163 Trigeminal Neuralgia: Diagnosis and Nonoperative Management

C H A P T E R Marlon S. Mathews n Devin K. Binder n Mark E. Linskey

Neuropathic facial pain (NFP) is dened as pain around the mouth or face that arises from a primary lesion or dysfunction of the nervous system.1 The management of NFP can be a frustrating as well as rewarding experience in neurosurgical practice because facial pain is often a difcult problem with a wide variety of potential causes. It is therefore important for neurosurgeons to have a broad understanding of the underpinnings of facial pain syndromes. NFP can be primary (with no recognizable underlying pathology) or secondary, such as following traumatic nerve injury. NFP includes a heterogeneous group of entities and can be broadly considered in two categories: paroxysmal and continuous.2 Paroxysmal neuropathies such as trigeminal neuralgia (TN) are characterized by short electrical shock-like or sharp pain. Continuous pain often has a burning characteristic and is a common feature of conditions such as postherpetic neuralgia (PHN). NFP can vary in severity and also commonly presents with thermal or mechanical allodynia.

GENERAL PRINCIPLES IN THE MEDICAL MANAGEMENT OF FACIAL PAIN

The initial treatment of most facial pain syndromes is medical. The differential diagnosis of facial pain includes pathology involving nerves, teeth and jaw, sinuses, the aerodigestive tract, and blood vessels and is summarized in Table 163-1. Treatment must be driven by proper diagnosis and the characteristic features of the pain (Fig. 163-1). Pain due to head or neck neoplasm is best treated by treatment of the lesion. Similarly, psychogenic pain is best managed by treatment of the underlying psychiatric condition. It is important to distinguish nociceptive from neuropathic pain. Nociceptive pain is caused by normal and appropriate neural activity in the setting of local tissue injury (e.g., trauma, malignancy, infection). Nociceptive pain is typically constant and aching and only occasionally paroxysmal. Besides appropriate management of the underlying condition, nociceptive pain is best managed by opioid medications. In contrast, neuropathic pain results from abnormal or inappropriate neural activity and frequently occurs in the absence of obvious organic pathology. Neuropathic pain is thought to arise from aberrant regeneration or conduction following injury to the nervous system. Neuropathic pain can be paroxysmal or constant and is frequently described as electrical, burning, itching, or crawling. Neuropathic pain is thought to be opioid resistant. Medical treatment of neuropathic pain focuses on reducing abnormal neural activity through the use of various anticonvulsant medications. Nonsteroidal anti-inammatory drugs may have a role in the treatment of facial pain with an inammatory component. Topical applications of salicylates and capsaicin may be used as adjunctive therapy in facial pain syndromes especially in the treatment of PHN.

HISTORICAL PERSPECTIVE
One of the earliest known descriptions of paroxysmal facial pain was by the Arab physician Jurjani in the 11th century. He described a type of pain which affects the teeth on one side and the whole of the jaw on the side which is painful.3 The 17th century physician John Locke described the symptoms of TN in the wife of the English ambassador to France. Faced with limited treatment options for the patients excruciating pain, the physician opted for eight rounds of cleansing of the gastrointestinal tract, which reportedly resulted in remission of symptoms.4 In the era preceding the description of TN, studies of the anatomy of the cranial nerves led to a better understanding of facial pain. In 1829, the Scottish anatomist Sir Charles Bell (1774-1842) described the anatomy of the fth cranial nerve and its motor and sensory functions, establishing the trigeminal nerve as the cranial nerve responsible for subserving facial sensation as well as motor innervation to the masticator muscles.5 Previously, it was widely believed that the seventh cranial nerve was the source of facial pain syndromes. Bells discovery shifted the focus of investigation of facial pain syndromes from the seventh to the fth cranial nerve.3 An important breakthrough in the management of TN occurred fortuitously in 1942 when Bergouignan administered his patients the then new anticonvulsant diphenylhydantoin (phenytoin).6 Before this, the condition was referred to as neuralgia epileptiform owing to a prior hypothesis by Trousseau in 1853 that TN being paroxysmal was related to abnormal impulse conduction, analogous to epilepsy.7 When carbamazepine, a new medication for epilepsy was introduced in 1962, it was soon found to be useful in patients with TN.8,9 It had greater efcacy and less toxicity than the hydantoins and remains to this day the mainstay of medical therapy.10

