Age of Onset Diabetic Peripheral Neuropathy Werdnig-Hoffman Disease (SMA type I) Amyotrophic Lateral Sclerosis Guillain-Barre Syndrome Charot-Marie-Tooth

(HSMN type 1) Adult-onset

Diseases of Peripheral n (neuropathies) Location of Lesion Pathogenesis Clinical Presentation Symmetric distal polyneuropathy Degeneration of LMN UMN & LMN Degeneration of peripheral nn Segmental demyelination Decreased sensation in distal extremities

At birth or w/in 1st 4 months Middle aged/elderly

Autosomal recessive Mutation in SMN1 (missing exon 7) Autosomal dominant Degeneration of LMN and UMN Immune-mediated disorder

Childhood, Degeneration of Autosomal dominant early peripheral nn Chromosome 7 adulthood duplication; PMP 22 Neurogenic atrophy: atrophy in m fibers due to pathological changes in n or PNS Denervation atrophy: myocytes atrophy due to axon/myelin sheath degeneration Wallerian degeneration: axonal degeneration distal to point of axonal damage or cell body damage Disease of NMJ Myasthenia Gravis NMJ Immune-mediated loss of Begins with extraocular m weakness; Ach receptors ptosis, double vision; generalized weakness Myopathies: have elevated creatine kinase and proximal weakness; random necrosis and/or m fiber regeneration Neuropathies: distal weakness; group atrophy; fiber type grouping

LMN lesion; gen weakness, hypotonia, m wasting, tongue fasciculations; floppy baby UMN lesion deficits (hyperreflexia, Babinski) LMN lesion (fasciculations, wasting, weakness) Ascending paralysis; weakness in distal limbs w/ rapid advance to proximal mm, slow n conduction Distal m weakness; inverted champagnelike calf; pescavas, hammertoes

Gross/Micro Pathology Axonal neuropathy Segmental demyelination, thickening of endoneurial arterioles, hyalinization Atrophy of ventral horns/n roots; neurogenic atrophy Atrophy of ventral horns/n roots; Wallerian degen Chronic inflammation, seg demyelination Onion bulb-Segmental demyelinationremyelination;

Electrophysiological tests: nerve conduction and electromyography; n/m biopsy

Increased ICP Cingulate gyrus Herniation Uncal Herniation

Increased Intracranial Pressure and Herniation Etiology Compression Clinical Features Depends on age of pt and speed of expansion Headache, vomiting, pailledema maybe (swollen optic n), abducens n. palsy Factors depend on speed of expansion, age of patient; Blurred optic discs; focal neurologic signs: limb weakness >200mm water in LP Herniates under the falxcerebri Hemorrhage, neoplasms, infections Uncus herniates across tentorium cerebelli -compress structures in post fossa; Compress PCA, midbrain cerebral peduncle, CN III, brainstem downward Cerebellar tonsil herniation thru foramen magnum Ptosis, dilated pupil, fully abducted eye, fixed pupil, infarct of unilateral occ lobehomonymous hemianopsia/hemianopia; Duret hemorrhages due to downward brainstem compression Brainstem compression: central herniation or rostrocaudal deterioration Compresses medullary respiratory centers leading to death

Cerebellar Tonsil Herniation Midline shift Central Herniation Rostrocaudal deterioration

Lateral displacement of diencephalon may produce decreased level of consciousness Supratentorial Small reactive pupils (loss of sympathetic), Dilated, fixed (loss CNIII parasympathetics because the parasympathetics travel in the space occupying PERIPHERY of CNIII), Midposition, fixed: compression of both III and midbrain (loss of sympa/para) mass; downward Duret hemorrhages may also occur displacement of Changes in consciousness (drowsiness, stupor, coma), resp changes; postural changes: Decorticate rigidity (leg extension/arm brainstem flexion); Decerebrate rigidity (leg/arm extension) *Cheyne-stokes in diencephalon *Central neurogenic hyperventilation in midbrain *Apneustic Respiratory in pons *Ataxic Respiratory in medulla * In infants, skull may expand and in elderly, brain may have atrophied due to old age, so may have more room for expansion. Infections involving Nervous System Etiologic Agents Pathogenesis Clinical Features Spinal Notes Fluid Changes Epidural/Subdural Abscess or Pyogenic bacteria: Direct inoculation or spread from nearby infection Localized collection of Complications: Empyema step, staph pus Hydrocephalus Meningitis Bacterial Homogenous spread Purulent exudate in SAS w/ Hydrocephalus, edema P Edema from body to brain; PMN, bacteria, vasculitis; Edema, ICP, seizures, glucose CN palsies Pyogenous direct inoculation, cellular infiltration of CN/sp thrombosis, abscess, protein Thrombosis direct spread roots CN palsies cells Brain abscess Viral Aseptic Normal P Seizures Acute Lymphocytic Normal glc

Fungal Chronic

Viral Encephalitis

Candidiasis, Cryptococcus, tubercle bacillus, T. pallidum (syphilis) Depend on age, location of pt, time of year

Exudate, mononuclear infiltrate, vasculitis Granulomatous Meningoencephalitis, encephalomyelitis Homogenous spread after viremia, spread along nn Arthropod-bourne VE Epidemic; 10% by arbovirus HSV Type 1 Tx w/ acyclovir, effect mood, memory, behavior HSV Type 2 Meningitis or encephalitis Rabies Negri bodies: inclusions in pyramidal neurons of hippocampus VZV shingles granulomatous arteritis infarcts CMV common in opportunistic viral pathogens in HIV pts Poliomyelitis infect antierior horn neurons, motor deficits, flaccid paralysis Intracerebral inflammation called granulomas Homogenous spread; caused by acute bacterial endocarditis, cyanotic congenital heart disease; Discrete lesions w/ liquefactive necrosis, with zone of fibrous tissue Infiltration of meninges & vessels by lymphocytes/ plasma cells Atrophy, loss of cortical neurons in frontal lobes, gliosis, prolif microglial cells, perivasc lymphocytes, spirochetes Perivascular cuffing, neuronal/hemorrhagic necrosis, microglial nodules/proliferation, inclusion bodes

protein cells P glc ptn cells

RBCs present

Intracranial Abscess

Pyogenic bacteria (Staph/strep)

