Trigeminal Neuralgia

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April 2017 )isfrequently sts regarding the classification, tic douloureux 3 Accurate diagnosis of trigeminal um channel blockers that are selective or neurologic disease, such as multiple mistaken forredundant dental diagnostic pain, proceduresas leading such x-rays of to thea jaw and, few in cases, moreof teeth. than unnecessary extractions neuralgia dependspatient’s critically description of on itstic characteris- the features. Clarificationacteristics of the of char- necessary the to pain guide is clinical therefore diagnosis known as lion lesions, gamma knife radiosurgery, root near its entry into the pons), and pression from an irrelevant contact will be ncy-dependent sodium channel blockers) ment, although many patients experience 1,2 ts for microvascular decompression. 1.7) receptor will hopefully help. Although all the v Although trigeminal neuralgia is well known to neurologists, Currently, a worldwide controversy exi Cruccu, MD This article proposes that the diagnosis of trigeminal neuralgia, with or Giorgio surgical interventions (percutaneous gang and microvascular decompression)differentiating are a real very neurovascular com of efficacious, benefit precise in better MRI selecting criteria patien for ABSTRACT Continuum (Minneap Minn) 2017;23(2):396–420. Purpose of Review: recent developments in classification and clinicaldebate diagnosis, new about surgical MRI options methods, necessitate and anRecent update a Findings: on the topic. diagnostic process, and surgical treatment of trigeminal neuralgia. Thisbeen controversy caused has on one side by theneuralgia, recognition that apart some from 50% of characteristic patients paroxysmal withthe attacks, trigeminal same also territory, which have results continuous in pain greatera diagnostic in lower difficulties and response to is medical associated with and surgicalin treatments. MRI In contrast, methods recent allow developments differentiationeffective between compression a of mere the neurovascularmore trigeminal contact and root an difficulties by anmicrovascular in anomalous decompression becoming vessel, more the which restricted. implies Summary: choice ofwithout surgical concomitant continuous pain, treatment, musttests rely are with on necessary to clinical the distinguish grounds threeralgia only. etiologic (nothing indication Diagnostic categories: is idiopathic found), trigeminal classic neu- for trigeminalmorphologic neuralgia (an anomalous changes vessel produces ofsecondary the trigeminal neuralgia trigeminal (due to maj are still thesignificant first-choice side effects, medical and treat well those to with treatment. concomitant The continuous development pain of respond sodi less sclerosis or tumorscarbazepine (ie, at voltage-gated, the freque cerebellopontine angle). Carbamazepine and ox- for the sodium channel 1.7 (Na Conversely, trigeminal neuralgia (also INTRODUCTION Facial painWhen is the pain easily is intenseand and misdiagnosed. recurrent the underlying etiologythe is condition elusive, is ofteninal labeled neuralgia, trigem- althoughtions other are condi- much morecause. likely The to be prevalenceneuralgia the in of the trigeminal populationcompared is to 0.07%, patients approximately with 2% facial pain in in general. Trigeminal Neuralgia Review Article . Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is 30, Rome, ContinuumJournal.com ´

Supplemental digital content: Direct URL citationsthe appear in printedcluded text in and the HTML,app are PDF, versions and of in- this article. Address correspondence to Giorgio Cruccu, Department of Neurology and Psychiatry, Viale Universita Italy 00185, [email protected] Relationship Disclosure: Dr Cruccu has received personal compensation for serving on the advisoryof board and as aAngelini consultant and for Biogen, Inc and has receivedcompensation personal for serving on the advisory board of andspeaker as for a Sigma Tau Pharmaceuticals, Inc. Dr Cruccu has received research/grant support from Sapienza University of Rome and Sigma Tau Pharmaceuticals, Inc. Unlabeled Use of Products/Investigational Use Disclosure: Dr Cruccu discusses the unlabeled/investigational use of BIIB074 for theof treatment elderly patients with trigeminal neuralgia. 396

Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 KEY POINTS and management. Successful diagnostic and trigeminal neuralgia secondary h Although trigeminal criteria must account for established to neurovascular contact. To solve neuralgia is variants of the phenotype (eg, typical this problem, the International Clas- still frequently versus atypical trigeminal neuralgia), sification of Headache Disorders misdiagnosed, its incorporate symptoms or signs that (ICHD) endorsed the term classic, peculiar clinical features correlate with different etiologies (pri- specifying that classic trigeminal neu- are unmistakable. mary trigeminal neuralgia versus trigem- ralgia should be diagnosed when no h A neurovascular inal neuralgia secondary to a major cause other than neurovascular contact compression is 8 neurologic disease), and identify pain is apparent. acknowledged as features that indicate underlying patho- The author agrees with this solu- the most frequent physiologic mechanisms (peripheral ver- tion because it avoids confusion. cause of trigeminal sus central), as they are relevant to direct However, the author favors additional neuralgia (classic further investigations or treatment de- differentiation of idiopathic trigeminal trigeminal neuralgia). cisions (pharmacologic therapy versus neuralgia from classic trigeminal neu- h Notwithstanding the surgery). Physicians should be aware ralgia. Even after surgical exploration most accurate and that the literature on trigeminal neural- of the posterior fossa at the base of advanced investigations, gia has been hampered by a terminolog- the skull for microvascular decom- no cause can be found ical dishomogeneity, which must be pression, approximately 11% of pain about 11% of solved to the benefit of researchers, tients with trigeminal neuralgia patients with trigeminal neuralgia (ie, idiopathic clinicians, and, ultimately, patients. remain without diagnosis of an appar- trigeminal neuralgia). Although tic douloureux is fre- ent cause.7,9 The frequency of cases quently used as a synonym for trigem- without an etiology justifies their inal neuralgia, the term was originally designation as idiopathic. For trigem- introduced to describe the involuntary inal neuralgia caused by a neurologic wincing associated with the occur- disease other than neurovascular com- rence of pain. Other diagnostic labels pression, the author prefers the term have been proposed to indicate differ- secondary rather than symptomatic ences in the etiology or clinical pre- because it is less ambiguous. The term sentation of trigeminal neuralgia. symptomatic may also indicate the Variable use of seemingly inter- painful side of the face or the affected changeable labels, such as classic and trigeminal root on MRI. idiopathic or secondary and symptomatic, has been a major source of CLINICAL DIAGNOSIS OF confusion. To differentiate idiopathic TRIGEMINAL NEURALGIA trigeminal neuralgia from manifesta- The International Association for the tions of neuralgia that are secondary Study of Pain (IASP) defines trigeminal to an identified disease, in 1973 neuralgia as ‘‘sudden, usually unila- Strandjord4 established the term pri- teral, severe, brief, stabbing, recurrent mary trigeminal neuralgia,which episodes of pain in the distribution of contradicts the notion of trigeminal one or more branches of the trigem- neuralgia as a condition of neuropathic inal nerve.’’10 The ICHD, Third Edi- pain. MRI shows neurovascular contact tion, beta version (ICHD-3 beta) in 70% to 83% of patients with typical describes trigeminal neuralgia in sim- trigeminal neuralgia.5,6 In neurosurgical ilar terms, ‘‘as a disorder characterized case series, this frequency increases by recurrent unilateral brief electric to 89%.7 Hence, primary trigeminal shocklike pains, abrupt in onset and neuralgia was loosely used by many termination, limited to the distribu- authors to describe both trigeminal tion of one or more divisions of the neuralgia without identifiable cause trigeminal nerve and triggered by

