is also an indication of impending neurologic deterioration.4 In patients with cerebellar infarction, additional cranial nerve and long tract signs at presentation are indicative of ischemia from an occluded circumferential artery.Their subsequent appearance is a sign of secondary compression from edema. Progressive decline in the levels of consciousness, quadriparesis, and decerebrate posturing are features of severe brainstem compression or obstructive hydrocephalus. Signs of progressive neurologic deterioration develop quite rapidly or more slowly over days and up to 1 week.
MANAGEMENT
Early diagnosis is critical. Preservation of consciousness often corresponds to a favorable outcome.5 Once coma develops, however, mortality escalates and may exceed 80%. Consequently, immediate surgical intervention has been advocated for all cerebellar hematomas. Clinical scrutiny, however, shows that a more discriminating approach is justied (see Figure 11-4). Hematomas that affect only gait and station often reabsorb, without a serious functional consequence.These patients require medical support. Brainstem signs on presentation are, however, an indication for immediate evacuation of a cerebellar
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hematoma. Obstructive hydrocephalus is suggested by signs of increased intracranial pressure. It occurs at presentation or is delayed. Scanning shows expansion of the lateral ventricles, especially the temporal horns (Figure 112). Immediate decompression is accomplished by a ventriculostomy. Improvement is more likely in patients with hemorrhages less than 3.0 cm in which increased intracranial pressure is the major pathologic process. Substantial recoveries are reported,6 sometimes in less than 1 hour (Case 2).7 The potential rapid benet, avoidance of general anesthesia, and obviated postoperative complications justify this approach. Failure to rapidly improve should be followed by surgical intervention, which is needed in over half of these patients.8 In patients with larger masses, there is concern for upward herniation of the anterior cerebellar vermis, especially when the midbrain is already dorsally compressed. In such patients, direct surgical intervention is advised, as with patients with early brainstem signs. Importantly, and in contrast to other intracerebral hemorrhages, surgical relief has prospects for a substantial recovery. In patients with cerebellar infarction, simultaneous cranial nerve and long tract signs are due to lateral circumferential artery ischemia from a more proximally obstructed cerebellar artery. Early on, symptomatic compression from a soft cerebellar infarct is less likely. Many patients require no more than medical support. However, in some patients, hydrocephalus develops rapidly, sometimes in the rst 3 days, or more insidiously over the course of 7 to 10 days. Alterations in the mental status, declines in the level of alertness, long tract motor signs,
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and decerebrate posturing indicate acute hydrocephalus. Blockade of cerebrospinal uid egress and dilation of the lateral ventricles is quickly conrmed by CT. An immediate ventriculostomy is potentially curative (Figure 11-4). Concern for upward herniation of the cerebellum is low because of the lack of substantial pressure within the infarcted mass.
REFERENCES 1. Little JR, Tubrian ED, Ethier R. Cerebellar hemorrhage in adults. J Neurosurg 1978;48:5759. 2. St Louis EK,Wijdicks EFM, Hongzhe L. Predicting neurologic deterioration in patients with cerebellar hematomas. Neurology 1998;51:13649. 3. Heros RC. Cerebellar hemorrhage and infarction. Stroke 1982;13:1069. 4. Chin D, Carney P.Acute cerebellar hemorrhage with brainstem compression in contrast with benign cerebellar hemorrhage. Surg Neurol 1983;19:4069. 5. Theodore WH, Striar J, Burger A. Nonsurgical treatment of cerebellar hematoma. Mt Sinai J Med 1979;46:32832. 6. Wijdicks EFM, Maus TP, Peipgras DG. Cerebellar swelling and massive brain stem distortion: spontaneous resolution documented by MRI. J Neurol Neurosurg Psychiatry 1998; 65:4001. 7. Seelig JM, Selhorst JB, Young HR, Lipper M. Ventriculostomy for hydrocephalus in cerebellar hemorrhage. Neurology 1981;31:153740 8. Mathew P,Teasdale G, Bannan A, Oluoch-Olunya D. Neurosurgical management of cerebellar haematoma and infarct. J Neurol Neurosurg Psychiatry 1995;59:28792.
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CHAPTER 12
WERNICKES ENCEPHALO PATHY

John B. Selhorst, MD CASE 1
63-year-old alcoholic man underwent a radical neck dissection for carcinoma of the tongue. Afterward, dysphagia restricted his diet to semisolids. Six months later, he became irritable and lethargic. Eye movements were impaired (Figure 12-1). One day after receiving 100 mg of intravenous thiamine, he was fully alert and more coherent and had a full range of eye movements (Figure 12-2).
Figure 12-1 (A) Right gaze was moderately paretic and (B) left gaze was severely impaired. Abduction was more affected than adduction. (C) Upgaze was preser ved, but convergence occurred with (D) downgaze.
Figure 12-2 Eye movements were completely restored 24 hours after admission of intravenous thiamine to the patient in Figure 12-1.
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Wer nickes Enc ephalop a thy
CASE 2
A 21-year-old woman developed recurrent vomiting in the second trimester of her rst pregnancy. At 7 months gestation, she became confused. Gaze-evoked nystagmus was observed in all directions of gaze. Magnetic resonance imaging (MRI) illustrated diffuse hyperintensity observed around the third ventricle (Figure 12-3).
Figure 12-3 Fluid-attenuated inversion recover y imaging shows high intensities (A) in the mammillar y bodies, (B) in the periaqueductal area, and (C) in the medial thalami.
CASE 3
A morbidly obese, 31-year-old woman underwent a gastric stapling procedure. Two months later, she became disoriented and complained of diplopia. She required support to walk.The remaining neurologic examination was normal.
INTRODUCTION
As depicted in these cases, the triad of confusion, gait instability, and impaired ocular motility is diagnostic of
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Wernickes encephalopathy (WE). Sometimes, however, the full-blown picture is not present or the typical signs are indistinct. Because the timely administration of thiamine is crucial, this review presents the protean manifestations of thiamine deciency and the underlying conditions in which it occurs.A more comprehensive discussion is found in the landmark monograph by Victor and colleagues.1
NEUROPATHOLOGY
Unique pathologic ndings in Carl Wernickes seminal 1881 report were punctate hemorrhages in the gray matter surrounding the third ventricle and the oor of the fourth ventricle.1,2 These discrete hemorrhages, however, are found in only 10% of autopsy examinations. Atrophy of the mammillary bodies is the most common (7585%) macroscopic nding. Dilation of the third ventricle and aqueduct is less distinctive but is often observed. Microscopic ndings are (1) necrosis of neurons and their axons, (2) proliferation of microglia and astrocytes, (3) endothelial swelling in capillaries, and (4) petechial hemorrhages. These histologic changes occur along the anatomic midline, that is, the periventricular gray matter of the hypothalamus, thalamus, periaqueductal area of the midbrain, oor of the fourth ventricle, and cerebellum. With the onset of thiamine deciency, experimental studies indicate that glucose use declines in these regions and is followed by an increase in glucose turnover. Reversible reductions in thiamine-dependent -ketoglutarate dehydrogenase are found in the cerebellum of thiamine-decient rats and are proposed to account for neuronal degeneration.3
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PATHOGENESIS
For 50 years, the biochemical defect associated with WE was unknown.The rst clue to its pathogenesis arose from the production of typical neuropathologic changes of WE in rats fed diets lacking vitamin B1. Shortly thereafter, these changes were also observed in athiaminotic pigeons. Subsequently, an inactivator of thiamine, thiaminase, found in raw sh, was shown to be responsible for Chastek paralysis, a disorder of silver foxes with a neuropathology resembling WE in man. An inactivator of thiamine kinase, pyrithiamine, was later used in rats to block the activation of thiamine from its active form, thiamine pyrophosphate (TPP), and to reproduce the neuropathologic ndings of WE.The rst report of the reversal of the signs and symptoms of WE was in 1937, when B vitamins were given to a woman suffering from hyperemesis gravidarum. By 1941, Jolliffe and associates conclusively demonstrated that thiamine was the benecial B vitamin for treating WE.4,5 Thiamine is required as a coenzyme at three intermediate points in carbohydrate metabolism: pyruvate dehydrogenase in the glycolytic pathway, transketolase in the hexose monophosphate shunt, and dehydrogenase of -ketoglutaric acid in the citric acid cycle. Reductions in TPP-dependent enzymes have been found in autopsy specimens of the cerebellar vermis.The precise mechanism leading to cellular degeneration, however, is uncertain. In a study of pyrithiamine-treated rats, a decline in pyruvate activation and an accumulation in lactic acid occurred in the hypothalamus, thalamus, and midbrain after neurologic signs appeared.6 NMDA receptormediated excitotoxicity
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has also been proposed but not substantiated in the laboratory.6

EPIDEMIOLOGY
A number of large, systematic autopsy studies have shown a low but regular rate of WE. Histopathologic changes were found in 1.7% of 1,600 consecutive autopsies in New York, 3.4% of 4,000 sequential pathologic examinations in Brooklyn, 2.2% of 3,548 necropsies in Cleveland, 1.7% of 2,891 pathologic examinations in Western Australia,2 and 0.8% of 8,735 autopsies in Norway. Except for the latter report, these studies may be biased by sampling a population with a high incidence of alcoholism or malnutrition. It is well recognized that WE most often occurs in alcoholics suffering from malnutrition. Consequently,WE is more common in men than in women. Presumably, alcohol displaces food in the diet but provides calories that require thiamine for their metabolism. Liver disease in the alcoholic possibly impairs the storage and activation of thiamine. Additionally, impaired thiamine absorption in the intestine is reported in alcoholics, but this claim has been challenged.7 Victor and colleagues obtained a denitive history of alcoholism in 175 (71%) of 245 patients with WE.1 In Harpers study, 88% of 51 patients were known alcoholics.2 Many other reports conrm that a majority of patients with WE are chronic alcoholics, but they also show that WE occurs in a varied minority of nonalcoholic patients (Table 12-1). Neoplasms and gastrointestinal diseases are
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particularly common in this group. More recently,WE has been identied in patients infected with the acquired immune deciency syndrome (AIDS) virus. A host of iatrogenic causes have also been reported, including an increasing number of patients developing WE after gastric bypass surgery.810
CLINICAL MANIFESTATIONS
Although the triad of confusion, gait ataxia, and oculomotor decits is diagnostic, all three features occur in a small minority of patients.11 Components of the triad occur singularly or in combination with one another. Confusion is by far the most prevalent sign (Figure 12-4) and results from defective retention of recent events and their temporal sequences. Commonly, the altered mental status also includes disorientation, apathy, and poor concentration. The gait consists of a reeling, wide-based stance, and short, unstable steps. Maintaining the stance, if it is at all possible, requires support. Involvement of the vestibular system in addition to the cerebellum accounts for the imbalance. If an intention tremor is present, it is found in the lower limbs. The ocular signs are the least frequent of the diagnostic triad. Their distinctive occurrence, however, provides the principal means of conrming the diagnosis.Typically, they are bilateral, but they are often asymmetric (see Figure 12-1). Ocular weakness is partial or complete. Horizontal disturbances generally precede vertical ones.A constellation of eye signs is described: (1) gaze-evoked, downbeat, or upbeat nystagmus; (2) impaired abduction;
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Table 12-1 Illnesses Associated with Wernickes Encephalopathy

