The new england journal of

Review Article

Allan H. Ropper, M.D., Editor

Giorgio Cruccu, M.D., Giulia Di Stefano, M.D., Ph.D., and Andrea Truini, M.D., Ph.D.​​

From the Department of Human Neuro­ rigeminal neuralgia, traditionally called tic douloureux, is a science, Sapienza University of Rome, chronic disorder characterized by spontaneous and elic- Rome. Address reprint requests to Prof. Cruccu at Dipartimento Neuroscienze ited paroxysms of electric shock–like or stabbing pain in a region of the Umane, Università Sapienza di Roma, T face. A poor quality of life and suicide in severe cases have been attributed to the Viale Università 30, 00185 Rome, Italy, or disorder.1,2 A classification of trigeminal neuralgia has been adopted by several at ­giorgio​.­cruccu@​­uniroma1​.­it. professional societies and forms the basis of its description in the International N Engl J Med 2020;383:754-62. Classification of , 11th Revision (ICD-11).3 DOI: 10.1056/NEJMra1914484 Copyright © 2020 Massachusetts Medical Society. Clinical Characteristics and Diagnosis The diagnosis of trigeminal neuralgia is clinical and is based on three main cri- teria: pain restricted to the territory of one or more divisions of the trigeminal ; paroxysms of pain that are sudden, intense, and very short (<1 second to 2 minutes, but usually a few seconds) and are described as a “shock” or an “elec- tric sensation”; and pain triggered by innocuous stimuli on the face or intraoral trigeminal territory. Triggered paroxysmal pain is particular to trigeminal neural- gia and is reported by 91 to 99% of patients,4-6 indicating that this feature may be pathognomonic of trigeminal neuralgia.3 The pain of trigeminal neuralgia most frequently affects the distribution of the second (maxillary) or third (mandibular) division of the trigeminal nerve, with the right side of the face affected more often than the left side. Bilateral trigeminal neuralgia is rare and should raise concern about facial neuralgia due to an under- lying neurologic or a non-neurologic disorder affecting the cranium. The incidence of trigeminal neuralgia is higher among women than among men and increases with age.7 Many forms of facial pain have been conflated with trigeminal neuralgia, but they are likely to be distinct entities, sometimes subsumed under the category of “” or “painful trigeminal neuropathy.” The posterior third of the scalp, the outer ear (with the exception of the tragus), and the skin overlying the angle of the mandible are not innervated by the trigeminal nerve and are not sites of pain due to trigeminal neuralgia (Fig. 1); pain in these areas suggests an alternative process. The pain of trigeminal neuralgia may be triggered by common gestures of daily life, and the triggers are in small receptive sensory zones — for example, the touch of a napkin or tissue on the upper lip or even a breeze flowing across a sensitive area of the face. The location of the pain is not always concordant with the site of a sensory trigger. For example, stimuli in and around the lower lip may induce pain in the temple, or sensory triggers in the lateral portions of the nose may induce a shocklike pain radiating toward the forehead or upper lip. Specific trigger maneuvers from one series of patients are shown in Table 1, and the dis-

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A Facial territories of innervation of B the three trigeminal branches

Ophthalmic

Maxillary

Mandibular

Extraoral territories

C

Intraoral territories

Figure 1. Innervation Territories of the Trigeminal Nerve and Trigger-Zone Distribution. Panel A shows the facial territories of innervation of the three trigeminal branches: ophthalmic, maxillary, and mandibular. Panels B and C show the trigger­zone distribution in the face and mouth, respectively, on the basis of data from 120 patients with classical trigeminal neuralgia who were seen at the Center for Neuropathic Pain at Sapienza University in Rome between January 2015 and December 2019. The analysis was performed with dedicated software that allowed trigger­zone overlap profiling of the extraoral and intraoral territories. The colors represent the number of patients reporting a trigger zone in each region; this number ranges from 2 patients (grayish lavender, as in the uppermost spots in Panel B) to 28 patients (orange). Because of the patients’ difficulty in identifying a circumscribed trigger­ zone region in the mouth, the number of trigger zones in the intraoral territory is smaller than the number of patients who reported that talking or chewing was the main trigger maneuver. tribution of trigger zones that elicit pain are the physician may notice a blink or a small shown in Figure 1. Few patients report no triggers. mouth movement of which the patient is un- Examination for trigeminal neuralgia includes aware.4 Less often, during a paroxysmal attack, observation of the face while the patient is forceful contraction of the facial muscles, called seated and remains completely still. With a “tic convulsif,” may occur. Sensory examination spontaneous paroxysm of trigeminal neuralgia, of the face is generally unrevealing in cases of