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KEY POINT h innocuous stimuli.’’ According to the their recent meta-analysis, Cruccu Paroxysmal pain in 14 trigeminal neuralgia is International Headache Society (IHS) and colleagues reviewed studies of a very abrupt and definition, trigeminal neuralgia ‘‘may MS associated with trigeminal neural- short-lasting pain develop without apparent cause or gia and identified a total of 24 cases of usually described as be a result of another diagnosed dis- bilateral trigeminal neuralgia out of stabbing or similar to order. There may or may not be, 252 MS patients with trigeminal neu- an electric shock. additionally, persistent background fa- ralgia (ie, a frequency of slightly less cial pain of moderate intensity. Classic than 10%). trigeminal neuralgia develops without apparent cause other than neurovas- POSSIBLE TRIGEMINAL cular compression.’’11 Although these NEURALGIA descriptions are certainly correct, they A patient’s history must fulfil two do not allow for evaluating the strength requirements for the identification of of the diagnostic criteria. possible trigeminal neuralgia: the pain The starting points for a diagnosis must be paroxysmal, and its distribu- of trigeminal neuralgia include unilat- tion must be consistent with the eral facial pain, pain that cannot be felt innervation territory of the trigeminal outside the trigeminal territory, and nerve (Figure 3-1). pain that is paroxysmal. Trigeminal The paroxysmal characteristic of neuralgia must be considered when trigeminal neuralgia, with its abrupt episodes of orofacial pain exhibit the onset and termination, is unmistak- characteristics laid out in the defini- able, even if the verbal descriptors tions provided by IASP and IHS.11,12 vary from patient to patient. Typical Pain episodes in trigeminal neuralgia descriptions of temporal and sensory occur and end abruptly, are short and qualities of trigeminal neuralgia in- severe, and are felt on only one side of clude brief, sudden, stabbing, or elec- the face within the innervation terri- tric shockYlike. Although the duration tory of the trigeminal nerve. The of trigeminal neuralgia paroxysms may sensory characteristics of the pain are last up to 2 minutes, in most patients usually described as stabbing or com- they are only a few seconds long. The parable to an electric shock. Bilat- number of paroxysms per day may eral trigeminal neuralgia is very rare, range from zero to more than 50.15 except for secondary trigeminal neu- Refuting earlier assumptions,16 a re- ralgia in multiple sclerosis (MS). Oc- cent study of 200 patients with classic casional reports of bilateral classic trigeminal neuralgia did not find evi- trigeminal neuralgia reflect successive dence that frequency or duration of episodes of unilateral pain that move trigeminal neuralgia paroxysms in- to the opposite side of the face rather crease with duration of the disease.17 than pain episodes that occur simulta- Unlike other neuropathic pains, tri- neously on both sides.13 A recent geminal neuralgia may enter into meta-analysis of clinical studies did periods of complete pain remission not find any report of truly bilateral in up to 63% of patients.15 These trigeminal neuralgia in 234 patients periods may last from weeks to years, with classic trigeminal neuralgia and but most often last a few months.15,18 found only one case of bilateral pain Previous definitions of trigeminal neu- out of 74 patients with secondary ralgia emphasize a stereotypic charac- trigeminal neuralgia.6 This meta- ter of the pain. Stereotypy, however, is analysis included mixed causes of not a unique feature of trigeminal secondary trigeminal neuralgia. In neuralgia. Stereotypic pain character

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 3-1 New classification and diagnostic grading system for trigeminal neuralgia (TN). a Trigeminal neuralgia is typically a unilateral condition. Few patients develop trigeminal neuralgia on both sides of the face over the course of a disease (eg, in multiple sclerosis), but they almost never present with simultaneous bilateral pain. b The pain strictly follows the distribution of the trigeminal nerve branches. It does not extend to the posterior third of the scalp, the posterior part of the external ear, or the angle of the mandible (Figure 3-2). c Paroxysmal pain is the most noted symptom, but may be accompanied by continuous pain. d Trigger maneuvers include innocuous mechanical stimuli, facial or oral movements, or complex activities such as shaving or applying makeup. Confined trigger zones and a common combination with brisk muscle contractions (tics) help distinguish triggered trigeminal neuralgia from allodynia in other conditions of neuropathic pain. Trigger maneuvers may be tested by the examiner. e MRI readily identifies major neurologic diseases, such as tumors of the cerebellopontine angle or multiple sclerosis. Other investigations may include the neurophysiologic recording of trigeminal reflexes and trigeminal evoked potentials, which become necessary in patients who cannot undergo MRI. f Advanced MRI techniques can demonstrate neurovascular compression with morphologic changes of the trigeminal nerve root.

Reprinted with permission from Cruccu G, et al, Neurology.14 B 2016 American Academy of Neurology. neurology.org/content/87/2/220.short.

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KEY POINT h Stimulus dependence is may be observed with other forms of trigeminal divisions, they should be one of the most striking neuropathic and non-neuropathic contiguous (most frequently a combi- features of trigeminal pain. In addition, it is not uncommon nation of the maxillary and mandibular neuralgia. for trigeminal neuralgia to produce branches of the trigeminal nerve). pain of variable sensory characteristics Trigeminal neuralgia in the ophthalmic over the course of the disease.14,16,19,20 division or the tongue has long been Pain should be felt in one or more considered an indication of secondary divisions of the trigeminal nerve trigeminal neuralgia. However, this no- (Figure 3-2). The examining physician tion has not been adequately scruti- should ascertain that the pain does not nized in clinical studies.5,6 Of note, the extend to the posterior third of the affected division of the trigeminal nerve scalp, the posterior part of the external and the side of the face may change, ear, or the skin overlying the angle of before or after surgery.14,16,19,20 the mandible, as these territories are innervated by cervical nerves. The TRIGGERED PAIN AS A territory of the mandibular division CRITERION OF CLINICALLY extends up to the temple: a patient ESTABLISHED TRIGEMINAL with trigeminal neuralgia in the man- NEURALGIA dibular branch of the trigeminal nerve Stimulus dependence is one of the most may therefore describe pain at the striking features of trigeminal neuralgia. temple and the lower lip (Figure 3-2). In most patients, pain is evoked by If trigeminal neuralgia involves two non-noxious, light mechanical stimuli

FIGURE 3-2 Innervation territories of the trigeminal nerve. Facial and intraoral territories of innervation of the three trigeminal branches: ophthalmic (yellow), maxillary (green), and mandibular (orange). White areas are innervated by cervical nerves. Light gray areas in the back of tongue and throat are innervated by the glossopharyngeal nerve.