Neoplasms Gastrointestinal cancer Hematogenous tumors Lymphoma Gastrointestinal diseases Pyloric stenosis Radiation proctitis Recurrent vomiting Protracted constipation Iatrogenic causes Total parenteral nutrition Prolonged intravenous feedings High-glucose loads Gastric surgery for obesity Hemodialysis and uremia Drug complications Digitalis Diruetics Tolazamide Quinine Hyperemesis gravidarum Acquired immunodeciency syndrome (AIDS) Psychiatric disorders Anorexia nervosa Schizophrenia Dementia Neonatal illness Starvation Prisoners of war Hunger strikers Obesity treatment
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(3) ptosis, usually mild; (4) bilateral internuclear ophthalmoplegia; (5) conjugate gaze deficits; (6) impaired oculovestibular responses; and (7) complete ophthalmoplegia. In the largest clinical study, nystagmus occurred in 85% of 232 patients (Figure 12-4).1 Abduction paresis, found in 54% of patients, was the second most common ocular abnormality. Isolated palsies of the oculomotor or trochlear nerves were not encountered. Conjugate gaze palsy, present in 44% of patients, was the third most common ocular disorder. Similar oculomotor signs have been induced experimentally in monkeys fed thiaminedecient diets.12 In severe stages of deciency, nystagmus progressed to complete ophthalmoplegia. Dilation of the pupils and impaired pupillary light reexes were also observed. Interestingly, Victor and associates reported asymmetric pupils or impaired pupillary light reaction in 19% of patients but stressed that marked dilation or constriction of a pupil was never an initial manifestation of WE.1 Mild to severe ptosis occurred in thiamine-depleted
Figure 12-4 Clinical Signs in Wernickes Encephalopathy. Symptom frequency. Adapted from Harper CG et al.11
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Figure 12-5 Common Eye Signs in Wernickes Encephalopathy. Adapted from Harper CG et al.11
monkeys, but when present in humans, it is often a minor feature of the oculomotor disturbance. It cannot be overemphasized that dependence on the classic triad of signs to make a diagnosis of WE neglects the diverse presentations established by neuropathologic examination. The absence of the classic triad is perhaps especially true in the nonalcoholic patient. Therefore, attention to the less distinctive features of WE is important. Careful recording of symptoms occurring with the development of WE in prisoners of war suggests that an insidious affectation of the mental state, such as apathy, lethargy, and confusion, is the earliest manifestation of WE.13 Nausea and vomiting are often present as well. Infrequently, hypothermia may complicate recognition of
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WE; it is perhaps due to involvement of the preopticanterior hypothalamus. Hypotension, independent of hypovolemia, is also encountered on occasion. In the alcoholic or malnourished patient, such symptoms should raise suspicion and prompt treatment. The relationship between WE and Korsakoff s psychosis (KP) and polyneuropathy is important to understand. In 1887, Korsakoff described a syndrome in alcoholics that was characterized by both an amnesic state and polyneuropathy.1 Later, he observed the same condition among nonalcoholic patients. The mental alteration in these patients is remarkable for the disproportionate impairment of recent memory as opposed to other cognitive functions. The patients also lack concentration and insight into their memory loss.There is disorientation and confusion for a sequence of events.Temporal relationships are composed from fragments of memory scattered over time. Confabulation results and consists of real but confused facts as opposed to purely imagined and unreal events.The prognosis for recovery from KP is limited.
NEUROIMAGING
Changes found by computed tomography are not distinctive and are too infrequent to corroborate a diagnosis of WE. MRI, however, mirrors the neuropathologic lesions found in the midline of the brainstem. In the acute phase of WE, high intensities occur in the thalamus and periaqueductal area.14 Pathologic study suggests that these changes are caused by a spongy degeneration of the neuropil.15 These high intensities remit or decrease at later
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stages when the mammillary bodies and midbrain tegmentum atrophy and the third ventricle widens.16 Symmetric contrast enhancement also occurs in the acute stages of WE in the mammillary bodies, thalamus, periaqueductal areas, and tegmentum of the pons17; this breakdown in the blood-brain barrier is reversed with thiamine therapy.18 Fluid-attenuated inversion recovery (FLAIR) imaging shows high-intensity changes in the walls of the third ventricle and aqueduct of Sylvius (see Figure 12-3). FLAIR studies are perhaps a more sensitive study than routine MRI. These findings were found in 8 of 15 patients (53%) in one series, indicating that MRI is useful to conrm the disease but not to exclude it.19
LABORATORY STUDIES
Serum thiamine levels are not recommended because they are often within the normal range in deciency states.1 However, over 80% of whole-blood thiamine is found in red blood cells and reects tissue concentrations throughout the body. A reliable measure of thiamine stores is the erythrocyte transketolase level (ETK) or the effect of its activation by TPP, the TPP effect. Low values indicate a deciency in available thiamine.These assays are reliable20 but should not delay institution of treatment. More recently, high-performance liquid chromatography has more directly determined concentrations of erthrocyte thiamine monophosphate and diphosphate.21 These assays are reported as being as sensitive as ETK assays, as well as more stable, easier to standardize, and less affected by factors inuencing enzymatic activity.
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TREATMENT
Patients with WE have a mortality rate of 17% in the rst 3 weeks and 26% over 3 years.1 Therefore, haste in recognizing and treating the disease is essential.The amount of thiamine required is reected in laboratory studies that show that 0.3 to 0.6 mg of thiamine is needed for the metabolism of each 1,000 calories. The commonly accepted minimum daily allowance of thiamine is 1.2 to 1.7 mg. Symptoms of WE that developed in British prisoners of war subsisting only on a diet of polished rice were reversed by 2.0 to 4.0 mg/d of thiamine.13 Thiamine, 50 mg intravenous and 50 mg intramuscularly, should be given immediately whenever the diagnosis of WE is considered (Figure 12-6). Concerns about anaphylactoid reactions with intravenous administration have not been borne out. Intravenous administration should be continued daily until the ocular, ataxic, and mental disturbances remit. Daily supplements of oral 50 mg should be provided afterward to avoid a recurrence of WE. Because some patients have not responded to standard dosages, larger amounts, for example, 500 mg, have been recommended.11 In patients with ophthalmoplegia, the diagnosis is conrmed by reversal of the ocular motility decit within 4 hours to 2 days. Gait ataxia and confusion resolve more slowly. Full remission of the mental state depends on its severity and duration at onset of treatment. Administration of magnesium is possibly an important adjunct to proper therapy.22 Magnesium is a cofactor in many of the glycolytic reactions requiring TPP. Magne231
1. Acutely Confusion and/or Ataxia and/or Ocular deficits 50 mg B-1, i.v. + 50 mg B-1, p.o. + MgSO4, if needed resolution 50 mg B-1, p.o. preventively
no resolution
500 mg B-1, p.o.
2. Prophylactically Alcoholics Undernourished 50 mg B-1, i.v. or p.o.
Figure 12-6 Treatment algorithim for Wernickes encephalopathy. IV = intravenously; MgSO4 = magnesium sulfate; PO = by mouth.
sium deciency is known to develop in alcoholics, the malnourished, and patients having vigorous diuresis.Vertical gaze nystagmus and downbeat nystagmus are reported in patients with severe hypomagnesemia.23 It is likely that thiamine deficiency and magnesium deficiency commonly coexist. In one patient with WE, transketolase levels did not rise until magnesium was added 24 hours after thiamine was begun.24 For prompt therapeutic responses, magnesium levels should be measured and magnesium administered, if renal function permits, to those patients receiving thiamine for suspected WE.
PREVENTION
Prophylactic treatment depends on an understanding of the development of thiamine-decient states. A depleted

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state is possible within 18 days after beginning a diet totally devoid of the vitamin. Prisoners of war in 1941 developed WE in 6 to 8 weeks, but their diet was not completely lacking in thiamine.13 The necessity for prevention of WE and KP cannot be overemphasized. Thiamine should be provided presumptively to all alcoholics and patients with debilitating diseases (Figure 12-6). The importance of thiamine supplementation in many third world populations should also be apparent. Furthermore, the benet of routine thiamine administration in the undernourished is highlighted by reports of a high glucose load depleting the last available stores of thiamine and precipitating WE. Finally, patients with debilitating conditions are often vitamin deficient before becoming acutely ill.Therefore, when presenting with any acute illness, any emaciated patient, alcoholic or nonalcoholic, who develops an altered mental status or other signs of WE should immediately receive 100 mg of thiamine.
REFERENCES 1. Victor M, Adams RS, Collins GH. The Wernicke-Korsakoff syndrome and related neurologic disorders due to alcoholism and malnutrition. 2nd ed. Philadelphia: FA Davis; 1989. 2. Harper C.Wernicke encephalopathy: a more common disease than realized. A neuropathologic study of 51 cases. J Neurol Neurosurg Psychiatry 1979;42:22631. 3. Butterworth RF. Pathophysiology of cerebellar dysfunction in the Wernicke-Korsakoff syndrome. Can J Neurol Sci 1993;20 Suppl 3:1236.
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4. Joliffe N,Wortis H, Fein MD.The Wernicke syndrome.Arch Neurol Psychiatry 1941; 46:56997. 5. Wagner HP,Weir JF. Ocular lesion associated with postoperative and gestational nutritional deciency. Am J Ophthalmol 1937;20:2537. 6. Todd KG, Butterworth RF. Evaluation of the role of NMDA-mediated excitotoxicity in the selective neuronal loss in experimental Wernicke encephalopathy. Exp Neurol 1998;149:130-8. 7. Breen KJ, Buttigieg R, Oddifdis S, Lourensz C, et al. Jejunal uptake of thiamin hydrochloride in man: inuence of alcoholism and alcohol. Am J Clin Nutr 1985;42: 1216. 8. Rosenberg S, Lopez MBS, Tsanaelis AM. Neuropathy of acquired immunodeciency syndrome (AIDS). Analysis of 22 Brazilian cases. J Neurol Sci 1986;76:18790. 9. Doraiswamy PM, Massey EW, Enright K, et al. WernickeKorsakoff syndrome caused by psychogenic food refusal: MR ndings. AJNR Am J Neuroradiol 1994;15:5946. 10. Shimomura T, Mori E, Hirono N, et al. Development of Wernicke-Korsakoff syndrome after long intervals following gastrectomy. Arch Neurol 1998;55:12425. 11. Harper CG, Giles M, Finaly-Jones R. Clinical signs in Wernicke-Korsakoff s complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 1986;49:3415. 12. Cogan DG, Witt ED, Goldman-Rakic PS. Ocular signs in thiamine-decient monkeys and in Wernickes disease in humans. Arch Ophthalmol 1985;103:121220. 13. DeWardena HE, Lennox B. Cerebral beriberi (Wernickes encephalopathy). Lancet 1947;i:1117. 14. Gallucci M, Bozzao A, Splendiani A, et al. Wernicke encephalopathy: MR ndings in ve patients. AJR Am J Roentgenol 1990;155:130914.
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15. Suzuki S, Ichijo M, Fujii H, et al. Acute Wernickes encephalopathy: comparison of magnetic resonance images and autopsy ndings. Intern Med 1996;35:8314. 16. Yokote K, Miyagi K, Kuzuhara S, et al. Wernicke encephalopathy: follow-up by CT and MR. J Comput Assist Tomogr 1991;15:8358. 17. Shogry ME, Curnes JT. Mammillary body enhancement on MR as the only sign of acute Wernicke encephalopathy. AJNR Am J Neuroradiol 1994;15:1724. 18. Schroth G, Wichmann W,Valavanis A. Blood-brain-barrier disruption in acute Wernicke encephalopathy: MR ndings. J Comput Assist Tomogr 1991;15:105961. 19. Antunez E, Estruch R, Cardenal C, et al. Usefulness of CT and MR imaging in the diagnosis of acute Wernickes encephalopathy. AJR Am J Roentgenol 1998;171:11317. 20. Nordentoft M, Timm S, Hasselbaich E, et al. Thiamine pyrophosphate effect and erythrocyte transketolase activity during severe alcohol withdrawal syndrome. Acta Psychiatr Scand 1993;88:804. 21. Tallaksen CM, Bell H, Bohmer T. Thiamin and thiamin phosphate ester deciency assesed by high performance liquid chromatography in four clinical cases of Wernicke encephalopathy. Alcohol Clin Exp Res 1993;17:7126. 22. McLean J, Manchip S. Wernickes encephalopathy induced by magnesium depletion. Lancet 1999;353:1766. 23. Saul RF, Selhorst JB. Downbeat nystagmus with magnesium depletion. Arch Neurol 1981;38:6502. 24. Traviesa DC. Magnesium deciency: a possible cause of thiamine refractoriness in Wernicke-Korsakoff encephalopathy. J Neurol Neurosurg Psychiatry 1974;37:95962.
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CHAPTER 13
TIP S ON THE NEUR O LO GIC EXAMINATIO N