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Table 1. Trigger Maneuvers in 120 Patients with Classical for approximately 15% of cases, is attributable to Trigeminal Neuralgia.* an identifiable neurologic disease such as mul- tiple sclerosis or a tumor in the cerebellopontine No. of angle, which alters the root entry zone of the Triggers Patients (%) trigeminal nerve or otherwise compresses the Activities of daily living nerve in its extracranial course. Idiopathic tri- Talking 71 (59) geminal neuralgia, in which no apparent cause Washing face 52 (43) of nerve disturbance can be found, accounts for Chewing 49 (41) approximately 10% of cases. Brushing teeth 43 (36) The clinical features of classical and second- ary trigeminal neuralgia are similar, although Drying face 43 (36) patients with secondary trigeminal neuralgia are Eating 23 (19) usually younger, more likely to have sensory loss Drinking 17 (14) on a portion of the face, and are more likely to Shaving 16 (13) have bilateral pain.8 Since the three forms of Applying makeup 7 (6) trigeminal neuralgia may be clinically indistin- Combing hair 2 (2) guishable, magnetic resonance imaging (MRI) Washing hair 2 (2) with gadolinium to rule out and cerebellopontine masses is advisable at the Specific movements time of the initial diagnosis. A recent study Swallowing 13 (11) showed rare variants in genes encoding voltage- Blowing nose 11 (9) gated ion channels in patients with a family Gently touching face 106 (88) history of classical or idiopathic trigeminal neu- Jaw movement 7 (6) ralgia, but the frequency and clinical importance 9 Head movement 7 (6) of this finding are not known. Yawning 7 (6) Flexing the trunk forward 5 (4) Neurovascular Compression in Classical Trigeminal Neuralgia Pronouncing labial letters 5 (4) Raising voice 5 (4) Over the past several decades, the classical form Laughing 3 (3) of trigeminal neuralgia has been revealed through Eye movement 2 (2) the work of Peter Jannetta and others, and the Tongue movement 2 (2) potential for cure by means of intracranial mi- crovascular surgery has been studied. The patho- * Data are from 120 patients seen at the Center for Neuro­ physiology is considered to be compression of pathic Pain at Sapienza University in Rome between the sensory portion of the trigeminal nerve, January 2015 and December 2019. close to its root entry zone in the pons, by an adjacent small branch of the basilar artery, most trigeminal neuralgia, although some patients often the superior cerebellar artery. However, report areas of mild hypoesthesia. simple contact between the nerve and a vascular structure does not appear to be adequate to Types and Causes cause or explain the disorder. To attribute the disorder to neurovascular compression, the Three types of trigeminal neuralgia have been anomalous vessel should ideally be shown to delineated: classical, secondary, and idiopathic. induce anatomical alterations in the trigeminal The classical type, which is the most common, root, such as distortion or atrophy.5,10 The most is caused by intracranial vascular compression characteristic finding at operation is a small, of the trigeminal nerve root, as described below. tortuous artery or arterial loop impinging on the The responsible vessel is usually the superior medial aspect of the trigeminal root at its entry cerebellar artery, which induces morphologic zone, causing lateral dislocation, distortion, flat- changes in the adjacent trigeminal nerve root. tening, or atrophy of the trigeminal root (Fig. 2). Secondary trigeminal neuralgia, which accounts Neurovascular compression can be seen with