Reprinted with permission from Cruccu G, et al, Neurology.14 B 2016 American Academy of Neurology. neurology.org/content/87/2/220.short.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT within the trigeminal territory, includ- pulpitis). In other diseases, this brisk h 21 Trigger maneuvers ing the oral cavity (Figure 3-3). movement is evoked by noxious or are unique to Subtlety of the trigger maneuvers is potentially noxious stimuli. trigeminal neuralgia. unique to trigeminal neuralgia. The Although pain paroxysms may orig- stimulus may simply be a touch or a inate spontaneously, patients with a whiff of air, although more complex history of exclusively spontaneous maneuvers involving both tactile attacks are very rare. It is possible that stimuli and facial movement (eg, in the few patients with no apparent washing or shaving of the skin, appli- trigger, the pain attacks are evoked by cation or removal of makeup, eating movements that the patients are un- or drinking) are also common. Move- aware of, such as eye blinking or a ment alone (eg smiling, talking) may twitch of other facial muscles. The suffice to provoke a pain attack. The author searched the literature for location of the evoked pain may differ reports of pain with ‘‘no trigger’’ from the site of the stimulation, and the or ‘‘without trigger’’ and did not pain can be felt as radiating (similar to find these terms in any article. The sciatica). These triggers are usually few studies that looked specifically spontaneously reported by the pa- into the presence of trigger stimuli tient. However, they may also be or maneuvers in classic trigeminal tested by the examiner, who should neuralgia reported triggered pain in pay attention to the typical tic (ie, the 94% of patients.15,22,23 Hence, the involuntary facial movement in reac- author proposes that the presence tion to the evoked pain). The term tic of triggered pain matching the above refers to the abruptness and short description confirms the diagnosis duration of the movement. The pro- of trigeminal neuralgia and qualifies voked movement of the face is similar the patient as having clinically to other reactions to acute nocicep- established trigeminal neuralgia tive pain (eg, after inadvertently bit- (Figure 3-1). Because triggered pain ing one’s tongue or a tooth with paroxysms are a unique somatosensory

FIGURE 3-3 Mechanism of pain in trigeminal neuralgia. Distribution of 31 trigger zones in 30 patients. Circles denote the typically small areas where light touch or other innocuous mechanical stimuli trigger the pain paroxysms. In some patients, the trigger zones are larger (dashed areas) or intraoral (ovals).

Reprinted with permission from Kugelberg E, Lindblom U, J Neurol Neurosurg Psychiatry.21 B 1959 British Medical Journal. jnnp.bmj.com/content/22/1/36.short.

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KEY POINTS h In almost 50% of phenomenon, it also increases the acteristics differ from the paroxysmal patients with trigeminal diagnostic certainty of neuropathic pain and are commonly described as neuralgia, concomitant pain so that it should also be consid- dull, burning, or tingling. The distri- 24 continuous pain ered probable neuropathic pain. bution of this continuous pain co- adds to the typical Clinically established trigeminal neu- incides with that of the paroxysmal paroxysmal pain. ralgia represents a sufficient degree of pain, and fluctuations of its intensity h Diagnostic investigations diagnostic certainty to implement parallel in time those of the paroxys- 19,25 are needed to establish treatment or enroll patients in a mal pain. A recent cross-sectional the etiology in cases of clinical trial for trigeminal neuralgia. study in 158 patients with trigeminal trigeminal neuralgia. neuralgia has well defined the charac- h Treatment of trigeminal TRIGEMINAL NEURALGIA teristics of this other phenotype and neuralgia can be WITH CONCOMITANT has brought far more attention to it, 26 initiated before CONTINUOUS PAIN reporting a frequency of almost 50%. diagnostic investigations Some patients with trigeminal neural- No generally agreed-upon term are performed. gia experience pain between attacks exists to describe the form of trigem- (Case 3-1). This pain is continuous or inal neuralgia in which concomitant nearly continuous, but may vary in continuous pain is present. It has intensity and quality. Its sensory char- been known by several designations,

Case 3-1 A 77-year-old woman presented to the neurology clinic for a 1-month history of facial pain. She described the pain as being on the right side only and consisting of ‘‘a burning and stabbing pain’’ in her cheek that sometimes lasted for hours. She also stated that when drying her face, she needed to slowly press the towel without brushing it up and down; otherwise, a lightninglike pain would go from her nose to her lip. She had already been treated with several pain killers and benzodiazepines by her primary physician with no improvement, but she had not tried voltage-gated sodium channel blockers. The neurologic examination was normal, apart from the patient grimacing when a cotton swab was touched to the right side of her face. The patient was prescribed oxcarbazepine and titrated up to 300 mg 4 times a day. MRI of her brain with contrast was ordered to rule out major neurologic diseases. To look for a possible neurovascular compression, time-of-flight magnetic resonance angiography (MRA), three-dimensional reconstruction, and constructive interference in steady state (CISS) sequences were also ordered. A baseline complete blood count and comprehensive metabolic profile completed the investigations. After 3 weeks, the patient returned, reporting resolution of her symptoms. The patient was diagnosed with trigeminal neuralgia with concomitant continuous pain. Brain MRI showed a neurovascular compression that distorted and flattened the affected trigeminal root near its entry into the pons. Comment. This patient’s symptoms were typical of trigeminal neuralgia with concomitant continuous pain, including the presence of a trigger mechanism (in this case the patient exhibited the ‘‘sign of the towel,’’ where she could pat a towel slowly to her face but could not brush the towel up and down because of the pain that was triggered.). Although diagnostic investigations to ascertain etiology must be performed in all patients, medical treatment can be implemented early based on clinical information only.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS including atypical trigeminal neural- trigeminal neuralgia. The mechanisms h The presence of gia and trigeminal neuralgia type 2. underlying continuous as opposed to continuous pain is not The author prefers the term trigemi- paroxysmal pain are not fully under- related to etiology and nal neuralgia with concomitant stood. Continuous pain may develop as may occur in idiopathic, continuous pain because it directly a result of progressive root damage after classic, or secondary conveys the difference from typical prolonged compression27 or reflect trigeminal neuralgia. 28 paroxysmal pain. The author prefers central mechanisms. Several authors h MRI is the most widely describing the pain as continuous have suggested that continuous pain used diagnostic tool to rather than persistent because con- is associated with poorer outcome assess for secondary Y tinuous refers strictly to the temporal after surgical intervention.20,29 32 It is trigeminal neuralgia, manifestation of the pain, whereas unclear to what extent these reports because it is highly persistent may imply refractoriness to reflect patient selection or differences sensitive for detecting treatment (and can also be confused in nerve pathology. However, convinc- major neurologic with persistent idiopathic facial pain, ing evidence exists that continuous and diseases such as a tumor which is an unrelated painful condi- paroxysmal pain may improve differ- or multiple sclerosis. tion). Several authors have favored ently after microvascular decompres- describing the pain as constant,which sion, indicating that the mechanisms is nearly synonymous with continuous responsible for the two pain compo- but may also refer to unchanging nents may be distinct.19,32,33 intensity or sensory quality of the pain. Thus, continuous is the description ETIOLOGY least susceptible to confusion (Table 3-1). MRI is the most widely used diagnos- The presence of continuous pain is tic tool to assess for secondary tri- not related to etiology and may occur geminal neuralgia, because it is highly in idiopathic, classic, or secondary sensitive for detecting major neurologic