TRIGEMINAL NEURALGIA
TN, a neuropathic pain syndrome, is dened by the International Association for the Study of Pain (ISAP) as a sudden and usually unilateral severe brief stabbing recurrent pain in the distribution of one or more branches of the fth cranial nerve. It is an excruciating, short-lasting (<2 minutes), unilateral facial pain that may be spontaneous or triggered by gentle, innocuous stimuli and separated by pain-free intervals of varying duration (Fig. 163-2). TN is classied as follows: Classic (also known as primary or idiopathic) Symptomatic (or secondary)due to intrinsic brainstem pathology with trigeminal nerve, nuclei, or tract involvement (e.g., multiple sclerosis or lacunar infarction), or due to extrinsic cerebellopontine angle pathology (e.g., neoplasms or vascular lesions). 163-1

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TABLE 163-1 Differential Diagnosis of Facial Pain

LOCATION OF LESION
Nerve

Facial pain

CONDITION
Trigeminal neuralgia, postherpetic neuralgia, trigeminal neuropathic pain, glossopharyngeal neuralgia, sphenopalatine neuralgia, geniculate neuralgia (Ramsay Hunt syndrome), multiple sclerosis, cerebellopontine angle tumor Dentinal, pulpal, or periodontal pain; temporomandibular joint disorders Sinusitis, head and neck cancer, inammatory lesions Optic neuritis, iritis, glaucoma Giant cell arteritis, migraine, cluster headache, Tolosa-Hunt syndrome Psychogenic, atypical facial pain

Treat underlying cause Nociceptive

Diagnosis

Neuropathic

Opioids

Paroxysmal Anticonvulsants

Constant Psychotropics (TCAs/neuroleptics)

Teeth and jaw Sinuses and aerodigestive tract Eyes Blood vessels Psychological

FIGURE 163-1 General principles in the medical management of facial pain. TCAs, tricyclic antidepressants.

Most TN patients (>85%) have classic TN. Diagnosis in typical cases is often straightforward; however, most TN patients suffer from misdiagnosis. Common conditions that mimic TN as well as their presenting features are listed in Table 163-2.

Etiology and Pathophysiology

Considerable progress has been made in elucidating the etiology of TN. In most patients with classic TN, the pain is generated because of compression of the trigeminal nerve most commonly at the root entry zone by an artery or vein. Observations supporting this are summarized in Table 163-3. The plaques of demy-

elination lead to hyperexcitability of injured afferents, which results in after discharges large enough to result in a nonnociceptive signal being perceived as pain.11 One theory to explain TN is the one proposed by Devor and colleagues,12 called the ignition theory, which can be explained as follows. The triggering of pain in TN may follow innocuous stimuli, a phenomenon that is probably explained by postinjury changes in neuronal function. After nerve injury, there is an increased proportion of A-beta bers with subthreshold oscillations that ultimately generate ectopic discharges.13-15 These produce a transient depolarization in neighboring passive C neurons in the same ganglion.16 These ndings favor a mechanism whereby afferent nociceptors could be stimulated by activity in injured low-threshold mechanoreceptors. It is likely that both central and peripheral changes occur, which would explain why not all patients with a treated compression of the nerve get permanent relief. There are likely

Seconds, no after pain Shooting, sharp Terrifying, exhausting Unbearable Character Timing Attacks Seconds, dull after pain for minutes

Periods of complete remission weeks, months Clinical features of trigeminal neuralgia Eating Talking Spontaneous Site Sometimes sleep Relieving Drugs Trigger points Associated May be sensory change Washing

Moderate to severe

Severity

Light touch Provoking

Right up to 60% First division rare

Trigeminal nerve

Unilateral 97%

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FIGURE 163-2 Major clinical features of trigeminal neuralgia. (From Zakrzewska JM, Linskey ME. Trigeminal neuralgia. In: Zakrzewska JM, ed. Orofacial Pain. New York: Oxford University Press; 2008, pp 119-134.)