James D. Fleck, MD, and Jos Biller, MD
he goal of this chapter is to familiarize the clinician with the neurologic examination and to provide some helpful tips in obtaining or interpreting data from the examination. It is not intended as a thorough review of all details of a complete and comprehensive neurologic examination. We have tried to direct some of our comments to the specic conditions discussed in more detail in the other chapters of this book. Guidelines for a comprehensive neurologic examination and an examination on a patient with an altered level of consciousness have been proposed by the American Academy of Neurology (AAN) and are outlined in Tables 13-1 and 13-2.
GENERAL EXAMINATION
A general physical examination certainly complements a neurologic examination when evaluating patients with neurologic diseases.
Head and Neck Examination
In patients with altered levels of consciousness, it is important to inspect and palpate the patients head for signs of trauma, including looking for blood behind the ear (Battles sign) and around the eyes (raccoon eyes).The nose should be inspected for blood or cerebrospinal uid
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Tips on the Neurologic Examinat ion
Table 13-1 Guidelines for a Comprehensive Neurologic Examination

1. Mental status a. Level of alertness b. Language function i. Fluency ii. Comprehension iii. Repetition iv. Naming c. Memory (short and long term) d. Calculation e. Visuospatial processing f. Abstract reasoning Cranial nerves a. Vision i. Visual elds ii. Visual acuity iii. Funduscopic examination b. Pupillary light reex c. Eye movements d. Facial sensation e. Facial strengthmuscles of facial expression f. Hearing g. Palatal movement h. Speech i. Neck movements i. Head rotation ii. Shoulder elevation j. Tongue movements Motor function a. Gait i. Casual ii. On toes iii. On heels
Continued
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2.
3.

iv. Tandem Coordination i. Fine nger movements ii. Rapid alternating movements iii. Finger to nose iv. Heel to shin c. Involuntary movements d. Pronator drift e. Tone (resistance to passive manipulation) f. Bulk g. Strength i. Shoulder abduction ii. Elbow exion and extension iii. Wrist exion and extension iv. Finger exion, extension, and abduction v. Hip exion and extension vi Knee exion and extension vii. Ankle dorsiexion and plantar exion Reexes a. Muscle stretch reexes i. Biceps ii. Triceps iii. Brachioradialis iv. Patellar v. Achilles b. Plantar responses Sensation a. Light touch b. Pain or temperature c. Proprioception d. Vibration b.
4.
5.
Adapted from http://aan.com/students/clerkship/neurology_ clerkship.pdf (accessed Dec 10, 2003).

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Table 13-2 Guidelines for the Neurologic Examination in Patients with Altered Levels of Consciousness 1. Mental status a. Level of arousal b. Response to auditory stimuli (including voice) c. Response to visual stimuli d. Response to noxious stimuli applied centrally and to each limb 2. Cranial nerves a. Response to visual threat b. Pupillary light reex c. Oculocephalic (dolls eyes) reex d. Vestibulo-ocular (caloric testing) reex e. Corneal reex f. Gag reex 3. Motor function a. Voluntary movements b. Reex withdrawal c. Spontaneous and involuntary movements d. Tone (resistance to passive manipulation) 4. Reexes a. Muscle stretch reexes b. Plantar responses 5. Sensation (to noxious stimulation)
Adapted from http://aan.com/students/clerkship/neurology_ clerkship.pdf (accessed Dec 10, 2003).
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drainage. Otoscopy should be done to look for blood behind the eardrum. Auscultation for bruits should be done as part of the general cardiovascular examination. A stethoscope bell can be placed along the anterior border of the sternocleidomastoid (SCM) muscle in the region of the upper border of the thyroid cartilage to listen for cervical carotid artery bruits and along the posterior border of the SCM muscle to listen for vertebral artery bruits.The bell can also be gently placed over closed eyes to listen for ocular bruits. Auscultation of the mastoid processes, and temporal, frontal, or parietal head regions may be helpful in certain circumstances. Irritation of the subarachnoid space, by infection or blood, can lead to nuchal rigidity, a resistance to active and passive neck exion. No neck manipulations should be done until a cervical spinal cord lesion or fracture or dislocation of cervical vertebrae has been ruled out with appropriate radiologic tests. Brudzinskis neck sign is noted if passive exion of the head is followed by exion of both thighs and legs. Kernigs sign can also be used to test for meningeal irritation. The hip and knee are exed, and then the knee/leg is slowly and gently passively extended, looking for pain and resistance to leg extension. In patients with suspected giant cell arteritis, the supercial temporal arteries should be palpated for tenderness or induration. The temporal areas and scalp should be palpated for tenderness.
Chest/Respiration
For patients with neuromuscular respiratory difculties, there are some bedside tests of function. The simplest
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method is to ask the patient to count aloud on a single deep breath. If the patient can count to 10, the forced vital capacity (FVC) is approximately 1 L. If the patient can count to 25, the FVC is approximately 2 L. Other respiratory patterns may be helpful in localizing lesions in patients who are comatose.These are briey discussed in the section on examining the comatose patient.
Cardiovascular
An irregularly irregular pulse may be indicative of atrial brillation, multifocal atrial tachycardia, premature atrial contractions, or premature ventricular contractions.
Abdomen
In encephalopathic patients, hepatomegaly and splenomegaly may be signs of hepatic disease with portal hypertension. Massive splenomegaly may be seen in malaria. Abdominal striae may be a sign of Cushings syndrome.
Extremities/Spine
In patients with spinal cord or spinal column trauma, the spine, especially the cervical spine, should be immobilized until appropriate radiologic studies are done. In patients with potential spinal cord lesions, the spinous processes at the appropriate level may be tender to palpation.
Skin
Observation of the skin may be helpful. Skin temperature and color may help lead to a diagnosis. One should
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inspect the skin for ticks, needle marks, or characteristic rashes. Characteristic rashes may give away the diagnosis in infectious diseases such as Rocky Mountain spotted fever or meningococcal meningitis. Livedo reticularis may be seen in younger patients with ischemic stroke owing to hypercoagulable states such as antiphospholipid antibody syndrome. Kaposis sarcoma may be seen in human immunodeciency virus (HIV)-positive patients.
A COMPREHENSIVE NEUROLOGIC EXAMINATION
Guidelines for a comprehensive neurologic examination have been published by the AAN and are noted in Table 13-1. The major sections of the neurologic examination include mental status, cranial nerves (CNs), motor function, reexes, and sensation.We discuss these individually and provide some helpful hints on interpreting observations made during the examination. Much information regarding a patients mental status will be noted while obtaining the history. The patients level of alertness is noted when speaking with the patient. Asking patients simple orientation questions such as their name, the date, and their location will quickly give you information on their sensorium. Having them recite the months or spell words backward can test their attention span. The uency of speech and ability to comprehend spoken language are noted when the patient answers questions. Asking patients to name objects, repeat a phrase, read, and write will complete a quick screen of language function. Asking patients to remember three objects can test short-term memory. Simple calculations
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can be done on a piece of paper.Visuospatial processing can be tested by asking patients to reproduce drawn objects, such as interlocking pentagons, or perhaps to draw the face of a clock. Asking patients to interpret the meaning of proverbs can test abstract reasoning. Testing CN function is most easily done by remembering and testing them in numeric order. The olfactory nerve (CN I) is not often tested in a routine neurologic examination. However, having patients identify a common smell such as coffee or wintergreen with each nostril separately is a reasonable rst test. A noxious or irritating odor, such as ammonia, should not be used to test olfaction as these odors also activate the bers of the trigeminal nerve (CN V). The optic nerve (CN II) plays a major role in vision and is the afferent limb of the pupillary reex.Visual acuity is best tested using a distance chart but can be tested with a pocket visual chart. When testing visual acuity, patients should wear their appropriate corrective lenses. Reading glasses should be worn if necessary for near vision when using a pocket visual chart. Confrontation visual elds should be done with the patient covering one eye with a hand. A number of the examiners ngers can be presented in each of the four quadrants of each eye, and the patient is asked to state how many ngers were presented. Visual eld testing is often not done or forgotten by those not experienced in the neurologic examination but often provides useful information. For example, a homonymous hemianopia may be the most dramatic sign of an occipital lobe infarction. The pupillary light reex is one of the most important parts of the
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neurologic examination. Normally, both pupils will promptly constrict when light is focused on either retina, giving both the direct and the consensual response. The alternating light test is the standard clinical technique to look for a relative afferent pupillary defect (RAPD). Swinging the light from eye to eye will elicit a brisker reaction to light in the unaffected eye and a less brisk reaction or dilatation of the pupil in the affected eye. An RAPD is a sensitive indicator of a unilateral injury to the afferent pupillary pathway, typically large retinal lesions, or damage to the optic nerve, which is most common. For example, an ischemic optic neuropathy associated with giant cell arteritis may give an RAPD. A funduscopic examination is extremely important in establishing the appearance of the optic disk, retina, and macula. Ideally, the fundus should be viewed after pharmacologic mydriasis to ensure the best view. Papilledema, or a swollen optic disk, is often a sign of increased intracranial pressure and makes funduscopy one of the most important parts of the examination of patients with headaches. Papilledema can be seen in conditions that globally increase intracranial pressure such as meningitis, subarachnoid hemorrhage, or intracranial mass lesions.A pallid swollen disk is often seen in giant cell arteritis. Cholesterol emboli (Hollenhorst plaque) may be indicative of ulcerating atheromatous plaque in the ipsilateral carotid artery. The oculomotor nerve (CN III), trochlear nerve (CN IV), and abducens nerve (CN VI) innervate the muscles that move the eyes or extraocular muscles. The abducens nerve innervates the lateral rectus muscle. The
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trochlear nerve innervates the superior oblique muscle. The oculomotor nerve innervates the rest of the extraocular muscles, which include the medial rectus, inferior rectus, superior rectus, and inferior oblique muscles. The oculomotor nerve also innervates the muscles that constrict the pupil and the levator palpebrae superioris, which helps elevate the eyelid. The patient should be asked to follow an object that tests all directions of movement of both eyes. In a complete CN III palsy, there is ptosis or drooping of the eyelid and dilatation of the pupil, and the eye is deviated laterally and a bit downward. The trigeminal nerve (CN V) innervates the muscles of mastication or chewing and is responsible for facial sensation. The three main branches of the trigeminal nerve, the ophthalmic branch, maxillary branch, and mandibular branch, provide sensation for the forehead, cheek, and chin, respectively. Facial sensation can be tested in much the same way as sensation in other parts of the body is tested.This is outlined below. The facial nerve (CN VII) innervates the muscles of facial expression. The most easily tested facial muscles include the frontalis, which wrinkles the forehead; the orbicularis oculi, which close the eye tightly; and the buccinator, which helps one smile. The distribution of facial weakness will help localize lesions. A lesion of the facial nucleus, the facial nerve fascicles within the brainstem, or the facial nerve itself can lead to a lower motor neuron type of facial weakness in which all ipsilateral facial muscles will be equally weak. If the corticobulbar bers are affected, producing an upper motor neuron
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lesion, then the lower face will be much more affected than the upper face as the neurons guiding upper facial muscles receive bilateral innervation. For example, the entire ipsilateral face will be weak in a typical idiopathic facial nerve palsy or Bells palsy. In a patient with a hemispheric infarction, typically the smile is much weaker than forehead wrinkling, and, in fact, the frontalis function may be normal. The vestibulocochlear nerve (CN VIII) is essentially two ber systems that participate in hearing (cochlear nerve) and balance, equilibrium, and orientation in space (vestibular nerve). Hearing can be tested in several ways. The ability of the patient to hear two ngers rustled together, hear whispered words, or detect the sound of a vibrating tuning fork can be tested. The glossopharyngeal nerve (CN IX) and the vagus nerve (CN X) can be quickly tested by asking the patient to raise the soft palate. In a unilateral lesion, the uvula deviates to the opposite side and the ipsilateral soft palate will not elevate. The gag reex is discussed below. Dysarthria, or difculty with articulation of speech owing to disturbances of muscular control, can be seen in both central and peripheral nervous system disorders and therefore can be seen in many lesions of the nervous system. The spinal accessory nerve (CN XI) innervates the SCM muscles and the rostral or proximal parts of the trapezii muscles. It can be tested by having the patient shrug the shoulders (trapezii) and attempt to return the head to the midline position against resistance after it has been turned to the right and left. It is best to actually pal246
pate the SCM muscle being tested so that activation is felt. It is important to realize that the left SCM helps turn the head to the right and the right SCM helps turn the head to the left. The hypoglossal nerve (CN XII) innervates the tongue musculature. The tongue should be observed for atrophy and fasciculations as a clue to lower motor neuron lesions. The patient is then asked to protrude the tongue. If there is a unilateral weakness, then the tongue will protrude toward the side of the lesion. Examination of motor function is the next step in the neurologic examination. Although the testing of power or strength is important in examining the motor system, there are certainly other techniques that should not be missed. Inspection of overall and individual muscle bulk looking for atrophy or hypertrophy may be helpful in formulating a diagnosis. Testing of muscle tone, or resistance to passive manipulation, is also important and may be normal, decreased, or abnormally increased. Muscles being tested for tone should be relaxed. The most common forms of increased muscle tone are spasticity and rigidity. Neuroleptic malignant syndrome is associated with severe generalized muscle rigidity. The patient should be observed for involuntary hyperkinetic movements such as tremor, chorea, myoclonus, hemiballismus, athetosis, and dystonia. The testing of muscle power or strength is the most used part of the examination of the motor system and is the part most familiar to all physicians. Although a multitude of muscles can be tested for power, the main movements tested in the routine neurologic examination include shoulder abduction, elbow exion and extension, wrist exion and extension, nger
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exion, extension, and abduction, hip exion and extension, knee exion and extension, and ankle dorsiexion and plantar flexion. Muscle power can be rated on a 5-point scale, as listed in Table 13-3. A subtler test of upper extremity power is asking patients to hold their arms and hands outstretched in front of them, with eyes closed. If there is mild weakness, there may be slow pronation of the hand, slight exion of the wrist and elbow, and downward drift of the arm. The testing of patients with suspected hysteria or malingering may show give-away weakness. The muscle being tested may not sustain contraction and may give way abruptly rather than gradually.There may also be inconsistency in the amount of power exerted for the individual muscle groups. Coordination is the smooth execution of motor movements. Although cerebellar lesions often cause incoordination or ataxia, it can also be seen in lesions of the pyramidal system, extrapyramidal system, and sensory system. The most common methods of detecting incoordi-
Table 13-3 Grading of Muscle Power 0 1 2 3 4 5