TABLE 3-1 Definition and Classification of Trigeminal Neuralgia

Definition Trigeminal neuralgia is orofacial pain restricted to one or more divisions of the trigeminal nerve. Except for trigeminal neuralgia caused by multiple sclerosis, the pain affects one side of the face. It is abrupt in onset and typically lasts only a few seconds (2 minutes at maximum). Patients may report their pain as arising spontaneously, but these pain paroxysms can always be triggered by innocuous mechanical stimuli or movements. Patients usually do not experience pain between paroxysms. If they do report additional continuous pain, in the same distribution and in the same periods as the paroxysmal pain, they are considered to have trigeminal neuralgia with concomitant continuous pain. Classification Trigeminal neuralgia is classified in three etiologic categories. Idiopathic trigeminal neuralgia occurs without apparent cause. Classic trigeminal neuralgia is caused by vascular compression of the trigeminal nerve root. Secondary trigeminal neuralgia is the consequence of a major neurologic disease (eg, a tumor of the cerebellopontine angle or multiple sclerosis). Either phenotype (purely paroxysmal pain or with additional continuous pain) may occur with any of the three categories.

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KEY POINT h MRI may reveal diseases such as a tumor or MS. MRI cation of morphologic changes of the neurovascular contact may reveal neurovascular contact of the compressed trigeminal root. These of the trigeminal nerve trigeminal nerve root, but the frequency changes of symptomatic nerve roots root, but the frequency of mere contact between root and are highly suggestive of physical alter- of mere contact blood vessels in trigeminal nerves in ation and have a high predictive value between root and blood asymptomatic patients cautions against for pain relief after decompression.14 vessels in trigeminal its use as a diagnostic criterion. Sup- In a recent meta-analysis of nine nerves in asymptomatic ported by negative findings at opera- high-quality blinded and controlled patients cautions tion, recent studies have emphasized studies, mere neurovascular contact against its use as a the importance of differentiating the was found in 471 out of 531 symp- diagnostic criterion. type of contact and its physical impact tomatic nerves and in 244 out of 681 on the nerve, to the point that Cruccu asymptomatic nerves, indicating high and colleagues14 became convinced sensitivity but low specificity.7 Nerve that the reintroduction of the term dislocation or signs of atrophy in- idiopathic trigeminal neuralgia was creased the specificity to 97%. These needed.14 The degree of morphologic results are corroborated by two pro- trigeminal root changes is therapeuti- spective studies.34,35 Location of the cally relevant. The long-term outcome neurovascular contact appears to be after surgical correction of simple relevant. Compression of the trigemi- neurovascular contacts is poorer com- nal nerve at its entry into the brain- pared to the decompression of dis- stem increased the specificity to 100%. located, distorted, or flattened nerve It is important to acknowledge that roots (Figure 3-4).31,33 Advanced MRI all the studies cited here rely on a clin- techniques now allow radiologic verifi- ical diagnosis of trigeminal neuralgia

FIGURE 3-4 Morphologic changes of the trigeminal root showing examples of classic right trigeminal neuralgia. Two schematic drawings show axial sections at the level of the trigeminal roots where gray indicates nervous tissue, red indicates arteries, and black indicates bone. Atrophy of the right trigeminal root caused by a crossing artery (A) and a downward loop of the superior cerebellar artery that provokes distortion of the right trigeminal root at its entry into the pons (B) can be seen.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT prior to MRI. Consequently, MRI find- many believe that in the future DTI h Detection of ings alone cannot be used as bio- will reliably demonstrate microstruc- neurovascular markers to diagnose trigeminal tural damage in the trigeminal root compression requires neuralgia unless the investigation is and thus become the ultimate inves- the use of specific preceded by an evaluation of clinical tigation, so far the available evidence imaging paradigms symptoms and signs that indicate the is still insufficient. with three-dimensional presence of trigeminal neuralgia. Trigeminal reflex testing is an reconstruction However, a combination of clinical established neurophysiologic assess- MRI techniques. signs and morphologic changes caused ment of nerve function (Figure 3-539). by a vascular compression involving the Trigeminal reflex testing requires only symptomatic trigeminal nerve provides standard nerve conduction study strong enough evidence to confirm the equipment; for stimulation, it uses etiology of classic trigeminal neuralgia surface electrodes placed over the (Figure 3-1). emergence of the supraorbital, infra- Detection of neurovascular compres- orbital, and mental nerves and for sion requires the use of specific imaging recording uses surface electrodes paradigms with three-dimensional re- placed over the orbicularis oculi and construction MRI techniques. An in- masseter muscles. Allowing a between- creasing number of imaging options side quantitative assessment of the are available to depict the nerve and ophthalmic, maxillary, and mandibular any blood vessels in proximity to divisions, trigeminal reflex testing is a the posterior fossa. Typical imaging reliable method to detect secondary paradigms include sequences for forms of trigeminal neuralgia and has three-dimensional T2-weighted MRI been recommended in guidelines for (eg, constructive interference in steady the evaluation of neuropathic pain state [CISS]) for a detailed exami- involving the trigeminal nerve.40 In a nation of the cisternal and cavernous meta-analysis of 629 patients with segments of the nerve and three- trigeminal neuralgia, trigeminal re- dimensional time-of-flight magnetic flex testing achieved a sensitivity of resonance angiography (MRA) for 94% and a specificity of 87% in iden- visualization of arteries.34,36,37 The nec- tifying patients with secondary trigem- essary but sufficient scope of the MRI inal neuralgia, comparable to the evaluation to identify dislocation, dis- diagnostic accuracy of MRI.5,6 Trigem- tortion, flattening, or atrophy of the inal reflex testing is particularly helpful trigeminal root (ie, the morphologic if a patient cannot undergo MRI or if changes considered essential to distin- trigeminal neuralgia secondary to tri- guish between a mere contact and a geminal neuropathy is suspected in real compression)14 must still gain spite of a normal MRI result (refer to wide consensus. the following section on secondary Several studies suggest that trigeminal neuralgia). compression-induced microstructural Various evoked potentials after changes may be estimated using electric or thermal stimuli have been diffusion-tensor imaging (DTI) and studied in trigeminal neuralgia. In tractography to measure focal demye- contrast to trigeminal reflex testing, lination and edema.36,38 A recent which is normal in idiopathic or report suggests that effective treat- classic trigeminal neuralgia, evoked ment for trigeminal neuralgia reverses potentials may be altered, but their several DTI abnormalities at the tri- mean specificity of 64% is low.5,12,28 geminal root entry zone.38 Although Evoked potentials are adjuvant measures

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KEY POINT h In some 15% of patients with trigeminal neuralgia, the cause is a major neurologic disease, most often multiple sclerosis or benign tumors in the cerebellopontine angle (ie, secondary trigeminal neuralgia).