Progressive focal deficits, gen signs of increased ICP

pressure, few cells, WBC/ptn; normal glc

HIV-associated CNS Meningovasculitis Syphilis General Paresis

Meningitis, or vascular occlusion; similar to low-grade meningitis or stroke Mental changes, progressing to dementia, headache

Lightening pains, sensory deficits, loss PT/MVP; argullrobertson pupils Progressive Multifocal In pts w/ Viral encephalitis Intellectual Normal Death in 2-6 Leukoencephalopathy associated Latent infection of polyomavirus in kidney/B deterioration and mos immune lymphocytes dementia, visual, motor supp/chronic dis Demyelination; inclusion oligodendroglia nuclei dx, abnmvmts SubacuteSclerosingPanencepha Progressive Persistent but nonproductive infection of the CNS by Intellectual gamma Death in litis (SSPE) encephalitis altered measles virus; inclusion bodies in deterioration, seizures, globulin several years associated with oligodendroglia, neurons, astrocytes, perivascular spasticity of limbs, Ab titer altered measles cuffing, neuronal loss, gliosis, demyelination progressive personality against virus changes mealses CNS development dx, including malformations, perinatal brain injury, cerebral palsy Pathology Causes Clinical Features Types Diagnosis Cerebral Palsy Intraparenchymal Asphyxia, maternal high Ataxia/athetosis, Spastic: increased m tone; Correctly diagnosed bet 12-24 hemorrhage originating bp. Diabetes, trauma, dystonia, paresis, stiff/jerky mvmts mos in germinal matrix infarctions, hemorrhages spasticity Ataxic: decreased m tone/ -floppy/limp body OR stiffness of arms/legs in 1st few mos poor coordination -no smile by 3 mos Athetoid: due to -poor head control at 3-4 mos hyperbilirubinemia; cant -no sit up by 8 mos hold selves upright -difficulty standing at 12 mos -inability to walk by 18-20 mos Germinal Matrix Subependymal matrix hemorrhages; due to cerebral hypoxia between 25 th and 35th week of gestation Hemorrhage (Intraparenchymal) Periventricular Infarcts occur in the periventricular white matter; cyst may form Leukomalacia Chalky yellow plaques of discrete regions of white matter necrosis and calcification Ulegyria Due to ischemic lesionssulci bear the burnt of injury thinned-out, glioticgyri Cerebrovascular Diseases Epidural Hematoma Subdural Hematoma Disease Location/Etiology Pathogenesis Notes Stroke Ischemic 1% of head trauma admin; Bilateral in 10% of cases; Thrombosis 4:1 male to female; rare b4 more common in elderly Embolism age 2 & after age 60 Hemorrhagic Acute: Chronic: SAH, ICH Trauma, Infants, contusion elderly, dev Hypoxic Pyramidal cells of hippo, Decreased bld flow, anoxic poisons Man in barrel Death may occur 2-12

Tabes Dorsalis

Inflammation of meninges in SAS/dorsal n roots; wallerian degeneration

Encephalopathy (border zone: watershed infarcts) Focal Cerebral Ischemia Thrombotic Due to focal cerebral arterial occlusion Pale Infarct Non-hemorrhagic

pukinjie cells of cerebellum, GP neu Atherosclerotic plaque formation, coagulability of blood, vasc occl, ateriopathy, cerebral amyloid angiopathy, drug abuse, aneurysm

(CO, CN, CS2, hypoglycemia)

syndrome

hours after injury; causes uncal herniation or dnwd

over mos, dementia

Ischemia due to Embolism Thrombotic embolus in MCA Venous or Dural Sinus Thrombosis Spontaneous INtraparaencymal Hemorrhage

Sudden onset of focal impairment

Gross Path: 6-12hrs: no lesion discerned. 48 hrs: tissue pale, soft, swollen, gray-white matter jxn indistinct. 2-10 days: gelatinous, friable. 10d-3wks: tissue liquefies Micro Path: 12hrs: neu nuclear pyknosis, cytoplasmic eosinophilia; 1-3days: PMN, cap prom, endo swell, vacuolation of white matter. 3-5days: m appear. 7-21d: astrocytes proliferate, gemistocytic Shrinkage, distortion of structures, cysts, compensatory ventricular enlargement Ischemic neu (eosinophilic/red neurons); capillary prominence, vacuolation of white matter, macrophages, astrocytes become gemistocytic Hemorrhagic infarction; characterized by petechial hemorrhages

Skull fracture rupture of MMA-rapid bleeding mass effect Unconsciousness, lucid interval, coma, focal signs, ICP, death may occur 2-12 hrs due to herniation; obtundation, contra hemiparesis, ipsi pupillary dilation

Aneurysms Berry/Saccular/ Congenital Vascular Malform. AVM

Blood stasis in large vv/venous sinuses leads to infarction; increased pressure disrupts capillaries causing blood to enter infracted areas Hypertension; others are Arteriolosclerosis ; thickening of AV malformation, vessels, hyalinization, form of sm ruptured aneurysm, aneurysms; Charcot-Bouchard amyloid angiopathy, Aneurysms leukemia Uncal herniation-brainstem --basal ganglia/thalamus compression & 2 Duret brainstem and pons and cerebellum hemorrhages Occur at bifurcations of Rapidly developing severe headache Common cause of vessels at base of brain SAH

Shearing of bridging veins; accum around parenchymal laceration; 2 to accdeceleration injury No lucid interval Nonlocalizing, headache, confusion, progressive neurologic deteriation Chronic: seizures, headache, confusion, behave changes, signs of ICP Crescentic mass of high attenuation, may cross sutures; do NOT cross midline; less dense than EDH, but high density on CT Remove blood & associated organization tissue

Biconvex high density; sharply defined; rarely cross sutures, may cross midline & tentorium