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Chap T E r 163 Trigeminal Neuralgia: Diagnosis and Nonoperative Management

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TABLE 163-2 Common Conditions that Mimic Trigeminal Neuralgia

DIAGNOSIS
Dental infection or cracked tooth Temporomandibular joint pain Persistent idiopathic facial pain (previously called atypical facial pain) Migraine Postherpetic neuralgia Temporal arteritis

IMPORTANT FEATURES
Well localized to tooth; local swelling and erythema; appropriate ndings on dental examination Often bilateral and may radiate around ear and to neck and temples; jaw opening may be limited and can produce an audible click Often bilateral and may extend out of trigeminal territory; pain often continuous, mild to moderate in severity, and aching or throbbing in character Often preceded by aura; severe unilateral headache often associated with nausea, photophobia, phonophobia, and neck stiffness History of herpes zoster or vesicular outbreak Common in elderly people; temporal pain should be constant and often associated with jaw claudication, fever, and weight loss; temporal arteries may be rm, tender, and nonpulsatile on examination

Adapted from Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ. 2007;334:201-205.

other factors involved given the rarity of the disease, and there are reports of genetic and familial forms.17,18

Epidemiology
TN is considered a rare condition with the following features:
Annual incidence of 5.7 per 100,000 in women and 2.5 per Peak incidence in the 50- to the 60-year-old group, increas-

100,000 in men ing with age

A recent study using general practice research databases in the United Kingdom and very broad diagnostic criteria that may have allowed inclusion of neuropathic facial pain syndrome other than TN suggested a higher prevalence of 26 per 100,000.19

are usually subtle and partial and are associated with either chronicity of the syndrome or a history of prior surgical intervention.20,21 In a retrospective study by Pollock and colleagues,21 patients with bilateral TN were more commonly females (74% versus 58%; P < .1), had a higher rate of familial TN (17% versus 4.1%; P < .001), and had a greater increased incidence of additional cranial nerve dysfunction (17% versus 6.6%; P < .05) and hypertension (34% versus 19%; P < .05). Early, signicant, and nonsurgical sensory loss, in addition to bilateral involvement, should trigger a thorough investigation for symptomatic (i.e., secondary) TN.

Clinical Features
Diagnostic criteria for classic TN have been described in the International Classication of Headache Disorders (Table 1634). These include paroxysmal attacks of pain, characterized by intense, sharp, supercial, or stabbing precipitated from trigger areas or by trigger factors, similar attacks in a patient, absence of neurological ndings, and absence of other demonstrable cause. However, these criteria have not been validated.22 The most problematic feature of the diagnostic criteria is a requirement for absence of sensory decit in the absence of prior surgical intervention history. There is abundant evidence that subtle clinically detectable sensory decits are present in the setting of typical TN as well as evidence that electrophysiologic abnormalities may

Risk Factors
The major risk factor for TN is multiple sclerosis.11 Hypertension may play a role but is common in the age group at risk. Familial tendency is rare but has been reported.17,18 Bilateral involvement is present in only 5% of cases, and sensory decits

TABLE 163-3 Evidence of Neurovascular Compression as

Causative for Trigeminal Neuralgia
An aberrant loop of artery, or less commonly vein, is found to be compressing the root entry zone of the trigeminal nerve in 80% to 90% of patients at surgery. The trigeminal nerve is demyelinated next to the compressing vessel. Eliminating the compression by surgery provides long-term relief in most patients. Intraoperative assessments report immediate improvement in trigeminal conduction on decompression. Sensory function recovers after decompression. Other causes, such as compression by tumors or the demyelinating plaques of multiple sclerosis, produce similar lesions of the root entry zone of the trigeminal nerve.
Adapted from Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ. 2007;334:201-205.