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No contraction Flicker or trace of contraction Active movement with gravity eliminated Active movement against gravity Active movement against gravity and resistance Normal power
nation are the nger-to-nose test in the upper extremities and the heel-to-shin test in the lower extremities. Rapid alternating movements can also be done to test coordination and dexterity. Having the patient tap on the thigh with the palm and dorsum of the hand alternately or tap the toes on the ground can test for impairment of rapid alternating movements. The testing of muscle stretch reexes is also an important part of the motor examination. The most commonly tested muscle stretch reexes are the biceps, triceps, brachioradialis, patellar (or knee jerk), and Achilles (or ankle jerk). The part of the body to be tested should be relaxed, and the best position is usually intermediate between full extension and exion. Muscle stretch reexes can be graded on the scale presented in Table 13-4. Often it is not the absolute number assigned to the reex but the degree of symmetry or asymmetry noted.The most important supercial reex is the plantar response.With the patient supine and relaxed, the lateral sole of the foot is stimulated starting near the heel and moving toward the toes. The toes will ex in a normal plantar response. If the corticospinal tract is interrupted or diseased, the great toe will dorsiex and the other toes will often fan out. This great toe extension to plantar stimulation is the Babinski sign. When muscle weakness is noted, the most fundamental question to be answered by the examination is whether a lower motor neuron or upper motor neuron lesion is present. Chronic upper motor neuron lesions (those affecting the corticospinal tract) classically show weakness, increased tone/spasticity, hyperreexia, and a Babinskis sign in the appropriate distribution based on the anatomic location
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Table 13-4 Grading of Muscle Stretch Reflexes 0+ 1+ 2+ 3+ 4+ Absent Present but diminished Normal Increased but not necessarily to a pathologic degree Markedly hyperactive, often with associated clonus
of the lesion. Chronic lower motor neuron lesions classically show weakness, decreased tone, hypo- or areexia, and exor or neutral plantar response again in the appropriate distribution based on the anatomic location of the lesion. The sensory examination is the most subjective part of the neurologic examination because it relies on the responses of the patient and not on the examiners observations. It is often also the most tedious and timeconsuming part of the examination. At times, it seems unreliable and confusing. However, much information can be gained by an appropriate sensory examination. The most common modalities tested are light touch, pain or temperature sensation, proprioception, and vibration. Light touch can be tested with a cotton swab or a gentle touch with the examiners nger. Pain sensation can be tested with a sharp object, such as a safety pin. It is important to use sharp objects only once and dispose of them
250
appropriately because of the possibility of transmitting pathogens, especially viruses, between patients. Temperature sensation can be tested using the cool end of a tuning fork and comparing it to the examiners warmer nger. Vibration is tested with a tuning fork. Proprioception is tested by moving an isolated toe or nger up or down, often by only a few millimeters, and asking the patient in which direction the digit was moved. It is important to hold the digit on the lateral portions or sides and not the top or bottom as the patient may sense the pressure direction and correctly state the direction of movement based on the pressure sensation and not a true awareness of the joint position. Certainly, not every square inch of the skin is examined completely in every examination as this would be impractical. However, a detailed examination of the appropriate anatomy should be done in any patient with a complaint of sensory changes such as numbness, pain, or tingling. It is important to test the main sensory modalities as they take different anatomic paths within the central nervous system, especially the spinal cord. Pain and temperature sensations are carried by the spinothalamic tracts, and vibration and proprioception are carried in the dorsal columns of the spinal cord. In testing sensation of all types, the most accurate results are obtained by proceeding from the area of less sensation to the area of more or normal sensation. The pattern of sensory loss often guides in localizing a lesion within the nervous system, and some specic patterns are noteworthy. For example, in hemispheric brain infarcts, the pattern is typically one of loss of all modalities of sensation on the contralateral face, body, and
251
extremities. In peripheral neuropathies, the sensory changes are most often distal in the extremities, with the legs often being more affected than arms. With lesions compressing the spinal cord, there is most often loss of sensation distal to the lesion. Some noteworthy anatomic landmarks include the nipple level, which is at the T4 sensory level, and the umbilicus, which is at the T10 sensory level. Sensory loss may occur in the perianal and genital areas, a saddle distribution, due to lesions of the cauda equina or conus medullaris. Examination of gait should be done in every person capable of walking. In fact, if given only one part of the examination with which to make a diagnosis, most neurologists would choose the station and gait examination. An integration of most parts of the nervous system is necessary to walk normally. Patients should be observed walking with as little assistance as necessary to keep them safe. If possible, they should be asked to walk on their heels and toes. Tandem walking, or walking along a straight line with one foot directly in front of the other, should be attempted in all patients who are not at significant risk of falling. Certainly, some gait patterns can give away a diagnosis. Easy examples are the hemiparetic gait of a patient who has had a stroke, the shufing gait of a patient with parkinsonism, or the ataxic gait of a patient with cerebellar disease.
EXAMINATION OF THE PATIENT IN COMA OR ALTERED LEVEL OF CONSCIOUSNESS
Guidelines for the examination of patients with altered levels of consciousness are presented in Table 13-2. In
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general, any part of the comprehensive neurologic examination listed previously that can be performed should be performed. However, many aspects of the comprehensive neurologic examination cannot be performed in patients unable to follow commands or follow a course of action. Other reex testing is often done in comatose patients that is not routinely performed on alert patients. These are highlighted in this section. A general physical examination should be performed in all patients with an altered level of consciousness and may be helpful in arriving at a cause. Some examples are listed above in the general examination section. Simple methods such as smelling the patients breath may prove helpful in determining a cause, especially toxic ingestions. For example, a garlic breath odor may be seen in arsenic poisoning, and cyanide poisoning may cause a bitter almond odor. Ethanol ingestions can often be diagnosed by the characteristic breath odor. As implied by their name, evaluation of vital signs is important in the examination of a comatose patient. Hypertension may be due to increased intracranial pressure or just be due to chronic primary hypertension. Hypotension may be due to hypovolemia, hemorrhagic shock, or myocardial depression. Hyperthermia can be seen in infections such as meningitis, encephalitis, or sepsis. It can also be seen in disruption of autonomic pathways, neuroleptic malignant syndrome, or a serotonin syndrome. Hypothermia may be due to exposure (environmental), hypoglycemia, or hypothyroidism.Wernickes encephalopathy and sedative overdose can also lower body temperature. Respiratory patterns may also be help253
ful in diagnosing the cause of the altered level of consciousness or the location of a lesion in the brain. Hyperventilation can be seen in metabolic acidosis, pulmonary edema, or primary respiratory alkalosis or from central neurogenic hyperventilation. Hypoventilation may be due to pulmonary insufciency, central alveolar hypoventilation, or other causes. An abnormal breathing pattern may point to a lesion in a specic location within the brain. Cheyne-Stokes respiration or periodic breathing is probably the most common pattern and is typically caused by bilateral cerebral hemisphere dysfunction or dysfunction of the diencephalon. Central neurogenic hyperventilation is seen in low midbrain or upper pontine lesions. Dysfunction or lesions of the midcaudal pons often cause apneustic breathing. Ataxic breathing is caused by medullary lesions. The patients state of consciousness is measured by their awareness and responsiveness to the environment. There are many levels or states of awareness, and they have been identied by many descriptors, such as stupor, lethargy, somnolence, confusion, and delirium. The denitions for these states are a bit variable and are likely a continuum from normal to coma. Coma is dened as a state of complete loss of consciousness or a state of unarousable unresponsiveness. In practice, it is most helpful to describe the patients response to stimuli. These include auditory stimuli such as a voice or loud clap, visual stimuli such as light or a threatening gesture, or noxious stimuli applied in central locations (eg, the sternum) and each limb. Responses such as arousal, eye opening, or grimacing should be noted.
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Several CN reexes can be done to test the integrity of the brainstem from the midbrain to the medulla. The pupillary light reex is relatively resistant to metabolic insults and is one of the most important signs in distinguishing structural from metabolic causes of coma.Again, the afferent limb of this reex is some optic nerve bers and the efferent limb is the oculomotor nerve (CN III). For example, a structural lesion compressing CN III will typically cause an ipsilateral xed and dilated pupil. A pontine lesion may cause pinpoint pupils that require a magnifying glass to see the preserved trace light reex. Any eye movements present and their pattern should be noted. Roving conjugate spontaneous eye movements imply that the nuclei responsible for ocular motility in the midbrain and pons are communicating with each other. Eye movements can be induced by the oculocephalic (dolls eyes) and vestibulo-ocular (caloric testing) reexes. The oculocephalic reex is easier to accomplish but is less of a stimulus to eye movements than the vestibulo-ocular reex. In a comatose patient lying supine who may be intubated, performing horizontal oculocephalics is easier, but vertical oculocephalics can also be done. Before performing the oculocephalic reex, one must be sure that there are no abnormalities of the cervical spine. The head is then quickly turned from side to side. If the brainstem is intact, then the eyes will move in the direction opposite to the skull movement and stay looking forward. The corneal reex is done by touching the lateral portion of the cornea with a nonabrasive stimulus such as a wisp of cotton. A positive corneal reex occurs when both eyes blink to the stimulus.The afferent
255
limb of this reex is the trigeminal nerve (CN V), whereas the efferent limb is the facial nerve (CN VII).The gag reex is produced by stimulating the posterior tongue or pharynx and looking for elevation and constriction of the pharyngeal muscles, which often produces a cough, gag, or swallow. This reex may be difcult to do in intubated patients or in those with an altered level of consciousness. It can also lead to aspiration pneumonia. The gag reex may be an overrated test, and, given its potential for causing problems, it is often skipped in the evaluation of comatose patients. In testing the motor function of a comatose patient, inspection of muscle bulk and testing of muscle tone should not be forgotten. Obviously, the comatose patient cannot cooperate with formal testing of the power of all muscle groups, but some information regarding motor function can be deduced from some simple maneuvers. Watching for voluntary movements may show an asymmetry between the two sides. Reexive posturing, either decerebrate or decorticate, may indicate fairly severe brain injury. Reexive withdrawal of the extremities to painful stimulation such as nail-bed pressure may be the only way to see movement of the extremities.Testing the muscle stretch reexes and evaluating plantar responses are necessary. Asterixis, which is commonly sought in the upper extremities, may be indicative of a variety of metabolic encephalopathies or focal brain lesions. Testing of sensation is often extremely limited except for gross evaluation of responses to pain. Despite what appears to be a limited neurologic examination in the comatose patient, quite a bit of useful