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When the sheath becomes thin enough to allow the transmembrane passage of ions in the underlying axon, the axon is not equipped to promptly pump out sodium. The resulting depo- larization makes the axon hyperexcitable,10 caus- ing ectopic generation of impulses with high- frequency afterdischarges16,17 (discharges that occur after termination of the stimulus) and Figure 2. Neurovascular Compression. cross-talk between fibers (called ephaptic trans- An MRI scan, obtained with axial constructive interfer­ mission).18 Histologic evidence indicates that the ence in steady state imaging, shows neurovascular com­ nerve fibers most involved in demyelination are pression by a looped vessel (white arrow) at the entry zone of the trigeminal nerve root, with dislocation of the A-β fibers (large, non-nociceptive fibers), the nerve root (black arrow). which are the most susceptible to demyelination from mechanical damage or multiple sclerosis. It has been proposed that the high-frequency the use of MRI and three-dimensional recon- discharges originating at the site of demyelin- struction. Imaging techniques include three- ation along the A-β primary afferents are redi- dimensional T2-weighted MRI sequences with rected by brain-stem neurons to be perceived as detailed examination of the cisternal and cavern- paroxysmal pain.19 Some investigators have ob- ous segments of the nerve, three-dimensional served excessive excitability or reductions in the time-of-flight magnetic resonance angiography volume of several cortical and subcortical cere- for visualization of arteries, and phase-contrast bral areas in patients with trigeminal neural- MRI to display veins.11,12 The specific imaging gia,20,21 but such changes are probably conse- features that identify morphologic changes in quences of adaptation to chronic stimulation of the trigeminal root with certainty vary among these regions.21 investigators. However, several studies have sug- gested that microstructural changes in the nerve Trigeminal Neuralgia at sites of vascular compression can be quanti- with Continuous Pain fied with the use of diffusion tensor imaging and tractography to disclose focal demyelination Although paroxysmal facial pain is the hallmark and edema,13,14 although these sensitive tech- of trigeminal neuralgia, 24 to 49% of patients4,22 niques are not used in most centers, and the report continuous or long-lasting pain between imaging diagnosis can be made with more con- paroxysmal attacks. Background fluctuating pain, ventional MRI methods. Vascular decompression with a distribution that is consistent with that of may reverse these abnormalities at the trigemi- the paroxysmal pain, is described as burning, nal root entry zone, where the sensory portion throbbing, or aching.23 Trigeminal neuralgia of the nerve enters the ventral pons.13 characterized by this symptom, regardless of the cause, was previously classified as trigeminal Pathophysiology neuralgia type 2 or atypical trigeminal neural- gia24,25 and is now classified as trigeminal neu- At its entrance into the pons, the trigeminal nerve ralgia with concomitant continuous pain.26 The (like all peripheral ) loses its Schwann cell mechanism underlying continuous pain is dif- myelin sheath, which is replaced by central my- ferent from the mechanism underlying paroxys- elin generated by oligodendroglia. This zone of mal pain, as suggested by the lesser degree of transition is vulnerable to damage and particu- alleviation of continuous pain, as compared with larly to demyelination. Vascular compression is paroxysmal pain, after treatment with sodium- the usual cause of demyelination at the site just channel blockers or microvascular decompres- before the nerve enters the pons, and multiple sion.22,27 The pathophysiological link between sclerosis is the typical cause at the site just after the two pain entities is uncertain. Progressive entry into the pons. Demyelination at these sites damage of the nerve root and central sensitiza- has been shown in neurophysiological, neuroim- tion mechanisms have been hypothesized.28,29 aging, and histologic studies.15 Burning, throbbing, or aching pain is probably

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mediated by impairment of C fibers (unmyelin- meningiomas, epidermoid cysts, and cholestea- ated sensory axons that transmit impulses slow- tomas.40 Curiously, trigeminal neuromas (which ly), as shown in other neuropathic pain condi- are rare) have not been associated with trigemi- tions.19 Loss of C fibers in the trigeminal nal neuralgia. In an analysis of data from four sensory root may cause abnormal spontaneous studies that included 243 patients with trigemi- activity in second-order neurons in the brain nal neuralgia, tumors were the cause in 20 pa- stem as a result of denervation supersensitivity tients (8%).30 Compression of the trigeminal nerve of exposed postsynaptic membranes to neuro­ by tumors induces focal demyelination of the transmitters.19 The previous notion that continu- trigeminal nerve root, triggering the same gen- ous pain develops as a result of long-standing eration of high-frequency discharges in denuded trigeminal neuralgia is not supported by more axons that occurs in vascular compression of the recent data.22 nerve.40 Infiltrative malignant tumors can also cause axonal degeneration, resulting in hypoes- Secondary Trigeminal thesia in regions of the face and persistent pain. Neuralgia Trigeminal neuropathies due to trauma and rheumatologic diseases such as systemic lupus In 15% of patients with typical pain attacks, erythematosus and scleroderma can be mani- trigeminal neuralgia is caused by multiple scle- fested as paroxysmal pain mimicking trigeminal rosis or by benign tumors in the cerebellopon- neuralgia, but these associations are infrequent. tine angle.30 The risk of trigeminal neuralgia is Trigeminal neuropathy in these instances may increased by a factor of 20 among patients with start with unilateral paroxysmal pain, but bilat- multiple sclerosis, as compared with the general eral sensory loss soon develops over regions of population,7 with a prevalence of 2 to 5% among the face with ongoing pain, a disorder often patients with multiple sclerosis.31,32 Multiple termed trigeminal neuritis. Facial trauma, dental sclerosis–related trigeminal neuralgia has been procedures, or maxillofacial surgery may dam- attributed to a demyelinating plaque in the fas- age trigeminal nerve branches, causing paroxys- cicle of the trigeminal nerve as it courses mal stabbing, electric shock–like, or burning pain. through the ventral pons.33 Occasionally, trigemi- However, the pain attacks have a longer duration nal neuralgia is manifested as a clinically iso- than trigeminal neuralgia paroxysms, and most lated syndrome in patients with multiple sclero- patients also describe severe ongoing pain with- sis; the age at the onset of multiple sclerosis is out sensory trigger zones. Isolated idiopathic tri- higher for these patients than for those who do geminal neuropathy, a benign bilateral, symmet- not have trigeminal neuralgia.34 One neuroimag- ric, purely sensory trigeminal neuropathy, and ing study has shown an association between facial-onset sensory motor neuronopathy, a more neurovascular compression and multiple sclerosis– serious progressive disease, may also initially be related trigeminal neuralgia, suggesting that they manifested as unilateral paroxysmal facial pain.41 may coexist and be additive.35 The frequency of Trigeminal reflex testing has been used as a this dual mechanism is not known, but it has neurophysiological technique to detect trigemi- implications for treatment. Pharmacologic treat- nal nerve damage.8 This diagnostic test is useful ment of the pain of trigeminal neuralgia in pa- in patients who cannot undergo MRI or to detect tients with multiple sclerosis is challenging be- demyelination and neuropathies mimicking tri- cause of side effects of medications, worsening of geminal neuralgia (see the Supplementary Ap- symptoms of multiple sclerosis such as fatigue and pendix, available with the full text of this article , and limited evidence of its effectiveness at NEJM.org). in such patients.36,37 Case series indicate that sur- gical procedures to reduce vascular compression Treatment tend to be less effective in patients with trigemi- nal neuralgia caused by multiple sclerosis than in Medical Treatment patients with classical trigeminal neuralgia.38,39 The anticonvulsant agents carbamazepine, in Tumors in the cerebellopontine angle that doses of approximately 200 to 1200 mg per day, compress the trigeminal nerve root and cause and oxcarbazepine (300 to 1800 mg per day) trigeminal neuralgia include acoustic neuromas, have been considered the first-choice treatments

