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CRANIAL NEURALGIAS Zahid Bajwa, M.D.; Steve Scrivani, D.M.D., D.Med.Sc., and Anita H. Hickey, M.D 1 Advancements in various diagnostic capabilities have improved our understanding of the etiology and pathogenesis of the neuralgias of the face, head and neck since the last edition of this book was written. Recent modifications in the nomenclature have also occurred which reflect a more accurate organization and classification of the cranial neuralgias and facial pain. Although the nomenclature of these severe and often incapacitating pain syndromes remains controversial, immense efforts have been made to scientifically categorize these syndromes based on causal factors, when known, or strict diagnostic criteria, when causal factors are not known.(1,2,3) Although not perfect, this classification system continues to be refined and to serve as a valuable instrument to further advance the scientific understanding and treatment of these disorders.(4) The importance of accurate diagnosis and classification of these conditions is particularly critical as it pertains to treatment of many of the neuralgias for which successful medical and surgical treatments have been developed. Cranial neuralgias refer to paroxysmal pain in the distribution of a specific cranial nerve. Previous classifications separated facial pain into "typical", "atypical", and "secondary" neuralgias. Because a great body of the current literature continues to utilize these terms, it is important to understand the meaning of both the previously used nomenclature and the revised nomenclature.(2) Other features ascribed to the previous classification system are described in Table 1. The revised classification system utilizes the terms: "Classical" and "Symptomatic". The term classical refers to trigeminal neuralgia of unknown etiology. Classical rather than primary has been applied to those patients with a typical history even though a vascular or other source of compression or demyelination may be discovered during its course. The term symptomatic or secondary can then be reserved for those patients in whom a neuroma, tumor, multiple sclerosis or other cause has been demonstrated. The term, persistent idiopathic facial pain, has replaced atypical facial pain, in the taxonomy. This change reflects lack of a known mechanism, continued recognition of the potential contribution of multiple etiologic factors to this syndrome, and an emerging knowledge of the pathophysiology of diffuse pain syndromes previously not well understood.(5,6,7) This chapter is organized around the current classification of neuralgias of the cranial nerves and associated disorders beginning with classical trigeminal neuralgia. Emphasis will be made on updates in the classification, diagnosis and treatment of the cranial neuralgias and facial pain as pertain to the scientific literature and international consortium. A narrative bridge from past literature and understanding is included to enhance the reader’s understanding of more recent research, insights and therapeutic approaches. CLASSICAL TRIGEMINAL NEURALGIA (TIC DOULOUREUX) History Trigeminal neuralgia was described as early as the first century AD in the writings of Aretaeus. Treatments at that time included bloodletting and the application of bandages containing arsenic, mercury, hemlock, cobra and bee venom as well as other poisons. Eleventh century Arab physician Jurjani advanced the vascular compression theory as the causative factor of the severe pain and spasm of this syndrome.(9) The first clinical descriptions of trigeminal neuralgia in the European literature has been ascribed to Johannes Bausch in 1672 and John Locke in 1677. French physician Nicolaus André, who in 1756 described five cases of "unbearably painful twitch”, is credited with first recognizing this condition as a unique medical entity. It was André who coined the term tic douloureux, ("painful spasm"). English physician John Fothergill similarly published a full account of the syndrome and 2 presented the paper to the Medical Society of London in 1773 and thus the disorder has sometimes been referred to him.(9,10,11) Other historical names for trigeminal neuralgia include: prosopalgia and neuralgia of the fifth. In A Treatise on Neuralgia, published by Massachusetts physician E.P. Hurd in 1890, the following description of the clinical presentation of trigeminal neuralgia is found. Probably no more atrocious suffering is known...During the attack, the patients utter loud outcries, toss about on their beds and smite their heads. The muscles of the affected side of the face are often the seat of rapid contractions, convulsive shocks, which have given to this disease one of the names by which it is known,[tic douloureux}. These contractions may be limited to single groups of muscles, as the zygomaticae, or the frontal part of the occipito frontales…then the paroxysmal shocks diminish in frequency and intensity, and all becomes calm; the storm has passed, to be renewed again under the same form in a time not far distant. [This needs a reference](12) In the Nineteenth century, susceptibility to this condition was thought to be secondary to hereditary factors, (with "the ancestors of the neuralgic subject being either neuralgic or sufferers from hysteria, epilepsy or other neurosis"), in combination with other factors such as disease, intemperance or insufficient diet. Medical treatment was ineffective until the introduction of trichloroethylene inhalation in the 1920's. Prior to this, treatment in the late 1800's focused on advocating a nutritious diet, adequate sleep, hydrotherapy, vigorous exercise and moderation in all things. Patients were advised to avoid strain, reading and brain work, (which were felt to be instrumental in initiating an attack), as well as alcohol, tobacco and other stimulants. Successful non surgical treatment for treatment neuralgias was reported by such notable 19th century physicians as Wilhelm Erb and Duchenne de Boulogne. These included the use of electrotherapy in the form of interrupted current and galvanism.