AV Shunt Lacunes Infarcts

Tangles of abnormal vessels Seizure, headache, focal neurological signs Causes high output cardiac failure; generally involves vein of Galen and MCA or PCA Small infarcts, associated with HTN ; tissue loss with scattered lipid-laden macrophages and surrounding gliosis

Slit Hemorrhages Hypertensive Encephalopathy

Rupture of penetrating arterioles small ICH resorption leaving slit-like cavity Rapidly evolving syndrome of severe HTN Headache, nausea, & vomiting

Epidemiology/ Demographics Etiology

General Features Clinical manifestations/ course

Diagnosis

Seizures 3% of all ppl living to age 80 will be diagnosed w/ epilepsy; highest incidence in young children and elderly ; 70% well controlled w/ meds, 30% w/ intractable epilepsy Newborn Asphyxia, intracranial hemorrhage, hypocalcemia, hypoglycemia, hyperbilirubinemia, water intoxication, inborn errors of metabolism, trauma Infancy Febrile (5 mos-5 yrs), CNS infection, trauma, congenital defects, inborn errors of metabolism Childhood Trauma, CNS infection, arteriovenous malformation, congenital defects, tumor Adolescence Trauma, CNS infection, tumor, arteriovenous malformation, drgus/alcohol Early Adulthood Late Adulthood Drugs/alcohol, trauma, tumor, vascular disease, degenerative disease, CNS infection Generalized Seizures Partial Seizures No aura, postictal confusion (not in absence/myoclonic Simple: no alteration in level of consciousness, no postictal state seizure); may have bowel or bladder incontinence, tongue Complex: alteration (not loss) in LOC; may have aura, postictal confusion trauma Tonic m. rigidity (extension or flexion) Motor Tonic or clonic, versive head or eye movements Clonic Gen. m. jerking activity Sensory Positive phenomena: parasthesias/dysesthesias, visual halllucinations Tonic-Clonic Rigidity followed by jerking; ictal scream; Autonomic/ Gustatory, olfactory, epigastric fullness, nausea, pupillary Grand mal apnea may appear Visceral changes Atonic Bried loss of m. tone fall or head drop Psychic Dj vu, jamais vu, depersonalization Petit mal Absence Staring spell 5-15 sec; provoked by hyperventiliation (only in childhood); no postictal Myoclonic Localized/widespread jerking mvmts; infantile, juvenile CT or MRI, EEG, hematology (CBC, electrolytes, Ca, Phosphate)

Primary Tumors

More in adults than in children

Usually supratentorial; can spread via CSF, but no spread beyond CNS

Children ICP may be only sign presented

Intracranial Neoplasms Pilocytic astrocytoma Medulloblastoma Most common Ependymoma Retinoblastoma Neuroblastoma Gliomas Astrocytomas Grade 2: diffuse Grade 3: anaplastic Grade 4: glioblastoma Oligodendrogliomas Ependymomas Primary Brain Lymphoma Germ Cell Tumors Pineal Parenchymal Tumors Meningiomas

Adult 50-75% are primary

Cystic lesion with mural nodule of tumor; good prognosis; grade 1; in cerebellum Grade 4; usually in cerebellum; poorly differentiated neoplasm; truncal ataxia, ICP; seeding thruout SAS; mitotically active prognosis: gloomy Mostly in 4th ventricle; due to ICP; solid tumor, true ependymal rosettes Sometimes bilateral, may extend to optic n; good prognosis PNS, often in adrenal gland; poor prognosis Cerebral hemispheres; low grades=firm, white/gray, poorly circumscribed, infiltrates & distorts brn tissue; grade 3-4: well circumscribed, infiltrates widely, many colors due to hemorrhage, necrosis, &cysts Often in cerebral hemispheres; fried egg appearance; slow-growing tumor Within skull are rare; often in lateral ventricles more common in the spinal cord From B lymphocytes in CNS to deep cerebral hemispheres headache, seizures; soft, multiple separate nodules Origin: ectopic germ cells; location: midline (pineal/suprasellar region); good prognosis Clinical effects: visual disturbances and headache Well-circumscribed mass, no invasion; whorls or sheets of meningothelial cells, psammoma bodies

Metastatic Tumors

Intra-Axial Tumors

Extra-Axial

Frequently multiple, distributed by volume, supratentorial Meningioma Metastasis Schwannoma Neurofibroma Astrocytoma

Spread via CSF

Grade 2: nuclear pleomorphism (solid, infiltrating, may show

Survival over 5 years is rare

Tumors

Diagnosis VonHippelLind au Syndrome Hemangio blastoma Neurofibro matosis I Neurofibro matosis II Tuberous Sclerosis

Ependymoma Oligodendrogli oma Metastasis Always cranial MRI with gadolinium enhancement Mutation in tumor Multiple CNS hemangioblastomas Increased renal cell carcinoma

cystic change Grade 3: plus mitotic activity Grade 4: Glioblastoma: Necrosis with palisading, and/or vascular endothelial proliferation; may show hemorrhage Usually in spinal cord in adults (4th ventricle in children) Can be associated with loss of chromosome 1p and 19q

Prognosis related to resectibility

Thin-walled vessels w/ vacuolated cells; cystic lesion with mural nodule usually in cerebellum; 10% of patients have polycythemia when tumor cells make erythropoietin Mutation in Chromosome 17; peripheral neurfibromas may show malignant degeneration; pilocyticastrocytomas (optic nerve) Multiple meningiomas& bilateral acoustic schwannomas, ependymoma, mutation on chromosome 22-merlin protein Cortical tubers, angiomyolipoma of kidney, renal cell carcinoma, renal/hepatic cysts

Disease Clinical Features Hypokinetic Movement Disorders Parkinson Rigidity, gait instability, resting Disease tremor, bradykensia --mood dx, later dementia, dysautonomia --olfactory dysfxn, constipation, autonomic, dysfxn, sleep dx, dep/anxiety

Pathology

Movement Disorders Epidemiology 11/100,000 in general population 50/100,000 over age 50 Cumulative lifetime risk: 2.7%; Slightly more common in men Risk Factors: age, severe head trauma, family history, env exposure, low uric acid Protective factors: estrogen, caffeine, heavy alcohol, smoking, NSAIDS