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information can be gained. Often a tentative diagnosis can be made on the basis of the examination alone. For example, for a patient with intact brainstem reexes, symmetric spontaneous and induced movements of the face and extremities, and symmetric reexes, the most likely cause of their coma would be a metabolic derangement that is affecting the brain diffusely. If the patient is comatose, with bilateral papilledema, a unilateral CN III palsy with a xed and dilated pupil, and no movement of the contralateral body, one must be suspicious of a mass or structural lesion.
RECOMMENDED READINGS Biller J. Practical neurology. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2002. DeMyer WE. Technique of the neurologic examinationa programmed text. 4th ed. New York: McGraw-Hill; 1994. Guarantors of Brain. Aids to the examination of the peripheral nervous system. London: Baillire Tindall; 1986. Haerer AF. Dejongs - the neurologic examination. 5th ed. Philadelphia: JB Lippincott; 1992. Orient JM. Sapiras art and science of bedside diagnosis. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2000.
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INDEX
A Abdomen examination of, 241 Abducens nerve, 244 Abducens nerve palsy, 42 Abduction paresis with Wernickes encephalopathy, 227 Abscess with coma, 52t, 53t, 57t epidural, 85, 86 paraspinal, 85, 8687 Absence status epilepticus, 64 ACE for hypertension, 161 for ischemic stroke, 136, 146 Acetylcholine receptor (AChR), 95, 99 Acinetobacter calcoaceticus, 203 Acquired immunodeciency syndrome (AIDS) with Wernickes encephalopathy, 226t Acute intermittent porphyria, 116, 117t Acute quadriplegic myopathy, 125126 Acyclovir for encephalitis, 186 AIDS with Wernickes encephalopathy, 226t Airway management generalized tonic-clonic status epilepticus, 64 Airway obstruction with neuromuscular respiratory failure, 91, 94 Alcoholism, 85 with stroke, 141, 147 with Wernickes encephalopathy, 220233 ALS, 89 pitfalls, 129130 respiratory involvement in, 128129 Amantadine for neuroleptic malignant syndrome, 175 Aminoglycosides contraindicated in myasthenia gravis, 104 Ampicillin for bacterial meningitis, 196, 199t for Listeria monocytogenes meningitis, 204 258
Amyotrophic lateral sclerosis (ALS), 89 pitfalls, 129130 respiratory involvement in, 128129 Anemia, 112 Aneurysm anterior cerebral artery, 3f anterior communicating artery, 5 berry, 9, 1113 internal carotid-posterior communicator, 5 mycotic, 10 posterior fossa, 5 Angiotensin-converting enzyme (ACE) for hypertension, 161 for ischemic stroke, 136, 146 Anisocoria, 47 Ankle jerk, 249 Anorexia with giant cell arteritis, 23 Anterior cerebral artery, 5, 143 ruptured aneurysm, 3f Anterior communicating artery aneurysm, 5 Antiplatelet therapy for lacunar syndrome, 161 for stroke, 159 Antithrombotic therapy for stroke, 159 Apathy with Wernickes encephalopathy, 228 Apneustic breathing, 4445 Apomorphine for neuroleptic malignant syndrome, 177 Appetite with giant cell arteritis, 21 Arboviral encephalitis dened, 187 Arboviruses, 187 geographic distribution of, 188t Areexia with Guillain-Barre syndrome, 115 Arm outstretched drift of, 4 Arm pain abrupt onset of, 5 Arsenic poisoning, 116, 253 Arterial blood gases
Index
for comatose patient, 48 neuromuscular respiratory failure, 93 Arteriovenous malformation, 11 Arthropod-borne virus, 187 Aspiration with neuromuscular respiratory failure, 94 Aspiration pneumonia with stroke, 155 Aspirin for atherosclerosis, 160 for stroke, 156, 159 Asterixis, 256 Ataxia, 45 Ataxic breathing, 254 Atelectasis, 112 with neuromuscular respiratory failure, 94 Atherosclerosis with stroke, 140, 160161 Ativan for generalized tonic-clonic status epilepticus, 67, 68t Atrial brillation, 241 with stroke, 141, 146 Atrial tachycardia, 241 Atropine, 97 intoxication dilated and xed pupils with, 42 Auscultation, 240 Autoimmune disease with myasthenia gravis, 95 Autonomic instability with neuroleptic malignant syndrome, 170 Azathioprine for myasthenia gravis, 109, 113 for vasculitis, 161 B Babinskis sign, 46, 48, 170, 249 Bacillary meningitis gram-negative treatment of, 203 Back pain abrupt onset of, 5 Bacterial meningitis, 8, 191209 antimicrobial therapy of, 198t200t brain damage pathogenic mechanisms, 205209 CSF, 192197 CT, 194, 195 empiric therapy for, 196197
laboratory diagnosis of, 192196 management of, 207f208f MRI, 194 PCR, 194 Barbiturate intoxication small pupils with, 42 Basilar artery, 143 occlusion, 59 stroke, 145 Basilar skull fracture in comatose patient, 38 Battles sign, 236 in comatose patient, 38 Bells palsy, 246 Benign positional vertigo mimicking stroke, 138t Benzodiazepines causing neuroleptic malignant syndrome, 169 for generalized tonic-clonic status epilepticus, 67, 71 overdose umazenil for, 38 Benztropine mesylate, 167 Berry aneurysm ruptured, 9, 1113 Biots breathing, 45 Bitter almond odor with cyanide poisoning, 253 Bladder loss of control with headaches, 5 Blepharospasm with neuroleptic malignant syndrome, 170 Blinking, 44 Blood patch for post-lumbar puncture headache, 8 Blood pressure labile with neuroleptic malignant syndrome, 170 Blood vessel CT angiography, 158 transcranial Doppler ultrasonography, 158 Blurred vision with botulism, 122 Botulinum toxin contraindicated in myasthenia gravis, 104 Botulism, 89, 121124 classic, 121 clinical course of, 123 259
Index
clinical features of, 122 diagnosis of, 122 infant, 123124 management of, 122123 Brain central herniation, 46 CT, 157 uncal herniation, 4648 Brain herniation syndromes, 4548, 47f, 56 CT, 56 MRI, 56 Brainstem, 35, 143 indicators of function, 3839, 40f41f stroke signs in, 144 Brainstem disease signs of, 4647 Breath garlic with arsenic poisoning, 253 shortness of with neuromuscular respiratory failure, 90 Breathing apneustic, 4445 Biots, 45 Bromocriptine for neuroleptic malignant syndrome, 168, 175 Bronchiolar mucus plugging with neuromuscular respiratory failure, 94 Brown-Sequards syndrome, 78, 79f Brudzinskis sign, 4, 38, 240 with bacterial meningitis, 191 Buccofacial dyskinesia with neuroleptic malignant syndrome, 170 Buttery rash, 127 C Caffeine sodium benzoate for post-lumbar puncture headache, 8 Caloric testing, 255 Campylobacter jejuni with Guillain-Barre syndrome, 115, 116 Carbamazepine causing neuroleptic malignant syndrome, 169 Cardiac telemetry with stroke, 158 Cardioembolism 260
with stroke, 140 Cardiovascular system examination of, 241 Carotid endarterectomy with ischemic stroke, 147 for stroke, 160 Carotid stenosis asymptomatic with stroke, 141 Cefepime for bacterial meningitis, 196, 198t for encephalitis, 186 for pneumococcal meningitis, 202 Cefotaxime for bacterial meningitis, 196, 198t, 200t for encephalitis, 185 for gram-negative bacillary meningitis, 203 for Haemophilus inuenzae meningitis, 204 for meningococcal meningitis, 197 for pneumococcal meningitis, 202 Ceftazidime for gram-negative bacillary meningitis, 203 Ceftriaxone for bacterial meningitis, 196, 198t for encephalitis, 186 for gram-negative bacillary meningitis, 203 for Haemophilus inuenzae meningitis, 205 for meningococcal meningitis, 197 CEI for myasthenia gravis, 100102 Celfazidine for bacterial meningitis, 200t Central neurogenic hyperventilation, 44 Cerebellar hematoma CT, 211f, 213f diagnosis of, 215217 Cerebellar hemorrhage, 11 with hypertension, 213214 Cerebellar hemorrhage and infarction, 210219 cases of, 210213 management algorithm, 216f management of, 217219 Cerebellum, 142143 stroke signs in, 144 Cerebral artery anterior, 5, 143 ruptured aneurysm, 3f
Index
posterior, 143, 145 Cerebral edema, 54f with coma, 53t Cerebral herniation with bacterial meningitis, 195 Cerebrospinal uid (CSF) bloody examination of, 10 rhinorrhea or otorrhea in comatose patient, 38 Cerebrum CT, 212f Cerebyx. See Fosphenytoin (Cerebyx) Cervical carotid artery, 240 Cervical fractures with coma, 43 CT, 77 MRI, 77 respiratory arrest, 77 Chest examination of, 240241 Cheyne-Stokes respiration, 44, 46, 254 China motor axonal neuropathy in, 116 Chloroquine contraindicated in myasthenia gravis, 104 Cholesterol emboli (Hollenhorst plaque), 244 Cholinergic crisis, 105t, 108 Cholinesterase inhibitors (CEI) for myasthenia gravis, 100102 Chorea with neuroleptic malignant syndrome, 170 Cigarette smoking with ischemic stroke, 133, 147 with stroke, 141 Cimetidine prolonged paralysis from, 125 Classic botulism, 121 Clopidogrel for stroke, 159 Clostridium botulinum, 121, 123124 Clostridium difcile, 112 Clozapine causing neuroleptic malignant syndrome, 169 Clumsy hand-dysarthria syndrome, 145 CN reex tests, 255 Coagulation times with stroke, 158 Cocaine, 124
with stroke, 158 Coccidioidal meningitides, 4 Coitus headaches during, 13 College freshmen meningococcal meningitis, 201 Colorado tick fever virus geographic distribution of, 188t Coma, 3261 bihemispheric cause of abnormal CT with nonoperable lesions, 53t abnormal CT with operable lesions, 52t vs. brainstem, 35t, 3839 normal CT, 54t55t brain herniation syndromes, 4548 brainstem causes of abnormal CT with nonoperable lesions, 58t abnormal CT with operable lesions, 57t normal CT, 60t case study of, 3233 cervical fractures with, 43 CT, 49 dened, 33, 254 diagnosis and treatment algorithm, 50f51f examination of, 252257 general medical evaluation of, 3638, 37f lumbar puncture, 49, 59 management of, 4859 motor responses, 45 neurologic examination, 3839, 40f41f reversible causes of, 38 Communicating artery anterior aneurysm, 5 Complex partial status epilepticus, 64 Computed tomography (CT) brain herniation syndromes, 56 cerebellar hematoma, 211f, 213f cerebrum, 212f cervical fractures, 77 coma, 49, 52t58t, 60t epidural abscess, 86 ischemic stroke, 134, 134f, 136, 136f prior to lumbar puncture for headaches, 8 spinal cord tumors, 81 261
Index
Confusion with neuroleptic malignant syndrome, 170 with Wernickes encephalopathy, 221, 228 Congestive heart failure, 112 Conjugate gaze decits with Wernickes encephalopathy, 227 Consciousness anatomy of, 3334 dened, 33 grading levels of, 36 loss of with headaches, 2, 5 Constipation with botulism, 122 with Wernickes encephalopathy, 226t Contrast agents intravenous contraindicated in myasthenia gravis, 104 Corneal reex, 255 Coronary artery disease with ischemic stroke, 133 Cortex left, 142 right, 142 Cortical disease bilateral, 34 cause of, 34 Corticosteroids for giant cell arteritis, 27 for myasthenia gravis, 102103 prolonged paralysis from, 125 Cough for diaphragm function assessment, 92 Cough/gag, 44 Counting test for diaphragm function assessment, 92 Cranial nerves assessment of, 237t C-reactive protein for giant cell arteritis, 23, 28 for headaches, 2 Creatine kinase with neuroleptic malignant syndrome, 171 Crescendo transient ischemic attack (TIA), 156157 Critical illness myopathy, 125126 neuropathy, 126 Cryptococcal meningitides, 4 CSF 262
bloody examination of, 10 rhinorrhea or otorrhea in comatose patient, 38 CT. See Computed tomography (CT) Cushings syndrome, 241 Cyanide poisoning, 253 Cyclophosphamide for vasculitis, 161 Cytomegalovirus with Guillain-Barre syndrome, 115 D Dantrolene for neuroleptic malignant syndrome, 167168, 175 Decerebrate posturing, 45 Decorticate posturing, 45 Dementia with Wernickes encephalopathy, 226t Dermatomyositis, 126128 laboratory ndings, 128 Descending paralysis, 122 Dexamethasone for bacterial meningitis, 206 Dexterity, 249 Diabetes mellitus, 26, 85 with stroke, 141 Diaphoresis with neuroleptic malignant syndrome, 170 Diaphragm assessment of with neuromuscular respiratory failure, 9193 Diarrhea with Guillain-Barre syndrome, 115 Diazepam (Valium) for generalized tonic-clonic status epilepticus, 67, 68t Diet with ischemic stroke, 147 Diffuse axonal injury with coma, 60t Digitalis toxicity with Wernickes encephalopathy, 226t Dilantin for generalized tonic-clonic status epilepticus, 67, 71 Dilated pupils with botulism, 122 Dioxymethamphetamine, 171 Diplopia