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Trigeminal Neuralgia for control of paroxysmal pain in patients with tients, this type of surgery is generally under- trigeminal neuralgia, regardless of the cause.8 taken only if standard doses of medications are Although these treatments are not supported by not sufficient to control symptoms or if side ef- data from randomized, controlled trials, clini- fects prevent continued use. cians consider the drugs to be highly effective, One group of surgical interventions, now with meaningful pain control in almost 90% of used infrequently, involves peripheral blockade patients.8 The treatment effect is proposed to be of trigeminal nerve branches at their emergence related to blockade of voltage-gated sodium from the facial bones by means of neurectomy, channels, resulting in stabilization of hyperex- alcohol injections, or induction of radiofrequency cited neuronal membranes and inhibition of re- lesions or cryolesions. The purpose of these pro- petitive firing.16 However, clinical improvement cedures is to produce an area of anesthesia on the is often offset by side effects, including dizzi- face that corresponds to the distribution of the ness, diplopia, ataxia, and elevated aminotrans- damaged nerve. However, the benefit of such ferase levels, one or more of which may lead to treatments has not been adequately supported by treatment withdrawal in 23% of patients.42 Ox- trials,8 and the procedures often led to anesthe- carbazepine may have fewer side effects and a sia dolorosa (intense pain in the area of sen- lower potential for drug–drug interaction than sory loss). carbamazepine,43 though it may be discontinued A second group of interventions seeks to per- because of excessive central de- cutaneously damage the trigeminal ganglion in pression or dose-related hyponatremia.10 Other, Meckel’s cave or exiting branches of the ganglion more selective sodium-channel blockers are un- at the base of the skull by means of radiofre- der development. Contraindications to the use of quency thermocoagulation,45 chemical destruction sodium-channel blockers include cardiac conduc- through injection of glycerol,46 or mechanical tion problems and allergic reactions, with a high compression through balloon inflation.47 Radio- degree of cross-reactivity (40 to 80%) with aro- frequency thermocoagulation preferentially dam- matic antiepileptic drugs.44 Carbamazepine and ages small-diameter pain fibers. To prevent oxcarbazepine reduce the high-frequency dis- corneal deafferentation and resultant keratitis, charges that characterize the electric shock–like the electrode is aimed so as to avoid damaging paroxysms, but the effect of these drugs on con- the first division of the trigeminal nerve. Balloon comitant continuous pain is usually limited.22,37 compression and glycerol injection preferentially Gabapentin, pregabalin, and antidepressant damage large myelinated fibers. Pain relief is agents, which have been shown to be effective in immediate with these techniques and has been the treatment of other neuropathic conditions reported in the following percentages of cases: characterized by continuous pain, may be tried 68% (range, 55 to 80) with balloon compression as additional agents along with oxcarbazepine or (follow-up, 4.2 to 10.7 years), 58% (range, 26 to carbamazepine. Clinical experience suggests that 82) with radiofrequency thermocoagulation (fol- gabapentin may have a lesser effect on trigeminal low-up, 3.0 to 9.3 years), and 28% (range, 19 to neuralgia than carbamazepine and oxcarbaze- 58) with glycerol rhizolysis (follow-up, 4.5 to pine but is associated with a lower incidence of 8.0 years).8 Trigeminal sensory deficits are usually adverse events and can be attempted either as transient with balloon compression and glycerol monotherapy or as add-on therapy, if it is associ- injection and are more severe and longer lasting ated with an acceptable side-effect profile, in- after radiofrequency thermocoagulation. cluding in patients with multiple sclerosis.8,37 If Generating a lesion of the trigeminal root a course of medical treatment is ineffective or with a gamma knife is a more recently intro- associated with unacceptable side effects, surgi- duced procedure and is supported by several cal decompression of the trigeminal nerve may studies. A challenge of this procedure is accurate be considered. identification of the coordinates of the trigemi- nal root before their entrance into the pons, Local Surgical Procedures where the radiation beams must be collimated Although surgical procedures are effective in to avoid damaging the pons. In contrast to the reducing the severity and frequency of attacks of immediate pain relief associated with percutane- trigeminal neuralgia in appropriately chosen pa- ously caused lesions of the trigeminal ganglion,