Differential Diagnosis Secondary Parkinsonism Other Tremor Syndromes Akinetic-Rigid Syndromes Drug-induced, post-traumatic, post-infectious, immune-mediated, vascular, normal pressure hydrocephalus Essential, myoclonic, dystonic

Degeneration of pigmented brainstem neurons in substantianiagra, lewy bodies, Da in striatum

Hereditary disorders w/ Parkinsonism

Progressive Supranuclear PalsyAccumulation of hyperphosphorylated tau ptn in neuronCBT/CST signs, wide unblinking face, axial rigidity, dn gaze paresis Multiple System Atrophy Cerebellar signs, dysautonomia, CST signs, stridor Corticobasal Degeneration Progressive asymmetric rigidity, apraxia, alien limb, rarely gaze palsy Diffuse Lewy Body Disease Wilsons: AR, deficient copper excretion, serum/urine copper hepatic failure, basal gangliaakinetic-rigid, wing-beating tremor Huntingtons

Hyperkinetic Movement Disorders Tremor Repetitive rhythmic alternating contractions of agonistic/antagonistic muscles: terminal, resting, postural/action, wing-beating tremor Dystonia Sustained and/or phasic contraction of m causing abnormal posture or repetitive movements Myoclonus Rapid, lightning-like m contraction producing irregular jerking Chorea Brief, irregular jerking movements flowing from on body part to the next (metabolic, auto-immune, degenerative, vascular, drugs) Huntingtons Disease: expansion of CAG: chorea, dementia, psychiatric, cerebellar features, prominent atrophy of caudate nuclei Hemiballismus Rapid, large amplitude, unilateral, proximal flinging movements Tics Repetitive, stereotypic, brief semi-involuntary movements

Disease Multiple Sclerosis Autoimmune Dx

Neuromyelitis Optica (Devic Dis) Acute Disseminated Encephalomyelitis Acute Necrotizing Hemorrhagic Encephalomyelitis Central Pontine Myelinolysis Three Vital Signs Glaucoma Optic Neuritis Giant Cell Arteritis

Demyelinating Diseases Etiology & Pathogenesis Pathological Changes Diagnosis CD4 TH1, TH17 cells react Initially: Optic neuritis MRI, CSF analysis : oligoclonal against self-myelin Ag & Plaques of demyelination in bands, IgG secrete cytokines, B cells, T white matter of brain/sp cd, not CSF: gamma globulin elevated, cells, & innate immune oligoclonal gamma globulin PNS; # of oligodendrocytes, systemdemyelination bands gliosis, activation of microglia and macrophages Remitting and relapsing Development of both optic neuritis and spinal cord demyelination at similar points in time Age of Onset/ Epi Age of onset: 2050; more common in women and Caucasians 30-300/100,000 Rapidly progressive diffuse demyelinating disease, develops 1-2 wks after viral infection Demyelination in perivenous distribution Common in young adults and children, usually in upper resp infection; CNS demyelination Demyelination in basis pontis and pontine tegmentum; classically associated with rapid correction of hyponatremia Visual System Disorders Visual acuity, Pupils, Pressure

Treatment Ag non-selective immunomodulators : copaxone, inhibits myelin basic protein (MBP)

Headache, jaw claudication, weight loss, malaise A true neuro-ophthalmic emergency Vestibular System Disorders Central Causes Vertigo, diplopia, weakness, and/or numbness TIA not only vertigo, but combo of diplopia, dysarthria, numbness, incoordination Tumor or mass rarely with isolated vertigo; tx w/ traditional prophylactic migraine meds Migraine

Traumatic Optic neuropathy Disease Vertigo Sensation of movement of self/env, often rotary. Mismatch of visual, vestibular, & sensory proprioception Clinical Features Nystagmus, (hallmark) Peripheral Causes Vertigo, hearing loss, tinnitus Benign Paroxysmal Positional Vertigo Vestibular most common cause of vertigo; Dix-Hallpike testing (pt rapidly moved from seated position to lying position Vestibular Neuritis monophasic episode of vertigo; days to weeks, nausea/vomiting; tx w/vestibular suppressants (meclizine, diazepam, Dramamine, lorazpam) Menieres Disease endolymphatic regulatory dysfunction; last hours; ear pressure/fullness, change in tinnitus & hearing

Etiology Concussion Contussion Diffuse Axonal Injury Spinal Cord Lesions (Direct v. Indirect) Trauma

Multiple Sclerosis important cause Nervous System Trauma Clinical Manifestation Transient acute unconsciousness, headache, cognitive and sleep disturbances, vertigo Areas of hemorrhagic necrosis, Brain moves linearly or rotates, slam into skull Located in deep white matter regions, Diffusion of tensor imaging Sensory loss of sensation in a specific dermatone indicated location of lesion Headache Characteristics

function Trauma Notes Not an anatomic lesion No evidence of permanent structural damage Coup lesions, counter coup, intermediary lesions Major cause of prolonged traumatic coma, and poor neurological outcome Macrophages, gliosis, loss of architecture Contusions, Wallerian degeneration

Trauma most common: orbital gyri, temp/occ pole Trauma; present in 35% head trauma deaths Blow to back of neck or trunk Trauma to C4, C5, C6, C7, T1 or T12, L1, L2 Epidemiology Duration of Episode 30 min-7 days

Location Bilateral

Treatment Regular meals, hydration, rest, remove stress, anxiolytics Abortive Preventive NSAIDS, Anti-depressants, antihistamines, anti-convulsants, -adr blockers, adr blockers, occ/supraneuroleptics orbital n block Ergotamines, Lithium, topiramate, lidocaine, ergotamine prednisone, verapamil, sodium 100% O2, valporate sumatriptan NSAIDS, salicylates Doesnt respond to O2