FIGURE 3-5 Trigeminal reflex test to disclose secondary trigeminal neuralgia. Left, Schematic drawing of the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions; stimulation sites at the supraorbital (V1), infraorbital (V2), and mental (V3) nerves; and recording from the orbicularis oculi (A) and masseter (B) muscles. Right, Early (R1) and late (R2) blink reflex (V1-A), and early (SP1) and late (SP2) masseter inhibitory reflex (V2-B and V3-B). Calibration is 10 ms/100 2V.

Reprinted with permission from Cruccu G, et al, Neurology.39 B 2006 American Academy of Neurology. neurology.org/content/66/1/139.long.

to demonstrate functional abnormalities tified by MRI or other appropriate in trigeminal neuralgia. It is worth investigations. In 15% of patients emphasizing that all electric stimula- with typical pain attacks, trigeminal tions within the trigeminal territory are neuralgia is caused by benign tumors bound to elicit reflex responses that un- at the cerebellopontine angle or MS avoidably contaminate the scalp signals. (Figure 3-642).5,6 Tumors causing tri- Only electric stimulation via two fine geminal neuralgia are mostly benign needle electrodes inserted into the in- and compress the root near its entry fraorbital foramen provides a safe scalp into the pons. They include meningi- recording of subcortical far-field poten- omas, epidermoid cysts, acoustic neu- tials whose generation site has been romas, and cholesteatomas. Local located near the trigeminal ganglion, compression induces focal demyelin- root, or pons.12 In a clinical setting, this ation and may trigger paroxysmal method of stimulation detailed by ectopic discharges, whereas infiltrative Leandri and Gottlieb41 is useful during tumors lead to axonal degeneration. radiofrequency thermocoagulation of The different pathology of nerve dam- the ganglion because it allows the iden- age by malignant tumors is commonly tification of the affected trigeminal associated with hypesthesia and con- division under general anesthesia. tinuous pain rather than trigeminal neuralgia. Evidence of tumors as a cause of secondary trigeminal neural- SECONDARY TRIGEMINAL gia comes from four main studies that NEURALGIA reported a total of 20 (8%) out of Trigeminal neuralgia caused by a ma- 243 patients with trigeminal neuralgia.6 jor neurologic disease is readily iden- On the other hand, about 20% of

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 3-6 Common causes of symptomatic trigeminal neuralgia. A, Benign tumors along the extraaxial course of the trigeminal root (arrows). B, Demyelinating plaques along the intraaxial course of the trigeminal afferents (arrows).

Reprinted with permission from Cruccu G, et al, Handb Clin Neurol.42 B 2010 Elsevier. sciencedirect.com/science/article/pii/ S0072975210970565. cerebellopontine angle tumors produce geminal neuralgia as their sole clinical trigeminal neuralgia.43 All symptomatic manifestation for all their life, thus tumors compress the trigeminal nerve being classified as having clinically root.44 Trigeminal neuromas almost isolated syndrome.30 These patients never produce trigeminal neuralgia. typically have multiple demyelinated Patients with MS have a 20-fold areas on MRI and strongly delayed increased risk of trigeminal neuralgia.18 responses on neurophysiologic tests The prevalence of trigeminal neuralgia (trigeminal reflexes and evoked poten- in MS is 2% to 5%.18,45,46 The cause of tials), which are characteristic of MS. It trigeminal neuralgia has conventionally has been hypothesized that the pontine been attributed to demyelinating plaque and a neurovascular compres- plaques in the pons.47,48 It has been sion exert a dual, additive mechanism, clearly shown, however, that the onset in which inflammatory demyelination age of the population with trigeminal (the intraaxial plaque)48 and mechani- neuralgia and MS is lower than that of cal demyelination (the extraaxial neuro- classic trigeminal neuralgia but signifi- vascular compression)50 create a double cantly higher than that of MS.49 Al- crush syndrome on the same primary though trigeminal neuralgia in MS may afferents near the root entry zone.51 be one of several other common MS Very recently, this theory has found disturbances, some patients have tri- sound evidence.52

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KEY POINT h Both in classic and Because patients with MS-related PATHOPHYSIOLOGY OF secondary trigeminal trigeminal neuralgia usually respond TRIGEMINAL NEURALGIA neuralgia, the primary insufficiently to pharmacologic treat- Oneaspectofpathophysiologyis mechanism is focal ment or must stay on high dosages supported by established neurophy- demyelination of primary that worsen their fatigue or may be- siologic, neuroimaging, and histologic afferents near the entry come toxic for the liver, microvascular evidence. Both in classic and second- (extraaxial or intraaxial) decompression or another surgical ary trigeminal neuralgia, the primary of the trigeminal root procedure for trigeminal neuralgia mechanism is focal demyelination of into the pons. becomes necessary sooner or later. In primary afferents near the entry these patients, however, the benefit (extraaxial or intraaxial) of the trigem- yielded by any type of surgical treat- inal root into the pons. Some investi- ment is shorter in duration than in gators believe this area represents a 53,54 classic trigeminal neuralgia. locus minoris resistentiae (a site of A smaller group of patients may lower resistance or higher susceptibil- present with trigeminal neuralgia sec- ity to damage) because it is the site ondary to a trigeminal neuropathy. where Schwann cells are substituted These neuropathies may be divided by oligodendroglia in providing the into three subgroups in descending myelin sheath. order of frequency: posttraumatic, as- A second pathophysiologic theory, sociated with connective tissue dis- admittedly more debatable, is that the eases, and idiopathic/genetic. Facial damaged primary afferents in the area trauma, dental procedures, or maxillo- of focal demyelination become a facial or neurosurgical procedures may source of ectopic generation of im- damage branches of the trigeminal pulses. The author proposes that, be- nerve. Although the primary symptom cause mitochondria and the energetic in trigeminal neuropathy is sensory loss, apparatus necessary to pump sodium sometimes these focal neuropathies off are physiologically concentrated present with episodes of paroxysmal at the level of the nodes of Ranvier, pain. The pain attacks are usually longer when the demyelinating process allows than those associated with trigeminal the passage of ions in and out of the neuralgia, and most patients also de- axon, then the axons do not have 55 scribe continuous pain. The trauma enough energy to promptly reestablish or the intervention should not escape the resting potential. Hence, the axons medical history. Painful trigeminal neu- tend toward a depolarization level, ropathy caused by a connective tissue which makes them hyperexcitable. disease or genetic disorder is usually Spontaneously, or because of a local bilateral but may begin asymmetrically direct mechanical stimulus such as and occasionally present with parox- the artery pulsation, ectopic activity is ysmal pain similar to trigeminal neu- generated. More supported by evi- 25,29,56,57 ralgia. Indeed a paroxysmal dence in animal models of focal demy- pain similar to that of trigeminal neu- elination of the trigeminal root is the ralgia may be the first symptom of an concept of ephaptic transmission 58 underlying connective tissue disease. (cross talk) from close, healthy nerve The patients will eventually develop bilat- fibers and the generation of high- eral sensory deficits and continuous frequency discharges.59Y61 pain, which clarifies the diagnosis. MRI A third potential pathophysiologic is normal, but trigeminal reflexes are theory, with almost no sound evi- 56 invariably delayed or absent. dence at all at this time, is that the