TABLE 163-4 Diagnostic Criteria for Classic

Trigeminal Neuralgia
Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes that affect one or more divisions of the trigeminal nerve Pain the has at least one of the following characteristics: Intense, sharp, supercial, or stabbing precipitated from trigger areas or by trigger factors. Attacks that are similar in individual patients No clinically evident neurological decit is clinically evident Not attributed to another disorder
Adapted from Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ. 2007;334:201-205.

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antedate detectable sensory loss on examination.23-27 There are other forms of TN that most frequently have been called atypical trigeminal neuralgia and trigeminal neuropathy. Because there are no long-term cohort studies, it is not possible to determine whether these atypical forms are in fact the same condition but further on in the natural history or whether they may represent a distinct condition. The timing of the attacks and remission periods, as well as the character of the pain, are the distinguishing features for classic TN. Many patients with increased pain severity during the day and only one third of patients will report nocturnal pain resulting in awakening.11 Patients with atypical TN often describe a burning, dull, aching after pain that is persistent with a completely pain-free interval.11 Quality of life in TN can be severely impaired. Because the attacks are usually spontaneous and provoked when eating or talking, this reduces the ability to relax and enjoy social activity. Depression is common, and suicides have been reported.11 Although on routine examination most patients have no sensory decit, existing minor sensory decits may be very subtle and may increase in frequency with chronicity of the syndrome. Abnormalities in neurophysiologic testing may identify subclinical decits.25-27 Patients may exhibit tactile trigger areas within the trigeminal distribution, which will precipitate an attack when stimulated. There are no autonomic features.

TABLE 163-5 Key Points in the Management of Patients

with Trigeminal Neuralgia
A comprehensive history and examination, including baseline measure of pain and quality of life, is essential. Magnetic resonance imaging is used for diagnosis of symptomatic trigeminal neuralgia and evaluation of neurovascular compression. Medical management starts with carbamazepine and then trial of other drugs. Refer early for a neurosurgical opinion. Ablative surgery results in some degree of trigeminal nerve injury and gives pain relief for 3 to 5 years. Microvascular decompression offers the longest pain-free period with little sensory loss but risk for mortality. Psychological support is important and includes the need to provide access to written information. Patient is provided details of a support group.

Ancillary Tests
The diagnosis of TN is purely clinical. However, hematologic and biochemical monitoring is important in patients on drug therapy (see later). Radiologic investigations are important to differentiate between symptomatic and idiopathic TN. Magnetic resonance imaging (MRI) is useful to rule out secondary TN (e.g., neoplasms, cysts, vascular pathologies, multiple sclerosis plaques, lacunar infarctions). MRI does not have sufcient positive or negative predictive value to assess vascular compression as an etiology for the syndrome. Sensory testing is not done routinely, but quantitative sensory testing (QST) and evoked potentials may play an important role in differentiating between symptomatic and idiopathic TN.26-27

Medical Management
All patients with TN are initially managed medically. Medical management begins with a comprehensive history and physical examination, including baseline measure of pain and quality of life. Psychological support is important, and patients should be provided information about support groups. Key points in the management of patients with TN are summarized in Table 1635. Commonly used drugs are carbamazepine, oxcarbazepine, gabapentin, lamotrigine, and baclofen. The evidence for their use is summarized in Table 163-6. Patients should keep pain diaries and change their drug levels to adjust to the changing severity of the pain and tolerability of side effects. Most of the drugs need to escalated and withdrawn slowly to avoid side effects. Carbamazepine is the drug of choice, with good evidence to show that this drug is highly effective.1 Common adverse effects such as drowsiness, dizziness, constipation, ataxia, and syndrome of inappropriate diuretic hormone (NNH, 3; 95% condence interval, 2 to 4), although most can continue taking the drug.28 Other adverse effects include rashes, leucopenia, and abnormal liver function tests. The efcacy of the drug may diminish with long-term use.29 The pharmacokinetics of the drug also result in numerous drug interactions, and one of special note is that with warfarin. If the patient responds well, a controlled-release preparation can be substituted, and the dose can gradually be reduced. What is less clear is what to do if a patient is intolerant or allergic to carbamazepine, or if the drug is ineffective. In the absence of