Tension

Both genders Age 20-60 Female Age 20-50

Migraine

No aura: 4-72 hrs Aura: 2 or more attacks

Progresses throughout day, no aura, no phonophobia/photophobia, no N/A, pulsating, tightening, pressing, no aggravation by exertion Can be with or w/o aura Aura: N/V, photophobia, phonophobia

Unilateral

Cluster

Male

Histamine mediated Eye swollen and red, lacrimation, ptosis, miosis, eyelid edema, nasal congestion, rhnorrhea, facial sweating No frank Horners syndrome; extremely responsive to indomethacin

Unilateral

Paroxysmal hemicrania

Female

Vascular Giant Cell (temporal) Arteritis Trauma-associated Intracranial Disorders Metabolic Cranial Neuralgias

Secondary Headaches Sentinel bleed (AVM, SAH), stroke, arteritis, carotid/vertebral dissection, venous/sinus thrombosis, arterial hypertension Sentinel Thunderclap Headache: worst headache of life, ruptured aneurysm Older patient Achiness in jaw, neck, palpate artery, get sed rate, CRP Subdural hemorrhage, SAH, concussive, post-concussive Increased ICP w/ mass, benign intracranial HTN, intracranial infection, low ICP even Hypoxia, hypercapnia, hypoglycemia, dialysis; non-cephalic infection, facial pain Trigeminal Neuralgia Severe pain in face, stabbing electric shockTx: Carbamazepine, gabapentin, lamotrigine, Tic Douloureux like pain baclofen; Surgery: rhizotomy, microsurgical decompression, gamma knife 2 to compression/inflammation of CN V Glossopharyngeal Neuralgia Lancinating pain referred to tongue, ear Anticonvulsants, microsurgical decompression 2 base of skull lesion, neck mass, vasc compression Occipital Neuralgia Aching pain, referred over scalp Unilateral Anticonvulsants, occipital n branch block, microsurgical decompression 2 to cervical trauma, arthritis, C1-C2 Drug overuse, non-compliance, somatization, anger/anxiety, family dysfunction Discontinue offending analgesics, EDUCATE, hydrate, preventive pharmacotheraphy Toxic, acquired metabolic, and nutritional dx of the CNS Source or Clinical Effects Notes Deficiency Paints chips or paint CNS: in cerebral or cerebellar cortex dust in homes -Acute: seizures, ataxia, ICP -Chronic: seizures, attention/mental deficits, loss of motor skills PNS: in motor nn segmental demyelination; wrist-drop, slowed n conduction Vapor Inhaled dental Negligible analgams Methyl Fish Visual field constriction & ataxia Ethyl Thimerosal in No evidence of damaging effects vaccines Insecticide Miosis, blurring vision, chest tightness, wheezing, GI, increased Tx w/ Atropine sweating, increased salivation Workplace Organic affective syndrome: irritability, fatigability, difficulty in concentrating, loss of interest Mild chronic toxic encephalopathy: personality or mood change, impairment in intellectual function

Rebound

Lead Motor peripheral neuropathy

Mercury

Organophosphate Insecticide Organic solvents

Botulinun Toxin

Clostridia

Tetanus

C. tetani Soils and spores Ventilation of heating sources, engine exhaust Direct effects or 2 nutritional deficits

Carbon Monoxide Methanol Toxicity Ethanol

Radiation Wernickes encephalopathy & Korsakoffs syndrome Thiamine, vitamin B1 deficiency

Severe chronic toxic encephalopathy: dementia with global deterioration of memory & other cognitive functions Mechanism of Action Clinical Effects Cause deficiency of synaptic Nausea, dry mouth, double vision, transmission; must enter weakness, difficulty speaking and axon terminal; prevent swallowing; symmetrical flaccid synaptic vesicles from paralysis docking/fusing w/ presyn term Tetanospasm; inactivates Lock jaw, opisthotonos synaptobrevin (block synaptic transmission that normally inh MN Form carboxyhemoglobin Headache, myalgia, dizziness, neuronal necrosis, and neuropsychological impairment apoptosis confusion, loss of consci, death Degeneration of retinal ganglion cells blindness Effects are reversible; atrophy and loss of granule cells 1 in anterior vermis Unsteady gait and nystagmus Symptoms of intracranial mass, headaches, nausea, vomiting, papilledema Large areas of necrosis and adjacent edema Wernickes Encephalopathy: ataxia, confusion, ophthalmoplegia Korsakoffs pyschosis: severe memory defects and confabulation Pathological changes: vascular changes, capillary tortuosity, prominence, endothelial swelling, petechial hemorrhage, neuronal damage, macrophage response and gliosis Numbness, paresthesias, weakness Degeneration of both myelin & axons w/ axonal reaction in anterior horn cells Peripheral neuropathy, optic neuropathy; associated with pernicious anemia Loss of MVP, LE weakness, DTR, babinski signs; degeneration of post/lat columns Spongy degeneration of white matter Hypoalbuminemia is a cause Anoxia, acidosis Amidation of glutamateglutamine via glu synthetase takes place in

Located in mammillary bodies , periaqueductal gray

Alcoholic Polyneuropathy Subacute combined degeneration Vitamin B12 deficiency

Kernicterus Hepatic encephalopathy

Bilirubin toxicity

Neuronal Storage Diseases Leukodystrophies Mitochrondrial Encephalomyopathies Common Sphingolipidoses Tay-Sachs Disease (type of Neuronal Storage Disease) Metachromatic Leukodystrophy Krabbe Disease

Location Gray matter Myelin and white matter Gray matter and skeletal muscle Age of Onset 3-8 mos Early childhood 3-6 mos

astrocytes Brain edema, disturbances in consciousness & motor abnormalities (pre-dominately involves glial Alzheimer type II cells in gray matter Inherited Nervous System Metabolic Diseases Deficit Result Genetic inheritance Clinical Expression Lysosomal enzyme Accumulation of Autosomal recessive Can range from focal (usually) enzyme substrate abnormalities to mental retardation Variety of clinical Autosomal recessive expression Oxidative Mitochondrial encephalopathy lactic acidosis phosphorylation stroke-like episodes Accumulated Product GM2 gangliosides Sulfides Galacto-cerebroside Clinical Signs Psychomotor arrest, exaggerated startle reflex, seizures, cherry red spot Progressive mental and motor deterioration, peripheral neuropathy signs Mental and motor deterioration, seizures, irritability, crying Pathology Storage in central and peripheral neurons Myelin deficit in CNS/PNS, storage in glia Myelin deficit; globoid cells (large nucleated macrophages)