Index
with botulism, 122 with giant cell arteritis, 22 Diprivan for generalized tonic-clonic status epilepticus, 69t, 71 Dipyridamole for stroke, 159 Disturbed sleep with amyotrophic lateral sclerosis, 128129 Diuretic toxicity with Wernickes encephalopathy, 226t Dizziness with cerebellar hematoma, 215 Dolls eye maneuver, 43, 255 Dopamine for pentobarbital burst suppression, 74 Dopamine receptor blocking agents adverse effects of, 168 Doxycycline for Rocky Mountain spotted fever, 186, 188, 189 D-penicillamine contraindicated in myasthenia gravis, 104 Drug intoxication with coma, 38, 55t Dry mouth with botulism, 122 Dysarthria, 246 with botulism, 122 Dyskinesia buccofacial with neuroleptic malignant syndrome, 170 Dysphagia with botulism, 122 with neuroleptic malignant syndrome, 170 Dysphonia with neuromuscular respiratory failure, 91 Dyspnea with myasthenia gravis, 97 with neuromuscular respiratory failure, 90 Dystonia with neuroleptic malignant syndrome, 170 E Eastern equine encephalitis virus geographic distribution of, 188t
Ecchymoses in comatose patient, 38 Ecstasy, 171 Edrophonium test (Tensilon test) for myasthenia gravis, 9799 Elderly with giant cell arteritis, 23 Electrolyte disturbances with coma, 55t Embolic amaurosis fugax, 21 Encephalitis, 66, 182189 case of, 182 Endotracheal intubation of comatose patient, 36, 48 for generalized tonic-clonic status epilepticus, 64 for neuromuscular respiratory failure, 9394 Enterobacter, 203 Enteroviral encephalitis, 189 Epidural abscess, 85 CSF, 86 CT, 86 MRI, 86 Epidural hemorrhage with coma, 52t Epilepsia partialis continua, 64 Epilepsy, 62 Epstein-Barr virus with Guillain-Barre syndrome, 115 Erythrocyte sedimentation rate (ESR) for giant cell arteritis, 23, 28 for headaches, 2 Escherichia coli, 193, 197, 203 ESR for giant cell arteritis, 23, 28 for headaches, 2 Exercise with ischemic stroke, 147 with myasthenia gravis, 9697 Extensor plantar response, 4 Extramedullary spinal cord tumors, 81, 83t Extremities examination of, 241 Eye movements in comatose patient, 4245 F Facial nerve, 245246 Fever with bacterial meningitis, 190 with giant cell arteritis, 22 263
Index
with headache, 2 with neuroleptic malignant syndrome, 170, 171 Flumazenil (Romazicon) for benzodiazepine overdose, 38, 49 Fluphenazine causing neuroleptic malignant syndrome, 168169 Focal motor status epilepticus, 64 Folic acid for hyperhomocysteinemia, 161 Fosphenytoin (Cerebyx) for generalized tonic-clonic status epilepticus, 67, 68t, 69t, 71 Frisn scale of papilledema, 13, 17t G Gag reex, 246, 256 Gait examination of, 252 instability with Wernickes encephalopathy, 221 Garlic breath with arsenic poisoning, 253 Gastric surgery with Wernickes encephalopathy, 226t Gastrointestinal cancer with Wernickes encephalopathy, 226t Gaze-evoked nystagmus with Wernickes encephalopathy, 221 Gaze paresis with cerebral hematoma, 217 GCA. See Giant cell arteritis (GCA) Generalized tonic-clonic status epilepticus, 6263 cerebral spinal uid, 66 clonic phase, 7sf, 70f management of, 6474, 65f post-ictal phase, 73f Gentamicin for bacterial meningitis, 196, 200t for Listeria monocytogenes meningitis, 196, 204 Giant cell arteritis (GCA), 2, 2030, 240 clinical diagnosis of, 2223 diagnostic algorithm for, 24f25f laboratory diagnosis of, 2326 signs of, 22 symptoms of, 2021 treatment of, 2728 typical case of, 28 Gram-negative bacillary meningitis 264
treatment of, 200t,203 Gram-negative bacilli, 200t Grilled foods botulism, 121 Group B streptococcus, 193 Guillain-Barre syndrome, 89, 115120, 118t120t diagnosis of, 115116 differential diagnosis of, 116, 117t pitfalls, 129 treatment of, 116117 H Haemophilus inuenzae, 193 meningitis, 204 Haloperidol causing neuroleptic malignant syndrome, 168169 Headaches abrupt onset of worst, 2, 13 with bacterial meningitis, 191 changes in, 12 de novo in patient over 50, 2, 2223 as emergency, 117 with fever, 2 with giant cell arteritis, 21, 22 with leg weakness, 5 long-standing, 4 with loss of bladder control, 5 with loss of consciousness, 2, 5 lumbar puncture for, 58 with neuromuscular respiratory failure, 91 new, 12 with subarachnoid hemorrhage, 5, 913 with third nerve palsy, 5 Head and neck examination, 236242 Head trauma with coma, 55t, 58t papilledema with, 13 Heart valves mechanical with stroke, 141 Heavy metal poisoning, 116, 117t Heliotrope rash, 127 Hematocrit with stroke, 158 Hematogenous tumors with Wernickes encephalopathy, 226t Hematoma cerebellar CT, 211f, 213f
Index
diagnosis of, 215217 Hemisphere large unilateral lesions of, 35 left stroke signs in, 144 right stroke signs in, 144 Hemodialysis with Wernickes encephalopathy, 226t Hemodynamic stability of comatose patient, 36 Hemoglobin with stroke, 158 Hemorrhage cerebellar, 11, 210219 with hypertension, 213214 epidural with coma, 52t intracerebral with coma, 52t, 58t pontine, 59f subarachnoid, 2, 10 with coma, 52t with headaches, 5 vs. traumatic puncture, 12t subdural with coma, 52t Hemorrhagic stroke dened, 137 Hemotympanum in comatose patient, 38 Heparin for ischemic stroke, 136 for stroke, 156157 Hepatomegaly, 241 Herniation risk factors for in lumbar puncture for meningitis, 9t Herpes simplex virus 1 (HSV-1) encephalitis, 182189 CSF, 182, 185f EEG, 183 MRI, 183, 185f PCR, 183 Herpesviruses with Guillain-Barre syndrome, 115 Hexane toxicity, 116, 117t Hip pain with giant cell arteritis, 21, 22 HIV, 85, 242 with Guillain-Barre syndrome, 115 Hollenhorst plaque, 244 Home-canned foods
botulism, 121 Honey botulism, 121 Hospitalization myasthenia gravis, 97 HSV-1. See Herpes simplex virus 1 (HSV-1) encephalitis Human immunodeciency virus (HIV), 85, 242 with Guillain-Barre syndrome, 115 Hydrocephalus with cerebellar hematoma, 213214, 218 with coma, 52t, 57t Hypercarbia with neuromuscular respiratory failure, 91 Hypercholesterolemia with ischemic stroke, 146 Hypercoagulation with stroke, 158 Hyperemesis gravidarum with Wernickes encephalopathy, 226t Hyperglycemia with stroke, 155 Hyperhomocysteinemia with stroke, 161 Hyperlipidemia with stroke, 141, 161 Hypertension, 253 with cerebellar hemorrhage, 213214 with stroke, 133, 139, 141, 146, 161 Hyperthermia, 253 with stroke, 155 Hyperventilation, 254 central neurogenic, 44 Hypoglossal nerve, 247 Hypoglycemia in comatose patient, 38 with generalized tonic-clonic status epilepticus, 66 Hypoglycorrhachia, 10 Hypoperfusion with stroke, 140, 161 Hyporeexia with Guillain-Barre syndrome, 115 Hypotension, 253 with stroke, 154 with Wernickes encephalopathy, 229 Hypothermia, 253 with Wernickes encephalopathy, 228 Hypotonic intravenous solutions contraindicated in stroke, 156 265
Index
Hypoventilation, 254 with neuromuscular respiratory failure, 91 Hypoxemia with neuromuscular respiratory failure, 91 Hypoxia with coma, 55t I Ileus with botulism, 122 Illicit drug use with stroke, 158 Inclusion body myositis, 126128 laboratory ndings, 128 Infant botulism, 123124 Infection, 26 mimicking stroke, 138t Inammatory myopathies, 126128 diagnosis of, 126127 examination of, 127 laboratory ndings, 127128 Intensive care patient acute weakness in, 124125 Interferon contraindicated in myasthenia gravis, 104 Internal carotid-posterior communicator aneurysm, 5 Intracerebral hemorrhage with coma, 52t, 58t Intracranial pressure bacterial meningitis, 195 Intramedullary spinal cord tumors, 8284 prognosis of, 84 Intravenous contrast agents contraindicated in myasthenia gravis, 104 Intravenous feedings with Wernickes encephalopathy, 226t Intravenous immunoglobulin (IVIg) for Guillain-Barre syndrome, 117 for myasthenia gravis, 103104, 110111 Intubation. See Endotracheal intubation Irregular pulse, 241 Ischemic infarct with coma, 52t54t, 57t, 58t, 60t Ischemic penumbra, 150f Ischemic stroke, 133162, 242 causes of, 139140 conditions mimicking, 138t 266
CT, 134, 134f, 136, 136f dened, 137 ECG, 134 emergency care of, 147154 epidemiology of, 137138 incidence of, 138 neuroanatomy, 142143 risk factors for, 139142 thrombolytic therapy for, 134135 t-PA for, 135, 147150, 149f, 152154 transthoracic echocardiogram, 135 IVIg for Guillain-Barre syndrome, 117 for myasthenia gravis, 103104, 110111 J Japanese encephalitis virus geographic distribution of, 188t K Kaposis sarcoma, 242 Kernigs sign, 4, 38, 240 Kernohan-Woltman phenomenon, 48 Klebsiella pneumoniae, 197, 203 Knee jerk, 249 Korsakoff s psychosis, 229 L Labile blood pressure with neuroleptic malignant syndrome, 170 La Crosse encephalitis ribavirin, 189 La Crosse virus geographic distribution of, 188t Lacunar syndrome with stroke, 161 Latent strabismus, 42 Left cortex, 142 Left hemisphere stroke signs in, 144 Left middle cerebral artery stroke, 144 Legs abrupt onset of pain, 5 weakness with headaches, 5 Lethargy with bacterial meningitis, 191 with Wernickes encephalopathy, 228 Leukemia, 85 Limb ataxia with cerebellar hematoma, 215 Listeria monocytogenes, 196, 197, 200t
Index
meningitis, 204 Livedo reticularis, 242 Lorazepam (Ativan) for generalized tonic-clonic status epilepticus, 67, 68t Lumbar puncture contraindications to, 10, 11t CT prior to, 8 for headaches, 58 in meningitis risk factors for uncal and cerebellar herniation, 9t needle placement, 67 patient positioning, 56 patient preparation for pressure measurement, 78 site preparation, 6 Lymphoma with Guillain-Barre syndrome, 115 with Wernickes encephalopathy, 226t M Magnesium prolonged paralysis from, 125 for Wernickes encephalopathy, 231 Malaise with giant cell arteritis, 22 Malaria, 241 Malignancy, 26 Mannitol for brain herniation, 56 Mastoid processes, 240 Mechanical heart valves with stroke, 141 Mechanical ventilation for comatose patient, 48 of comatose patient, 36 for generalized tonic-clonic status epilepticus, 64 for neuromuscular respiratory failure, 9394 MenC polysaccharide vaccine, 201 Meningeal irritation signs of, 38 Meningismus with bacterial meningitis, 191 Meningitides coccidioidal, 4 cryptococcal, 4 Meningitis, 4, 13, 66. See also Bacterial meningitis lumbar puncture in
risk factors for uncal and cerebellar herniation, 9t meningococcal, 191, 242 college freshmen, 201 therapy of, 197201 pneumococcal, 191 treatment of, 202 staphylococcus treatment of, 203 Streptococcus agalactiae treatment of, 204 Meningococcal meningitis, 191, 242 college freshmen, 201 therapy of, 197201 Meningococcemia, 189 Meningoencephalitis with coma, 54t, 60t Mental confusion with giant cell arteritis, 21 Mental status assessment of, 237t Meropenem for pneumococcal meningitis, 202 Mestinon for myasthenia gravis, 101, 113 Metabolic acidosis with generalized tonic-clonic status epilepticus, 66 with prolonged paralysis, 125 Metastases affecting spinal cord, 8082 3,4-methylene-dioxymethamphetamine (Ecstasy), 171 Methylphenidate causing neuroleptic malignant syndrome, 169 Methylprednisolone for giant cell arteritis, 30 for transverse myelitis, 85 for traumatic spinal injury, 80 Midazolam (Versed) for generalized tonic-clonic status epilepticus, 67, 68t, 71 Middle cerebral artery, 143, 144 Miller Fisher syndrome, 116 Monocular visual loss abrupt onset of, 2 Motor axonal neuropathy in China, 116 Motor function assessment of, 237t238t Motor responses coma, 45 267
Index
Motor vehicle accidents, 76 Motor weakness with Guillain-Barre syndrome, 115 Mouth dry with botulism, 122 MSS, 110 Multiple sclerosis, 84 Muscle power, 248 grading of, 248t Muscle relaxants prolonged paralysis from, 125 Muscle stretch reex, 249 abnormalities with neuroleptic malignant syndrome, 170 grading of, 250t Muscular dystrophy, 89 Muscular rigidity with neuroleptic malignant syndrome, 170 Myasthenia gravis, 89115, 95100 acutely deteriorating, 105t cholinesterase inhibitors, 100102 clinical features of, 9697 eletrophysiologic tests for, 99100 hospitalization, 97 medications exacerbating, 104, 106t pitfalls, 130 serologic tests for, 99 treatment of, 100114 Myasthenic crisis, 104108, 105t treatment of, 107108 Myasthenic muscular score (MSS), 110 Mycoplasma with Guillain-Barre syndrome, 115 Mycotic aneurysm ruptured, 10 Myridostigmine for myasthenia gravis, 113 N Nafcillin for bacterial meningitis, 199t Naloxone (Narcan) for narcotic overdose, 38, 49 Narcan for narcotic overdose, 38, 49 Narcotic overdose naloxone for, 38, 49 National Institutes of Health Stroke Scale, 133 Nausea with bacterial meningitis, 191 268