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS hyperactivity of primary afferents sec- reaching aplastic anemia. Indeed, pa- h Medical treatment ondarily induces central sensitization tients on carbamazepine must under- of trigeminal neuralgia of wide dynamic range neurons in the go a complete blood count every 3 to is based on spinal trigeminal nucleus or even 4 months. Both drugs may cause frequency-dependent 28,62 more central changes. sodium depletion (Case 3-2). Both sodium channel drugs, being antiepileptic drugs, in- blockers, namely MEDICAL TREATMENT OF duce central nervous system (CNS) oxcarbazepine and TRIGEMINAL NEURALGIA depression, presenting as somno- carbamazepine. The guidelines on trigeminal neuralgia lence, confusion, or imbalance. These h The adverse events management that were agreed upon central side effects, which are more caused by both and jointly published by the American frequent with carbamazepine than oxcarbazepine and Academy of Neurology (AAN) and the oxcarbazepine (Figure 3-7),17 may carbamazepine may often European Federation of Neurological prevent patients from maintaining require discontinuation of Societies (EFNS) are very clear as adequate doses. Hence, in this third these agents. to medical treatment (Supplemental group of patients, who are neither Digital Content 3-1, links.lww.com/ responders nor nonresponders, other CONT/A215).6 Based on evidence, the drugs can be tried. In this case, the treatment should begin either with AAN/EFNS guidelines suggest trying carbamazepine 400 mg/d to 1200 mg/d other pharmacologic options as or with oxcarbazepine 900 mg/d to monotherapy or add-on medications. 1800 mg/d. The author’s first-line In particular, analysis of the evidence- choice is oxcarbazepine because of its based trials led to the following sug- better tolerability.17,63 If the patient gestions: lamotrigine, baclofen, and reaches the dosages adequate for most pimozide.6 Lamotrigine is supported patients (1200 mg/d to 1500 mg/d) by evidence if used as an add-on to without achieving the desired pain carbamazepine.64 Unfortunately, the relief (ie, she or he is one of the rare comparatively high risk of dermatitis cases of a real nonresponder), no imposes a very slow titration,63,65 and, otherdrugwillbeenough.Hence naturally, this drug is not devoid of surgery, being extremely efficacious side effects on the CNS, which would in trigeminal neuralgia, should be add to those of carbamazepine or proposed.5,6 oxcarbazepine. Baclofen, an agonist Aside from responders and non- of the ,-aminobutyric acid B (GABA-B) responders, however, a third type of receptor, was believed to be very prom- patient exists who requires some ising because it was well supported by consideration. Some patients cannot animal experiments.66 Now it is known take either of the two choice drugs that unless baclofen is administered because of specific contraindications intrathecally, the side effects restrict the (most frequently cardiac conduction oral dosage to a level lower than the problems or severe arrhythmias). one necessary to reach antinociceptive Some other patients encounter seri- effects. Although pimozide was found ous side effects and allergic dermatitis, more efficacious than carbamazepine in which, unfortunately, tend to be cross- a small head-to-head clinical trial, it was reactive (ie, the patients who had the never tried again.67 Some reports about allergic reaction to one of the two the efficacy of gabapentinoids and anti- drugs cannot be switched to the depressants exist, but there have been other) or, in the case of carbamaze- no adequate trials in trigeminal neuralgia. pine, a fall in blood elements (white Both gabapentinoids and antidepres- cells, red cells, or platelets) rarely sants, however, are expectedly more

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Case 3-2 A 67-year-old woman with a history of hypertension presented with a 6-month history of right-sided facial pain. The pain was paroxysmal (she described it as similar to an electric shock), and it was evoked by typical trigger maneuvers for trigeminal neuralgia: light touch on the forehead and eyebrow, eyelid movement when looking upward, and combing her hair. She had previously been prescribed carbamazepine 600 mg/d, and her pain had disappeared. Her problems were twofold: first, the carbamazepine induced central nervous system side effects (eg, somnolence, dizziness, imbalance), which she found unbearable, and second, no investigation had yet occurred to ascertain the etiology. Neurologic examination was normal. She was switched to oxcarbazepine, with increasing doses up to 1200 mg/d. In addition, trigeminal reflex testing, a standard brain MRI, and a dedicated three-dimensional MRI and magnetic resonance angiography (MRA) study were ordered to check for a neurovascular compression. The patient returned for follow-up 3 weeks later, and she still had central nervous system depression, although to a far lower degree, which she felt was tolerable. The trigeminal reflex testing was normal, and the standard MRI showed some small ischemic lesions in the cerebral white matter; however, the dedicated MRI study for possible neurovascular compression showed a very rare compression by a wide-collar berry aneurysm of the superior cerebellar artery. The artery looped downward, and the aneurysm distorted the trigeminal root. The possibility of an endovascular intervention was discussed, but its efficacy was considered uncertain. One week later, the patient suddenly developed severe weakness and confusion and was seen in a local emergency department, where she was diagnosed with severe hyponatremia (120 mEq/L) and was begun on saline infusions. She was also seen by another neurologist, who quickly tapered and stopped oxcarbazepine, as well as an interventional neuroradiologist who, as soon as the electrolyte abnormality resolved, proceeded with endovascular intervention first with a coil in the aneurysm and then with a stent in the artery. Within 24 hours after the intervention, she had complete disappearance of the neuralgic pain attacks and continued to have no further symptoms when seen in follow-up 6 months later. Comment. With oxcarbazepine, sodium depletion occurs in 6% to 8% of patients. Regarding medication side effects, although oxcarbazepine by no means requires the three to four checks per year of blood elements that are mandatory for the duration of therapy for patients on carbamazepine, monitoring of serum sodium is necessary at least once. In this case, in retrospect, this patient’s cardiologist had recently introduced a diuretic to her antihypertensive regimen that probably added to oxcarbazepine in depleting sodium. Regarding the etiologic classification of this patient, although secondary trigeminal neuralgia is usually attributed to tumors or multiple sclerosis, other major neurologic diseases (eg, the rare trigeminal isolated sensory neuropathy or aneurysms) should be kept in mind when something in the history or symptoms suggests a secondary origin. In this case, the only unusual clinical factor was the location of her pain, which exclusively involved the ophthalmic division (this was long considered a Continued on page 411