Enzyme Deficiency Hexosaminidase A Cerebroside sulfatase Galacto-cerebrosde -galactosidase

Alzheimers Disease

Age of Onset >60 years Early: 40-60

Location of Lesions Cortex, hippocampus, entorhinal, perirhinal cortex, basal forebrain Subcortical areas and substantia nigra Frontal and temporal lobes

Degenerative Diseases Clinical Features Memory loss, dementia Gait normal, no focal weakness or sensory loss

Gross/Microscopic Pathology Accumulation of tau, amyloid, neuritic bodies (extracellular), neurofibrillary tangles (intracellular) Presenilin 1: chromosome 14; age 30-50 onset Presenilin 2: chromosome 1; age 30-65 onset Amyloid Precursor ptn: chrm 21; age 40-60 Apolipoptn E (e4 carriersmore amyloid plaques) Lewy bodies with -synuclein and ubiquitin Faster progression/shorter survival knife-blade like atrophy of frontal and temporal lobe

Diagnostic Tests Neuritic bodies, neurofibrillary tangles

Dementia with Lewy Bodies (DLB) Frontotemporal Lobar Degeneration

Elderly Late-middle/ elderly

Dementia plus 2 of 3: parkinsonism, hallucinations, or fluctuating alertness/attn Similar to Alzheimers Behavioral changes most prominent , perseveration, decreased verbal

Sensitive to antipsychotic meds Inclusion bodies with tau fibrils in neurons

(Picks disease) Huntingtons Disease Wilsons Disease (hepatolenticular degeneration) Amyotrophic Lateral Sclerosis Spinocerebellar Ataxias

30-50 years

Caudate, putamen, GP, cortex Liver, brain, and eye Ventral horns, cortical atrophy in precentral gyrus Cerebellum

fluency Behavioral, cognitive changes and/or movement dx, esp chorea Liver dysfunction Mvmt dx (dystonia) Behavior/cog changes Gradual weakness w/ no sensory deficit

Gain of function of Huningtin gene CAG expansion; extensive gliosis Inborn error of Cu metabolism accumulation of Cu in liver, brain, eye Degeneration of BOTH UMN/LMN. Neurogenic atrophy

atrophy of caudate nucleus w/ ventricular dilation

10-30 years Middleaged/ elderly Mean age: 11

Creutzfeldt-Jakob Disease (CJD) Familial Fatal Insomnia Variant Creutzfeldt-Jakob Disease (vCJD) Disease Delirium Think: metabolic, toxic, aseptic, increased ICP Dementia Think Alzheimers or vascular dementia Vascular Dementia

Friedreich ataxia, hand clumsiness, Trinucleotide expansion in intron sensory deficits, progressive deterioration Prion diseases Age of Onset Location of Lesions Clinical Features Gross/Microscopic Pathology Diagnostic Tests 10% Polymorphism at codon Rapidly progressive Cortical atrophy and ventricular CSF 14,3,3 protein inherited 129 with Val; dementia and startle dilation, spongiform encephalitis MRI changes myoclonus (some ataxia) Polymorphism at codon Insomnia Neuronal loss, and gliosis in specific thalamic nuclei and 129 with Met inferior olivary nucleus Cortical plaques with surrounding halo of spongiform change; mad cow disease

Dementia and delirium Clinical Features Diagnosis Agitation, acute, inconsistent, fluctuating alertness, Acute onset & fluctuating course, hallucinations, inattention inattention, disorganized thinking, altered Widespread reduction in cerebral oxidative LOC metabolism; failure of cholinergic metabolism Chronic, progressive, memory loss, alert/attn ok, disorientation, constructional apraxia Focal motor, sensory, or reflex changes, sudden and/or multi-stepwise decline; focal cognitive impairments (visuospatial disturbance + aphasia) Neuropathology: neurofibrillary tangles/neuritic plaques in AD; lewy bodies in PD/DLB; structural/functional imaging, biomarkers (amyloid) Imaging: infarcts; ischemia

Treatment Prevention, treat underlying illness, antipsychotics, supportive care Contraindications: benzodiazepines, sedative-hypnotic, anti-cholinergics, drugs of parkinsonism, narcotic analgesics, histamine-2-receptor blockers

Atypical Vascular Dementia: insidiously progressive; not stepwise showing extensive confluent white matter

Normal Pressure Hydrocephalus Dementia associated with Movement Disorders Infectious causes

Gait disorder, urinary incontinence, dementia (triad); enlarged ventricles

abnormalities on T2 and FLAIR imaging 70% respond to shunting

HIV-associated Dementia (HAD) Can be somewhat reversible

Drug Cocaine

Lidocaine

Ester/Amide Estermetabolized by pl/hepatic cholinesterases AmideWeak bases; insoluble to water Metabolized by liver P450

Potency Low

Intermediate

Bupivicaine Mepivicaine Procaine (Novacain) Tetracaine Epinephrine

High Intermediate Low

Local Anesthetics Mechanism Topical Uses Blocks voltageLaryngeal, nasal gated Na surgery, UG channels by prolonging their inactivation Dermal (Shingles, state rash), laryngeal, oral (prevent Cation is active ventricular form arrhythmias) None Non-ionized form cross into m. None None

Parenteral Uses None

General uses Topical (lidocaine) Infiltration

Adverse Effects CNS: restlessness, dizziness, confusion, circumoral paresthesis, tinnitus, tremors, seizures CV: bradycardia, hypotension, heart block, cardiac arrest Peripheral neurotoxicity, hypersensitivity reactions, ester typesPABA (sensitizing)