Neck examination of, 236242 pain abrupt onset of, 5 with giant cell arteritis, 21 stiff, 4 with bacterial meningitis, 191 stiffness on forward bending, 38 Neisseria meningitidis, 186, 191, 193, 197, 199t, 201, 202 Nembutal for generalized tonic-clonic status epilepticus, 69t, 71 side effects of, 7174 Nerve ber layer infarcts, 13 Neurobroma of spinal cord, 82 Neurobromatosis, 8182 Neuroleptic malignant syndrome, 167178, 247 clinical features of, 170174 demographics of, 168 ECT, 177 etiology of, 168170 risk factors for, 168170 treatment algorithm for, 172f173f treatment of, 174178 Neurologic examination, 236257 with altered levels of consciousness, 239t comprehensive, 242252 guidelines for, 237t238t head and neck examination, 236242 Neuromuscular blockers prolonged paralysis from, 124125 Neuromuscular disease respiratory failure due to, 89130 Neuromuscular respiratory failure, 89130 clinical patterns of, 95100 examination, 9193 patient evaluation, 9091 precipitating factors, 9495 respiratory muscle weakness and fatigue, 90 New headaches, 12 Night sweats with giant cell arteritis, 22, 23 with serotonin reuptake inhibitors, 22 Nitrofurantoin neurotoxicity, 116, 117t Nonconvulsive status epilepticus, 63 Nonsteroidal antiinammatory drugs erythrocyte sedimentation rate, 23 Nose
Index
examination of, 236237 Nystagmus gaze-evoked with Wernickes encephalopathy, 221 O Ocular motility examination, 4 impaired with Wernickes encephalopathy, 221 Oculocephalic reex, 255 Oculogyric crises with neuroleptic malignant syndrome, 170 Oculomotor nerve, 244, 245 palsy, 42 Oculovestibular reex, 43 Olanzapine causing neuroleptic malignant syndrome, 169 Ophthalmoplegia with Wernickes encephalopathy, 227 Opiate intoxication pinpoint pupils with, 42 Optic disks swelling of, 13 Optic nerve examination of, 243 swollen, 4 Optic neuritis, 13 Optic neuropathy with giant cell arteritis, 22, 29f Oropharyngeal weakness with neuromuscular respiratory failure, 91 Osteoporosis, 28 Otoscopy, 240 Over 50 giant cell arteritis in, 21, 22 headaches arising de novo, 2 Oxygen for generalized tonic-clonic status epilepticus, 64 P Pain arm, 5 back, 5 hip, 21, 22 with intramedullary spinal cord tumors, 83
leg, 5 neck, 5, 21 with paraspinal abscess, 8687 shoulder, 21 testing of, 250 Pancuronium contraindicated in myasthenia gravis, 104 Papilledema, 4, 244 Frisn scale of, 13, 17t grade I, 15f grade II, 15f grade III, 16f grade IV, 16f grade V, 17f with head trauma, 13 recognition of, 13 Paradoxical abdominal wall movement for diaphragm function assessment, 92 Paralysis descending, 122 Paranoid delusions, 167 Paraplegia, 85 Paraspinal abscess, 85, 8687 Parinauds syndrome, 43 Parkinsons disease with neuroleptic malignant syndrome, 168 Penicillamine contraindicated in myasthenia gravis, 104 Penicillin G for bacterial meningitis, 199t, 200t for meningococcal meningitis, 197 for meningococcemia, 189 Pentobarbital (Nembutal) for generalized tonic-clonic status epilepticus, 69t, 71 side effects of, 7174 Periungual edema, 127 Pernicious anemia with myasthenia gravis, 95 Phenobarbital for generalized tonic-clonic status epilepticus, 69t, 71 Phenylephrine for pentobarbital burst suppression, 74 Phenytoin (Dilantin) for generalized tonic-clonic status epilepticus, 67, 71 Photophobia with bacterial meningitis, 191 Pituitary apoplexy 269
Index
with subarachnoid hemorrhage, 10 Plantar response, 249 Plasma exchange for myasthenia gravis, 103, 108114 Plasmapheresis for Guillain-Barre syndrome, 117 PMR, 20 Pneumococcal meningitis, 191 treatment of, 202 Pneumocystis carinii pneumonia, 204 Pneumonia aspiration with stroke, 155 with bacterial meningitis, 191 Pneumocystis carinii, 204 Poisoning, 117t, 166, 253 thallium, 116 Polymyalgia with giant cell arteritis, 21 Polymyalgia rheumatica (PMR), 20 Polymyositis, 126128 laboratory ndings, 128 Pontine hemorrhage, 59f Pontine infarct, 58f Posterior cerebral artery, 143 Posterior cerebral artery stroke, 145 Posterior fossa aneurysm in, 5 Postictal with coma, 55t vs. nonconvulsive status epilepticus, 6364 Post-lumbar puncture headache, 8 Posturing, 45 with neuroleptic malignant syndrome, 170 Powassan virus geographic distribution of, 188t Prednisolone for myasthenia gravis, 113 Prednisone for giant cell arteritis, 2728 for myasthenia gravis, 109 Premature atrial contractions, 241 Premature ventricular contractions, 241 Procainamide contraindicated in myasthenia gravis, 104 Proctitis radiation with Wernickes encephalopathy, 226t Propofol (Diprivan) 270
for generalized tonic-clonic status epilepticus, 69t, 71 Proprioception testing of, 251 Pseudomonas aeruginosa, 200t, 203 Ptosis, 245 with botulism, 122 with Wernickes encephalopathy, 227 Pulse irregular, 241 Pulse oximetry for comatose patient, 48 Pupillary light reex, 243244 Pupils in central brain herniation, 46 constriction of, 4 dilated, 245 with botulism, 122 dilated and xed with atropine intoxication, 42 examination of in comatose patient, 3942 light reactivity, 39 pinpoint with opiate intoxication, 42 size of, 39 small with barbiturate intoxication, 42 unilateral constriction of, 4 unilaterally enlarged with brainstem disorder, 42 Pure motor stroke, 145 Pure sensory stroke, 145 Pyloric stenosis with Wernickes encephalopathy, 226t Pyridostigmine (Mestinon) for myasthenia gravis, 101, 113 Pyrithiamine, 223 Q Quadriplegia, 85 Quetiapine causing neuroleptic malignant syndrome, 169 Quinidine contraindicated in myasthenia gravis, 104 Quinine contraindicated in myasthenia gravis, 104 toxicity with Wernickes encephalopathy, 226t
Index
R Raccoon eyes, 236 in comatose patient, 38 Radiation proctitis with Wernickes encephalopathy, 226t Radicular artery of Adamkiewicz thrombosis of, 78 RAPD, 244 Rash buttery, 127 differential diagnosis of, 189 heliotrope, 127 Raspy voice with neuromuscular respiratory failure, 91 Raves, 171 Reexes assessment of, 238t asymmetry of, 4 Reexive posturing, 256 Reexive withdrawal, 256 Relative afferent pupillary defect (RAPD), 244 Repetitive stimulation for botulism, 122 Respiratory arrest cervical fractures, 77 Respiratory failure. See also Neuromuscular respiratory failure with myasthenic crisis, 107 Respiratory muscle neuromuscular respiratory failure, 90 Rest with myasthenia gravis, 9697 Reticular activating system, 33, 34f, 35 Rhabdomyolysis with generalized tonic-clonic status epilepticus, 66 Rheumatoid arthritis with myasthenia gravis, 95 Rhythm strip with stroke, 158 Ribavirin for La Crosse encephalitis, 189 Rickettsia rickettsii, 189 Right cortex, 142 Right hemisphere stroke signs in, 144 Right middle cerebral artery stroke, 145 Rigidity, 247 with neuroleptic malignant syndrome, 170 Risperidone, 167
causing neuroleptic malignant syndrome, 169 Rock Mountain spotted fever, 189, 242 doxycycline for, 189 Romazicon for benzodiazepine overdose, 38, 49 Rombergs testing, 4 S Sarcoidosis with Guillain-Barre syndrome, 115 Scalp, 240 erythematous with giant cell arteritis, 22 tender with giant cell arteritis, 21, 22 Schizophrenia, 167 Seizures, 6274 mimicking stroke, 138t Selective serotonin inhibitors causing neuroleptic malignant syndrome, 169 Sensation assessment of, 238t Sensorimotor stroke, 146 Serotonin reuptake inhibitors night sweats with, 22 SFEMG for myasthenia gravis, 99100 Shortness of breath with neuromuscular respiratory failure, 90 Shoulder pain with giant cell arteritis, 21, 22 Sialorrhea with neuroleptic malignant syndrome, 170 Single-ber electromyography (SFEMG) for myasthenia gravis, 99100 Skin examination of, 241242 Sleep disturbed with amyotrophic lateral sclerosis, 128129 with neuromuscular respiratory failure, 9091 Slurred speech with ischemic stroke, 133 Smoking with ischemic stroke, 133, 147 with stroke, 141 Somnolent patients 271
Index
grading consciousness in, 36 Spastic hemiplegia, 45 Spasticity, 247 Speech slurred with ischemic stroke, 133 Spinal accessory nerve, 246 Spinal cord emergency conditions, 7687 infectious and inammatory disorders of, 8487 trauma, 7680 tumors, 8082 CT, 81 extramedullary, 81, 83t intramedullary, 8284 metastatic compressing, 82t MRI, 81 radiotherapy, 81 Spine immobilization, 77 examination of, 241 Spirometry for diaphragm function assessment, 9293 Splenomegaly, 241 St. Louis encephalitis virus geographic distribution of, 188t Staphylococcus aureus, 203 Staphylococcus meningitis treatment of, 203 Starvation with Wernickes encephalopathy, 226t Statins for hyperlipidemia, 161 Status epilepticus, 56f, 6274. See also Generalized tonic-clonic status epilepticus absence, 64 clinical features of, 6264 with coma, 55t complex partial, 64 EEG, 63 focal motor, 64 incidence of, 62 nonconvulsive, 63 Sternocleidomastoid muscle, 240 Steroids for vasculitis, 161 Stiff neck, 4 with bacterial meningitis, 191 Strabismus latent, 42 Streptococcus agalactiae, 197, 200t 272
meningitis, 203204 Streptococcus pneumoniae, 186, 191, 193, 198t, 202 Stroke. See also Ischemic stroke ECG, 158 emergency care of, 154157 hemorrhagic dened, 137 laboratory evaluation, 157158 practical emergency care of, 151154 primary prevention of, 146147 pure motor, 145 risk factors, 158159 secondary prevention of, 159160 sensorimotor, 146 signs of public education for, 147 Stroke syndrome, 143146 Stupor dened, 36 Subarachnoid hemorrhage, 2, 10 with coma, 52t, 55t, 60t with headaches, 5, 913 vs. traumatic puncture, 12t Subcortical areas, 142 Subdural hematoma, 53f Subdural hemorrhage with coma, 52t Succinylcholine, 104 Sympathomimetic drugs with stroke, 142 Syncope mimicking stroke, 138t Syringomyelia, 83, 84 Systemic lupus erythematosus, 84, 85 with myasthenia gravis, 95 T Tachycardia with neuroleptic malignant syndrome, 170 Tachypnea with neuroleptic malignant syndrome, 170 Temporal arteries, 240 biopsy for giant cell arteritis, 2627 biopsy for headaches, 2 palpation of, 4 Temporal arteritis. See Giant cell arteritis (GCA) Tensilon test for myasthenia gravis, 9799 Thallium poisoning, 116
Index
Thiamine, 223 deciency, 38, 116, 117t for Wernickes encephalopathy, 231 Thiamine pyrophosphate (TPP), 223 Thiazide diuretic for ischemic stroke, 136 Thigh pain with giant cell arteritis, 21 Third nerve palsy with headaches, 5 Thymic lymphoid hyperplasia with myasthenia gravis, 96 Thymoma with myasthenia gravis, 96 Thyroid disease with myasthenia gravis, 96 TIA, 139, 156157 crescendo, 156157 with stroke, 141 Tick paralysis, 116, 117t Ticlopidine for stroke, 159 Tissue plasminogen activity (t-PA) for ischemic stroke, 135, 147150, 149f administration of, 152154, 153t Tolazamide toxicity with Wernickes encephalopathy, 226t Tomatoes botulism, 121 Total parenteral nutrition with Wernickes encephalopathy, 226t t-PA. See Tissue plasminogen activity (tPA) TPP, 223 Transient ischemic attack (TIA), 139 crescendo, 156157 with stroke, 141 Transverse myelitis, 8485 CSF, 85 MRI, 85 Transverse myelopathy, 8485 Traumatic puncture vs. subarachnoid hemorrhage, 12t Tricyclic antidepressants causing neuroleptic malignant syndrome, 169 intoxication dilated and xed pupils with, 42 Trigeminal nerve, 245 Trimethoprim-sulfamethoxazole for bacterial meningitis, 197 Trochlear nerve, 244 Tuberculosis, 4
Tumors affecting spinal cord, 8082 with coma, 57t U Unconsciousness with cerebral hematoma, 217 with neuroleptic malignant syndrome, 170 Uremia with Wernickes encephalopathy, 226t Urinary retention with neuroleptic malignant syndrome, 170 V Vaccine MenC polysaccharide, 201 Valium for generalized tonic-clonic status epilepticus, 67, 68t Vancomycin for bacterial meningitis, 198t, 199t for encephalitis, 186 for pneumococcal meningitis, 202 for staphylococcus meningitis, 203 Vasculitis with stroke, 161 Vecuronium contraindicated in myasthenia gravis, 104 Venezuelan encephalitis virus geographic distribution of, 188t Venous sinus thrombosis with coma, 55t Ventriculostomy for cerebellar hematoma, 219 Versed for generalized tonic-clonic status epilepticus, 67, 68t, 71 Vertebral artery, 143 stroke, 145 Vertigo benign positional mimicking stroke, 138t Vestibulocochlear nerve, 246 Vibration testing of, 251 Vision blurred with botulism, 122 Visual acuity examination of, 243 273
Index
Visual eld examination of, 243 Visual loss with giant cell arteritis, 21, 22 monocular abrupt onset of, 2 Voice raspy with neuromuscular respiratory failure, 91 Vomiting with bacterial meningitis, 191 with Wernickes encephalopathy, 226t W Wall-eyed, 43 Warfarin for cardioembolism, 161 for stroke, 160 Weight loss with giant cell arteritis, 21, 23 with ischemic stroke, 147
Wernickes encephalopathy, 220233, 220f, 253 cases of, 220221 clinical manifestations of, 225229 clinical signs of, 227f epidemiology of, 224225 ETK, 230 eye signs of, 228f FLAIR, 230 illnesses associated with, 226t laboratory studies, 230231 neuroimaging, 229230 neuropathology, 222 pathogenesis of, 223224 prevention of, 233 treatment algorithm for, 232f treatment of, 231232 West Nile encephalitis, 189 West Nile virus geographic distribution of, 188t Wound botulism, 124
274