clear evidence of the effectiveness of other drugs, the choice among other agents can be made on the basis of adverse effects and ease of use. Oxcarbazepine is a prodrug of carbamazepine with similar efcacy of pain control.30 Although it is of similar efcacy to carbamazepine, it is much better tolerated and results in fewer drug interactions.31 Long-term follow-up has also shown that the drug is safe but gradually loses its efcacy because of either development of tolerance or increase in severity of the disease.32 Lamotrigine and baclofen have been suggested as second-line agents for TN on the basis of small studies. In practice, lamotrigine needs to be titrated over many weeks and has limited value in severe pain. Other drugs to consider are phenytoin, clonazepam, valproate, mexiletine, and topiramate. Gabapentin is widely used for neuropathic pain, although it lacks evidence in TN. Use of gabapentin therefore relies on the similarities between TN and other neuropathic pain syndromes, rather than their obvious differences.10 A recent randomized controlled trial suggests that gabapentin, combined with repeated topical injections of ropivacain, gives better pain control than gabapentin on its own.33 Familiarity with use of gabapentin in other neuropathic pain syndromes has led many clinicians to choose this as second-line for TN.34 Pregabalin has been licensed for use in neuropathic pain and has been reported to be effective in a cohort series in TN.35 Clonazepam, valproate, and phenytoin are often used. There are no high-quality studies on the use of polypharmacy as often practiced in epilepsy. Topical injections of lidocaine into trigger points can give some temporary relief. Drugs such as tocainide, tizanidine, and pimozide are ineffective or their side-effect prole is severe enough to exclude their use.36-38 The fear, loneliness, and depression associated with TN may require psychological, social, or other nonmedical help. Support groups can help to reduce feelings of isolation and despair and can also provide high-quality information.

Prognosis
Untreated, TN becomes gradually more severe with fewer remission periods, but the rate at which this occurs is unpredictable. Spontaneous remission periods of up to 6 months are common, yet the syndrome remains predominantly progressive in nature.29,32 Up to 44% of patients when followed for up to 16 years will fail to get complete pain relief with medical therapy.29

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Chap T E r 163 Trigeminal Neuralgia: Diagnosis and Nonoperative Management

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TABLE 163-6 Drugs Used in the Medical Management of Trigeminal Neuralgia

DRUG
Carbamazepine (the only rst-line agent)

LEVEL OF EVIDENCE
Systematic review of four randomized controlled trials (n = 160)

EFFECT
NNT for pain relief is 1.9; 72% of patients had excellent or good response

ADVERSE EFFECTS
Drowsiness, ataxia, nausea, constipation (minor); NNT 3.7

SUGGESTED DOSE
100mg twice daily; increase as necessary by 50-100mg every 3-4 days; target range 400-1000mg/day 10mg 3 times daily; increase as necessary by 10mg/ day; target dose 50-60mg daily 300mg once daily; increase as necessary by 300mg every 3 days in divided doses (3 times daily); target dose 900-2400mg daily 25mg twice daily; increase by 50mg weekly; target dose 200-600mg daily

COMMENT
Dose may need to be adjusted after 3 weeks because of enzyme induction

Baclofen

One controlled trial compared baclofen with placebo (n = 10) Five uncontrolled studies (n = 123)

Gabapentin

Seven of 10 patients improved with baclofen; 0 of 10 improved with placebo (P = .05) Good to excellent pain relief in 40%, any pain relief in 53%

Drowsiness, hypotonia; avoid abrupt withdrawal

May be useful in patients with multiple sclerosis when its antispasticity effects can be harnessed Widely used for trigeminal neuralgia although evidence is weak; evidence base in other types of neuropathic pains much stronger

Drowsiness, ataxia, diarrhea (minor); NNT 2.5.