Epidural, infiltration, nerve block, spinal Epidural, infiltration, nerve block, spinal Epidural, infiltration, nerve block, spinal Infiltration, nerve block, spinal anes Adjunct for local vasoconstriction;

Nerve block & field block Spinal/Epidural anesthesia

Should not be used in areas of end aa (fingers, nose, penis and toes) ears too Adverse Effects Explosive, airway irritation, stable CV response

Drug Diethyl ether

Mechanism of Action Correlation between lipid solubility/potency Potentiate GABA effects; hyperpolarization & excitability due to Clinflux and K efflux

Specific Actions

General Analgesics Potency

General uses Stages: I: analgesia II: delirium III: surgical analgesia IV: meduallary depression

Chloroform Nitrous Oxide (laughing gas) Desflurane Loss of consciousness & analgesia due to disruption of neuronal firing & sensory Fast induction and elimination Decrease vascular resistance, not CO High MAC, not metabolized MAC 6 Hypnosis Homeostasis Analgesia Amnesia

Arrhythmogenic, hepatotoxic, well tolerated Autonomic instability Hypothermia Cardiac

Enflurane Propofol IV

processing in thalamus Reduced motor activity due to inhibition of neuronal firing in layer IV of cerebral cortex

Decrease CO; produce bronchodiliation Facilitate effects of GABA at GABAClionophore

MAC 1.7 Rapid emergence, less confusion compared to thiopental

Muscle relaxation HHAAM Hypotension, resp depression, reduce cerebral bld flow/ ICP ; not analgesic, not amnestic if conscious, antiemetic Unconsciousness slower in onset, longer than thiopental Increased HR, BP, ICP and sympathetic tone

dysrhythmias Nausea Vomiting Delirium 1/250000 estimated deaths

Midazolam IV

Facilitate effects of GABA Produce amnesia

Less respiratory depression than propofol/thiopental, little effect on CVS Cause analgesia, sensory perception, immobility and amnesia Lower MAC

Ketamine

Blocks NMDA receptors Dissociative anesthesia dream-like w/o loss of consciousness

Thiopental Produce CNS, resp, IV CV depression The Ideal Anesthetic: potent, non-irritating, noninflammable, not toxic, not metabolized, not arrythmogenic, stable cardiovascular response, very slightly soluble in water, quite soluble in oil, unable to trigger malignant hyperthermia, stable in soda/lime, not harmful to metal fittings, potent m relaxant Anticonvulsants Drug Mechanism of Metabolism Clinical Use Drug-Specific Adverse Effects Common Adverse Action Effects Phenytoin Na ch blockade Hepatic- P450 Partial seizures, Ataxia,nystagmus, drowsiness, lethargy, Fatigue (Dilantin) system generalized seizures nausea, vomiting, rash, gingival hyperplasia, Dizziness blood dyscrasias Ataxia Diplopia Carbamazepine Na ch blockade P450; induce own Partial seizure; avoid in Dizziness, diplopia, nausea, ataxia, blurred Nystagmus (Tegretol) metab; primary generalized vision, aplastic anemia, agranulocytosis, epoxidation to seizures thrombocytopenia, Stevens-Johnson syndrome 10,11-epoxide Oxcarbazepine Na ch blockade Hepatic- induces Seizures Dizziness, nausea, headache, drowsiness, (Trileptal) hepatic enzymes ataxia, diplopia, fatigue, and nervousness; hyponatremia Ethosuximide Inhibits T type Cach Absence seizures only Nausea, GI, anorexia, wt loss Pregabalin Unknown- potential Renal excretion Adjunct to partial Confusion, edema, wt gain, typical side effects (Lyrica) effect on -2 seizures

Ketamine: trauma victims, sedation of children; coadmin w/ benzodiazepine to prevent delirium and hallucinations

Levetiracetam (Keppra) Valproic acid (Depakote) Gabapentin (Neurontin) Lorazepam Lamotrigine (Lamictal) Topiramate (Topamax) Zonisamide (Zonegran)

subunit of Cach Unknown Enhances GABA; modulate VG Na ch, inh T type Cach Enhance GAD; binds -2 subunit of C ach Na ch blockade Unknown Not completely understood; T- type Ca channels, Na channels, carbonic anhydrase inhibition

Renal excretion HepaticGlucuronidation Renal excretion, not metabolized HepaticGlucuronidation Renal and hepatic elimination Renal excretion

In combo with other AEDs Primarily generalized epilepsy- 1st line Partial seizures, neuropathic pain Partial and generalized seizures Multiple seizure types Adjunct tx for partial seizures

Somnolence, fatigue, ataxia, behavioral abnormalities; rare decrease in Hb& erythrocyte count Nausea, tremor, sedation, confusion, wt gain, hair loss, acute pancreatitis, bone mar sup, rash, hyperammonemia (fat, bald, & shaky) Somnolence, dizziness, nystagmus, ataxiz, fatigue, weight gain Ataxia, dizziness, diplopia, N/V, Stevens Johnson; 1% child/0.3% adults Somnolence, dizziness, ataxia, difficulty w/ memory, speech/langdysfxn, diplopia, aggressive behave, anorexia, renal lithiasis Somnolence, ataxia, dizziness, fatigue, renal lithiasis, anorexia

Phenobarbitol Drug Endophins Enkephalins Synthesis Or Distribution Arcuate nucleus & ant. pit Synthesized in small interneurons Found in Periacqueductal grey, lamina I/II Brain; often together w enkephalins Papaversomniferum Contraindications: Types Opioid Analgesics Agonistic Action General uses Mu/delta receptors LeuMetMu/delta receptors Adverse Effects Actions Mediated by Receptor Subtypes Analgesia: mu, kappa, delta Feeding: mu/kappa/delta GI fxn: mu/kappa Sedation: mu/kappa Psychotomimesis: Kappa Diuresis: kappa Resp fxn: mu

Dynorphins Morphine

A, B, alpha-neoPharmacokinetics Well abs; high 1st pass effect; conjugate to

Kappa receptors Mu/kappa/delta Inhibit adenylcyclase Clinical Use: PAIN: post-operative, acute MI, renal/biliary colic CV: myocardial O2 demand, vasodilation, hypotension, ICP