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A Location of surgical incision

B Trigeminal nerve

Basilar artery

Superior cerebellar artery

Sponge

Figure 3. Microvascular Decompression. In microvascular decompression, after craniotomy, the neurosurgeon cuts the dura mater, shifts the cerebellar hemisphere, and uses microscopy to visualize the nerves emerging from the ventral pons. The vessel that is compressing the trigeminal nerve root is identified and moved if necessary, and a small sponge is inserted to keep the pulsating artery separated from the root.

the pain-relieving effect of gamma-knife stereo- rovascular compression5 or finds a mere contact, tactic radiosurgery takes 6 to 8 weeks to devel- with no apparent nerve compression. In these op. Approximately 24 to 71% of patients report cases, the surgeon usually inserts the separating continued pain relief 1 to 2 years after undergo- sponge anyway, even though the rate of failure ing the procedure, and 33 to 56% report contin- is higher than it is when distortion of the nerve ued pain relief at 4 to 5 years.8 Facial numbness root is identified. This problem underscores has been reported in 16% of patients, whereas the advantage of using established MRI criteria anesthesia dolorosa is virtually absent. A meta- to identify morphologic changes in the trigemi- analysis showed that approximately 34% of pa- nal root.5 tients do not have pain relief at 1 year and re- Despite the lack of high-level evidence-based quire repeat procedures.48 data,49,50 meta-analyses have suggested that micro- vascular decompression is the most efficacious Microvascular Decompression surgical intervention for classical trigeminal Microvascular decompression has become the neuralgia. At 1 to 2 years after undergoing the surgical procedure that is now favored for most procedure, 68 to 88% of patients have pain relief, cases of trigeminal neuralgia that do not re- and 61 to 80% have pain relief at 4 to 5 years.8 spond to medication. The neurosurgeon identi- The average mortality associated with the sur- fies the vessel that is compressing the trigemi- gery is 0.3%. leaks occur in nal nerve root, moves it from under the nerve to 2.0% of patients, brain-stem infarctions or hema- over the nerve if necessary (Fig. 3), and typically tomas in 0.6%, and in 0.4%. Sensory inserts a small sponge to keep the pulsating loss in part or all of the trigeminal nerve sen- artery separated from the nerve root. In about sory distribution on the face occurs in 2.9% of 11% of patients, the surgeon does not find neu- patients. The most troubling long-term compli-

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Dr. Cruccu reports receiving fees for educational activities Conclusions from Alfasigma Italy and advisory fees from Grünenthal, Lilly, and Angelini Italy; and Dr. Truini, receiving consulting fees Trigeminal neuralgia is an extremely painful from Eliem Therapeutics, Angelini Italy, and Grünenthal. No condition that can be difficult to diagnose and other potential conflict of interest relevant to this article was reported. treat. Carbamazepine and oxcarbazepine consti- Disclosure forms provided by the authors are available with tute the first-line medical treatment. However, the full text of this article at NEJM.org.

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