Lamotrigine

One randomized controlled trial with lamotrigine as add on to carbamazepine or phenytoin (n = 14) Two uncontrolled studies (n = 21)

Ten of 13 patients improved on lamotrigine; 8 of 14 improved on placebo; (NS)

Drowsiness, dizziness, constipation, nausea (no different from placebo)

Oxcarbazepine

Pain relief in all 21 patients

Dizziness, fatigue, rash, hyponatremia

Phenytoin

Three uncontrolled studies (n = 30)

About 77% of patients reported some pain relief

Drowsiness, ataxia, dizziness, gum hypertrophy

300mg twice daily; increase by 600mg weekly; target dose 600-2400mg daily 300mg a day; dose altered to achieve therapeutic plasma concentration

Probably better tolerated than carbamazepine but needs slow titration; may therefore have a role in the elderly patients or patients with multiple sclerosis who have less severe disease Evidence weak; structurally similar to carbamazepine although probably better tolerated First drug used in the successful management of trigeminal neuralgia; little evidence but rapid dose titration and once-daily dosing are advantages

NNT, number needed to treat; NS, not statistically signicant. Adapted from Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ. 2007;334:201-205.

SUGGESTED READINGS
Anonymous. The International Classication of Headache Disorders: 2nd edition. Cephalalgia. 2004;24:9-160. He L, Wu B, Zhou M. Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database Syst Rev. 2006;3:CD004029. Jorns TP, Zakrzewska JM. Evidence-based approach to the medical management of trigeminal neuralgia. Br J Neurosurg. 2007;21:253-261. Lewis MA, Sankar V, De Laat A, et al. Management of neuropathic orofacial pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(Suppl 32):e1e24. Lopez BC, Hamlyn PJ, Zakrzewska JM. Systematic review of ablative neurosurgical techniques for the treatment of trigeminal neuralgia. Neurosurgery. 2004;54: 973-982. Merskey H, Bogduk N. Classication of chronic pain. Descriptors of chronic pain syndromes and denitions of pain terms. 2nd ed. Seattle: IASP Press; 1994:1-222. NHS Clinical Knowledge Summaries found at <http://www.cks.library.nhs.uk/>. Nurmikko TJ, Eldridge PR. Trigeminal neuralgiapathophysiology, diagnosis and current treatment. Br J Anaesth. 2001;87:117-132.

Spatz AL, Zakrzewska JM, Kay EJ. Decision analysis of medical and surgical treatments for trigeminal neuralgia: How patient evaluations of benets and risks affect the utility of treatment decisions. Pain. 2007;131:302-310. Weigel G, Casey KF. Striking Back: The Trigeminal Neuralgia and Face Pain Handbook. Gainesville: The Trigeminal Neuralgia Association; 2004. Wiffen P, Collins S, McQuay H, et al. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2005;3:CD001133. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database Syst Rev. 2005;3:CD005451. Zakrzewska JM. Insight: Facts and Stories behind Trigeminal Neuralgia. Gainesville: Trigeminal Neuralgia Association; 2006:1-403. Zakrzewska JM, Linskey ME. Trigeminal neuralgia. In: Zakrzewska JM, ed. Orofacial Pain. New York: Oxford University Press; 2008:119-134. Zakrzewska JM, Lopez BC. Trigeminal neuralgia. BMJ Clinical Evidence Concise, 462-464, or <www.clinicalevidence.com>, 2006.

Full references can be found on Expert Consult @ www.expertconsult.com

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Chap T E r 163 Trigeminal Neuralgia: Diagnosis and Nonoperative Management 163E-1

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