Major: head injuries, seizures, alcohol intoxication Relative: asthma, renal insufficieny, history of opioid abuse, liver disease

glucuronide in intestines/liver Peak effect: 1 hr after inj; duration: 3-4 hrs

hyperpolarization

pain; chronic pain

Analgesia, euphoria or dysphoria, inh of cough reflex, miosis, physical dependence, resp depression, sedation *w/o loss of consciousness

GI: constipation, biliary sphincter tone/pressure, nausea/vomiting GU: bladder sphincter tone, prolongation of labor, urinary retention Overdosestupor/coma, respdep, miosis; tx w/ naloxone

Withdrawal Effects: Vomiting, chills, fever, lacrimation, diarrhea, rhinorrhea, seeking, craving behavior Occur after 8-12 hrs of last dose Occur after 3 hrs last dose Onset after 24-48 hrs last dose

Meperidine

Methadone Fentanyl Oxycodone Buprenorphine Codeine

1/10th analgesic potency of morphine; poor oral abs; equivalent respdep; miosis (mydriasis at toxic doses); high addiction liability; short duration of action; metabolized to normeperidinerisk of seizures Slightly more potent than morphine; less sedative &spasmogenic; effective orally 100x more potent than morphine as analgesic; given via IV & as transdermal patch Use in combo w/ acetaminophen (7.5mg) or aspirin (5mg) 1/10th analgesic potency of morphine; less constipation, lower addiction liability, less sedation/respdep; used orally in combo w/ acetaminophen or aspirin for moderate pain; converted to morphine by CYP 2D6 Mixed opioid agonist (kappa)/antagonist (mu) Opioid receptor competitive antagonist (mu, delta, and kappa)

Help wean off heroin addict; maintain at 40-100mg Patch: useful in chronic pain (3 days)

Resp depression, nausea, vomiting, ICP, postural hypotension, constipation, urinary retention, itching & urticarial, restlessness, tremulousness, hyperactivity

Antitussive (suppress coughing)

Nalbuphine Parenteral only Naloxone IV Naltrexone Oral Tramadol

Synthetic codeine

Treats opioid overdose; blocks effects of morphine and other drugs Opioid antagonist, mu, delta, kappa Used to prevent relapse in chronic alcoholics Non-opioid Analgesic Weak mu agonist Mild to moderate pain

No dependence liability; all others do; no constipation Longer duration of action than naloxone

Dry mouth, dizziness, sedation,

analog

Inhibit uptake of NE and 5HT

headache, seizures, abuse potential-unclear

Drug Levodopa Carbidopa Bromocriptine Ropinirole Pramipexole Selegiline Rasagiline Entacapone Amantadine Benztropine Apomorphine

Drugs for Parkinsons Disease Notes Adverse Effects 100-250mg, 3-4 times daily Nausea, orthostatic hypotension, hallucinations, dyskinesias Less effective with food High dose lead to dyskinesias (peak dose chorea, biphasic chorea, dystonia) Works peripherally to block L-DOPA-DDC DA but cannot cross BBB; decrease symptoms in periphery, no CNS effects; does not effect parkinsonism For PD, DA agonist at D2 receptors Da agonists at D2 Longer duration of action, Low standing BP, nausea, dyskenisa, hallucinations, sleepiness but not as effective as Rare; lung & cardiac valve fibrosis, leg edema, compulsive behaviors levodopa MAO-B inhibitors Mechanism L-DOPA (amino acid)

COMT inhibitor used in combo therapy Blocks NMDA, weak inducer of DA rel; can treat dyskinesias Anticholinergics; block mAch receptor; offsets the imbalance between Ach and DA DA agonist at D1 and D2 receptors Drugs for Multiple Sclerosis Drug Type of Drug Mechanism of Action Adverse Effects Interferone-beta Ag non-selective immunomodulators, proposed to act through inhibiting IFN-gamma activity Glatiramer acetate Ag selective Natalizumab Humanized monoclonal Reduce the ability of immune cells to cross BBB Progressive multifocal leukoencephalopathy Ab against cell adhesion IV molecule alpha4integrin Antithrombotic agents Clopidogrel Pro-drug, function Irreversible inhibits P2Y12 receptor which is Hemorrhage, neutropenia related to ADP receptor important in platelet aggregation and crosson platelet cell linking of fibrin by blocking the activation of membrane P2Y12 glycoprotein IIa/IIIb pathway; metabolized by CYP2C19 Aspirin Irreversibly inhibits COX 1 GI ulcers, stomach bleeding, tinnitus Drugs for Dementia

Donepezil Galantamine Rivastigmine Memantine

Cholinesterase inhibitors NMDA antagonist

Slows the breakdown of Ach by blocking acetylcholinesterase levels of Ach increase

Nausea, vomiting, loss of appetite, increased frequency of bowel movements/diarrhea

No evidence it can prevent or slow neurodegeneration Drugs for Migraine Sumatriptan Abortive for cluster and 5HT agonist; exerted in bile and urine migraine 4-6mg sc at onset for cluster H/A, poor bioavailability with oral administration, faster acting, but with shorter duration with injection Dihydroergotamine Abortive for cluster and Act on 5HT receptors (agonistic) May increase BP, coronary artery vasopasm, migraine vasoconstriction; inhibition of proMI, ventricular fibrillation inflammatory neuropeptide release Propanolol Prophylactic for migraine, Decrease frequency and severity of migraines Drowsiness, difficulty breathing, slow -adr blocker heartbeat, cold hands/feet, depression Valproic acid Prophylactic for migraine, and cluster H/A, anti-convultant Amitryptyline Prophylactic for migraine, tricyclic anti-depressant-inhibits 5HT/NE uptake Causes delirium Topiramate Prophylactic for migraine and cluster, anti-convulsant Know that the following classes of drugs can cause Delirium Anticholinergics, Opioids, Benzodiazepines, narcotic analgesics, sedative-hypnotic, histamine 2-receptor blockers