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Continued from page 410 sign of probable secondary trigeminal neuralgia, although this association was not confirmed by the American Academy of Neurology [AAN] and the European Federation of Neurological Societies [EFNS] 2008 guidelines6). Regarding pathophysiology, it is well known that microvascular decompression relieves neuralgic pain far before a remyelinating process might take place. This case suggests the need for a pulsating stimulus on the demyelinated nerve fibers to induce the ectopic generation of high-frequency discharges. In microvascular decompression, the neurosurgeon leaves a tiny sponge to keep the artery and the nerve root separate. In this case, the artery pulsation was eliminated by the stent. efficacious in continuous than parox- patients, however, may not accept ysmal pain and are often tried as an add- surgery that easily. The author believes on to oxcarbazepine or carbamazepine that in those patients who do not want in patients with the atypical form of to undergo any kind of surgical in- trigeminal neuralgia with concomitant tervention, botulinum toxin injec- continuous pain. A dedicated clinical tions of the trigger areas should be trial has never been reported in trigem- tried.68Y71 Theamountofpublished inal neuralgia with concomitant contin- evidence is growing day by day, and uous pain, nor has the safety of these the safety profile is very high. Reportedly, combinations been verified. the pain relief lasts several months, Often, this third group of patients and the main side effect is a transient is eventually referred for surgery. Many weakness of the facial muscles in the

FIGURE 3-7 Trigeminal neuralgia (TN) treatment algorithm. MRI = magnetic resonance imaging.

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KEY POINT 71 h Several surgical injected area. Naturally, botulinum where surgery is most effective, each procedures for trigeminal toxin injections should be performed surgical method entails its own poten- neuralgia exist that are by neurologists experienced in botu- tial problems, thus the author believes very efficacious. linum toxin injections for other estab- that the first treatment should be lished indications. This treatment, so oxcarbazepine or carbamazepine. If the efficacious in other conditions, has standard dosages are not enough or the not yet achieved US Food and Drug side effects are too severe, then surgery Administration (FDA) indication for should at least be proposed and dis- trigeminal neuralgia. cussed with the patient. Finally, BIIB074, a new voltage- and Surgical methods for treating trigem- frequency-dependent sodium channel inal neuralgia can be divided in four blocker that has selectivity for the so- groups: lesions distal to the ganglion, dium channel 1.7 (Nav1.7) subtype, has lesions at the ganglion level, lesion of 72 been discovered. Nav1.7 is a major the root by gamma knife radiosurgery, sodium receptor in the nociceptive and posterior fossa intervention of system, but no Nav1.7 receptors exist microvascular decompression. in the brain. This absence of brain The first group of surgical methods Nav1.7 receptors promises to prevent includes all sorts of peripheral lesions any side effects associated with depres- of the trigeminal terminal nerves at sion of CNS excitability. Nav1.7 has their emergence from the facial bones: been validated as a key pain target by neurectomy, alcohol injections, radio- human genetic linkage, as gain of frequency lesions, or cryolesions. None function mutations are linked to a of these methods has ever been severe chronic pain syndrome, whereas supported by adequate trials.6,70 In loss of function mutations lead to the fact, these lesions were often the inability to feel pain.73 Furthermore, its source of anesthesia dolorosa (pain efficacy and extreme tolerability has in area of sensory loss). already been proved in patients in a The second group of surgical phase 2 trial. Zakrzewska and col- methods involve percutaneous gas- leagues74 have now demonstrated that serian (ie, trigeminal) ganglion le- BIIB074 can inhibit the firing of tri- sions. In all cases, a long cannula or geminal neurons, adding further mech- electrode is inserted first through the anistic support to the potential of this cheek, then between the mandibular new molecule. arch and the maxillary bone, to reach the infratemporal fossa, and aimed at SURGICAL TREATMENT OF the foramen ovale, through which it TRIGEMINAL NEURALGIA penetrates the skull base reaching the A first, difficult question is whether Meckel cave, where the gasserian some patients, according to their ganglion lies. All these procedures inclination, should be offered the early need fluoroscopic guidance. When on choice between medical and surgical target, three types of lesions can be treatment. A study in patients who done: thermocoagulation by radio- had undergone surgery for trigeminal frequency,76 chemical lesion by injec- neuralgia found that many, after tion of high-concentration glycerol,77 experiencing the long-lasting benefit, or mechanical compression by balloon would have opted for surgery from inflation.78 Radiofrequency thermo- the very beginning.75 coagulation was conceived to prefer- Although trigeminal neuralgia is per- entially damage the small pain fibers. haps the neuropathic pain condition Balloon compression and glycerol

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. injection preferentially damage the are piercing of the maxillary artery large myelinated fibers; thus, the (which is close to the trajectory toward rationale is that of blocking the trig- the foramen ovale), and that of the dura gering impulses. Whereas balloon mater covering the Meckel cave, with compression and glycerol injection various possible consequences, from can be performed under continuous burning of an oculomotor nerve to general anesthesia, radiofrequency infusion of glycerol into the CSF of the thermocoagulation requires anesthe- middle cranial fossa. Almost unavoid- sia when the electrode is moved to able are trigeminal sensory deficits, the target and then again at the which are usually transient with balloon moment of the lesion. Hence, patients compression and glycerol injection must be awakened in between be- and more severe and longer lasting cause they must report in what areas after radiofrequency (Figure 3-8). of the face they feel the paresthesia Stereotactic radiosurgery (gamma evoked by electric impulses delivered knife) is the most recent type of in- from the tip of the electrode to prevent terventionappliedtotrigeminalneu- damaging the wrong trigeminal divi- ralgia and therefore the one with the sion. The electrode is moved slightly fewest number of patients who have until the evoked paresthesia is coinci- been treated. However, the amount dent with the painful division, and then of favorable evidence is increasing the patient is anesthetized again before rapidly. Naturally, the main problem the actual thermocoagulation begins. is the same as for all stereotactic Sophisticated methods have been de- radiosurgery interventions (ie, the veloped, including the intraoperative reliability and accuracy of the recording of trigeminal evoked poten- methods of finding the exact co- tials.41 In any event, however, the ordinates of the trigeminal root just electrode cannot be aimed at the first before its entrance into the pons, trigeminal division because the dam- where the radiation beams should age to small fibers entails corneal collimate). A randomized controlled deafferentation and keratitis. Balloon trial studied whether expanding the compression and glycerol injection irradiated area more distally along are devoid of the risk of corneal therootwouldincreasetherateof keratitis because they damage large responders80: the total success rate myelinated fibers only. Regarding the was 68% regardless of the length of general pros and cons of the percuta- the irradiated area. Only the occur- neous ganglion lesion techniques, the rence of facial numbness or pares- pain relief is immediate and complete thesia correlated with the length of in a high percentage of cases, and the irradiated area. This study (one follow-up studies report a variable of the very rare randomized con- duration of pain relief, persisting in trolled trials of stereotactic radiosurgery about 70%, 60%, and 50% at 1, 3, and in trigeminal neuralgia) is very interest- 5 years, respectively.6,20 The success ing because it conveys strong evidence of ‘‘pulsed’’ radiofrequency, in con- that the root entry zone is the key spot trast, is not supported by evidence. In in the origin and maintenance of tri- fact, one study reported that in all geminal neuralgia. Unlike the other patients submitted to pulsed radio- types of intervention, the pain- frequency, the original pain returned relieving effect of gamma knife therapy by 3 months.79 The major risks of all per- is not immediate and generally re- cutaneous ganglion lesion procedures quires6to8weekstodevelop.