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BASIC NEUROLOGIC LIFE SUPPORT

2004 BC Decker Inc Hamilton London

167 182 190 210 220 236 258

HEADACHE AS AN EMER GENCY

Basic Neurologic Life Supp or t

Basic Neurologic Life Supp or t

Basic Neurologic Life Supp or t

Basic Neurologic Life Supp or t

PATIENT WITH SUSPECTED SUBARACHNOID HEMORRHAGE

Basic Neurologic Life Supp or t

Basic Neurologic Life Supp or t

Supernatant uid color RBC count and hematocrit WBC count

Occurs rarely Usually clear

Repeat puncture Findings similar at higher to those at interspace initial tap

Basic Neurologic Life Supp or t

Figures 1-2 through 1-6 can be viewed in color on the CD-ROM.

Basic Neurologic Life Supp or t

Table 1-4 Frisn Scale of papilledema

Adapted from Digre KB, Corbett JJ.13

Basic Neurologic Life Supp or t

GIANT CELL ARTERITIS

Giant Cell Ar ter i t is

Basic Neurologic Life Supp or t

Giant Cell Ar ter i t is

Basic Neurologic Life Supp or t

Continue corticosteroid treatment

Continue treatment Biopsy other side

Negative biopsy Positive biopsy

Headache goes away on steroids; systemic symptoms improve

Continue corticosteroid treatment Biopsy negative GCA

Discontinue corticosteroids and investigate for infection, inflammatory disease, or tumor

Continue oral corticosteroids Follow ESR, CRP, and symptoms

Giant Cell Ar ter i t is

Basic Neurologic Life Supp or t

TEMPORAL ARTERY BIOPSY To Biopsy or Not To Biopsy? 1,3,8

Giant Cell Ar ter i t is

Basic Neurologic Life Supp or t

Giant Cell Ar ter i t is

Basic Neurologic Life Supp or t

Giant Cell Ar ter i t is

APPR OACH TO THE COMATOSE PATIENT

Appro a ch t o the Comat os e Pa t ient

Basic Neurologic Life Supp or t

Figure 3-1 The ascending reticular activating system.

Appro a ch t o the Comat os e Pa t ient

Basic Neurologic Life Supp or t

Appro a ch t o the Comat os e Pa t ient

Patient is comatose Does patient have an airway?

Begin rescue breathing

Does patient have a pulse?

Begin cardiopulmonary resuscitation

Figure 3-2 General medical examination. IV= intravenous.

Basic Neurologic Life Supp or t

Appro a ch t o the Comat os e Pa t ient

Basic Neurologic Life Supp or t

Eye movements and other brainstem reflexes

Figure 3-3 Neurologic examination.

Eye movements and other brainstem reflexes

Appro a ch t o the Comat os e Pa t ient

Figure 3-3 Continued.

Basic Neurologic Life Supp or t

Appro a ch t o the Comat os e Pa t ient

Basic Neurologic Life Supp or t