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FIGURE 3-8 Dropouts due to adverse events in 100 patients on carbamazepine and 100 patients on oxcarbazepine. Note that central nervous system (CNS) disturbances affected patients on carbamazepine far more frequently than patients on oxcarbazepine, whereas hyponatremia only affected patients on oxcarbazepine. Blood cells = white cells, red cells, or thrombocytes.

KEY POINT According to the 2008 AAN/EFNS facial hypesthesia persisting in 50% of h Microvascular guidelines on trigeminal neuralgia,6 at patients at 1-year follow-up.82 decompression requires 1 year after gamma knife therapy, Although microvascular decom- major surgery but complete pain relief with no medica- pression is the only causal cure and is the only causal tion occurs in up to 69% of patients. huge numbers of patients have under- intervention of This falls to 52% at 3 years. Facial gone this procedure, no reported trial trigeminal neuralgia numbness is reported in 9% to 37% of meets the minimal criteria of evi- and offers longer-lasting pain relief. patients (although it tends to improve dence to be considered in a Cochrane with time), and troublesome sensory Review.81 Microvascular decompres- loss or paresthesia is reported in 6% sion is the only type of surgery for to 13%, whereas anesthesia dolorosa trigeminal neuralgia that cannot be is practically absent. No complications done as an outpatient surgical pro- outside the trigeminal nerve have cedure. It requires general anesthe- been reported. The most recent sia, intubation, craniotomy, cutting Cochrane Review81 does not add to the dura mater, shifting the cerebellar the 2008 guidelines.6 A recent meta- hemisphere, and microscopy to ade- analysis of gamma knife interventions, quately visualize the nerves emerging however, found that, because about from the cerebellopontine angle. The 34% of patients do not reach 1 year of neurosurgeon may then disentangle pain relief, repeated administration of the looping artery and leave a small radiations were necessary. With the sponge to keep the pulsating artery increasing number of interventions, separated from the trigeminal root. the rate of success and the pain-free Naturally, a placebo intervention or time increase significantly. Unfortu- blinded operators are unthinkable. nately, toxicity also increases, with Importantly, in about 11% of patients

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT referred for this type of intervention, When the decision is difficult, the best h Percutaneous ganglion the surgeons do not find any neuro- option is referral to a large center that lesions and gamma 9,14 vascular compression or they find a is led by experienced neurosurgeons. knife are efficacious in mere contact that apparently is not Insufficient evidence exists to sup- the treatment of damaging the nerve. Most surgeons in port or refute the effectiveness of the trigeminal neuralgia these latter cases interpose the separat- surgical management of trigeminal and can be repeated in ing sponge anyway, but they report a neuralgia in patients with MS. The cases of relapse. greater rate of failure, hence the need author, however, believes that MS pa- to establish MRI criteria that ensure tients with evidence of drug-resistant that morphologic changes of the tri- trigeminal neuralgia should be offered geminal root are observed.14 the surgical option. The recent demon- Allowing for the lack of evidence- stration of the concurring pathophysio- based data, still the meta-analyses of logic role exerted by neurovascular the largest studies make microvascular compression would seem to favor the decompression the most efficacious choice of microvascular decompres- of the surgical interventions for clas- sion in the posterior fossa.52 However, sic trigeminal neuralgia: according to positive reports occur with all the the AAN/EFNS guidelines,6 90% of main types of intervention, including patients obtain pain relief. More than percutaneous ganglion lesions and 80% of patients will still be pain free gamma knife.54 at 1 year, 75% at 3 years, and 73% at 5 years. The average mortality associ- CONCLUSION ated with the operation is 0.2%. Up to The diagnosis of trigeminal neuralgia, 4% of patients incur major problems with or without concomitant continu- such as CSF leaks, infarctions, or hema- ous pain, must rely on clinical grounds tomas. Aseptic meningitis is the most only. Diagnostic tests are necessary common complication (11%). Diplopia to distinguish three etiologic catego- is usually transient, and facial palsy is ries: idiopathic trigeminal neuralgia rare. Sensory loss occurs in 7% of pa- (nothing can be found), classic tri- tients. The major long-term complication geminal neuralgia (an anomalous is ipsilateral hearing loss (Figure 3-9). vessel produces morphologic changes In conclusion, percutaneous gasserian of the trigeminal root near its entry ganglion lesions, gamma knife, and into the pons), and secondary trigem- microvascular decompression may all inal neuralgia (due to major neurologic be considered, with microvascular de- disease such as MS or tumors at the compression offering the longest dura- cerebellopontine angle). Oxcarbazepine tion of pain relief. and carbamazepine are still the first- When considering the choice of sur- choice medical treatment, although gical treatment, the treating neurologist many patients experience significant should be involved in a collaborative side effects, and those with concomi- fashion with our neurosurgical col- tant continuous pain respond less. A leagues and the patient. Specific char- new sodium channel blocker that is acteristics should also be considered, selective for the Nav1.7 receptor has such as how clear the neurovascular promise of efficacy without inducing compression is on MRI, whether the side effects related to CNS depres- patient also has involvement of the sion. Three categories of surgical in- first division, and whether the patient terventions (percutaneous ganglion is prepared to wait at least 1 month to lesions, gamma knife, and microvas- get the pain relief from gamma knife. cular decompression) are all very

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FIGURE 3-9 Complications of surgery for trigeminal neuralgia. CSF = cerebrospinal fluid; GKS = gamma knife radiosurgery; MVD = microvascular decompression; PGL = percutaneous ganglion lesions. a Many Class IV studies on gamma knife surgery report trigeminal sensory disturbances in 9% to 37% of patients. Reprinted with permission from Gronseth G, et al, Neurology.6 B 2008 American Academy of Neurology. neurology.org/content/71/15/1183.full.

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