(11,12) Although early attempts at surgical treatment of trigeminal neuralgia, by Mareschal, surgeon to King Louis XIV, of France around 1750 and Veillard and Dussans in 1768, were unsuccessful, Bell and Magendie's clarification of the anatomy and function of the trigeminal and facial nerves in the early 19th century is thought to have contributed to subsequent effective surgical treatments for facial pain. Successful neurectomy of the inferior maxillary nerve was reported by Dr. Joseph Pancoast of Philadelphia in 1840 and in 1851. Dr. J.M. Carnochan described successful resection of the maxillary nerve and removal of Meckel's ganglion from the foramen rotundum to the infraorbital foramen. Subsequent surgical advances in technique were made by Horsley, Taylor and Coleman in 1891, (middle fossa approach), and Hartley and Krause in 1892, (sub temporal approach). Cushing’s modification to this approach, reported in 1900, involved approaching the trigeminal [Author confirm?yes/confirmed.] ganglion from below the middle meningeal artery. His contribution was credited with decreasing the mortality rate of the surgery to 5%. In 1921, Frazier suggested electrical stimulation to clearly define and spare the motor root and in 1928, Stookey recommended differential sectioning of the sensory fibers of only the affected divisions of the trigeminal nerve. In 1925, Dandy reported a novellateral suboccipital or cerebellar approach) which preserved the motor root and was associated with little blood loss. Because of his posterior fossa approach, he was able to observe vascular loops impinging on the root entry zone in many patients, and inferred that this was the cause of trigeminal neuralgia. (11,12,273)[You need to add some references for all of the excellent historical listings] In 1967, Peter Jannetta reported use of the posterior fossa approach with the aid of an operating microscope. .(21,22) [This needs a reference] He was able to confirm Dandy's observations of vascular loops compressing the root entry zone and subsequently performed a large series of successful surgical treatment of patients with trigeminal neuralgia using a technique that became known as microvascular decompression, (MVD). MVD involves decompression of the nerve by moving the offending vascular loop(s), which are then restrained with nonabsorbent Teflon felt. Due to its low complication and high 3 success rates, MVD has become the surgical procedure of choice for the treatment of intractable trigeminal neuralgia. The history of the medical and surgical treatments for trigeminal neuralgia has recently been thoroughly reviewed by Cole, Liu and Apfelbaum.(11,12,273) EPIDEMIOLOGY Several epidemiological studies have collected data on the incidence of trigeminal neuralgia during the last 60 years. Although there is some variation in the reported incidence, in all cases it continues to be reported as a rare neurologic disorder. A UK study by Brewis et al published in 1966 reported an incidence of 2 per 100,000 [reference ] (13). This number was thought to be low due to lack of inclusion of patients seen by Otolaryngologists. US studies by Kurtzke in 1982 and Katusic al in 1990 reported an incidence of 4 and 4.8 respectively, (age and sex adjusted per 100,000 per year). (13,14,15). A prospective UK study by MacDonald BK et al, reported an incidence of 8 per 100,000 per year.(16) The most recently published epidemiological study was also performed in the UK and reported an incidence of 26 per 100,000 per year between January 1992–April 2002.(17) This study reviewed patients diagnosed with trigeminal neuralgia by general practitioners rather than those referred to specialists. The incidence of trigeminal neuralgia has consistently been found to be higher in females, with a 1.74:1 female/male ratio. Onset is usually after age 40 with peak occurrence between ages 50 and 80. Occurrence of tic douloureux in patients younger than age 40 should raise suspicion of secondary causes such as tumor or multiple sclerosis. Trigeminal neuralgia occurs rarely in children. (table 2)(18,19) DIAGNOSTIC CRITERIA Clear and precise diagnostic criteria are essential for clinical communication and research. This is particularly true for a condition like TN, where there is no objective laboratory test to confirm the clinical diagnosis. The Sweet Criteria. White and Sweet [29, 30] helped resolve this confusion by articulating diagnostic criteria for TN that were both precise and succinct. Their criteria rapidly gained popular clinical acceptance. They identified five major clinical findings that, when present, established the diagnosis of TN.: 1. The pain in TN is paroxysmal. 2. The pain in TN may be provoked by light touch to the face. 3. The pain in TN is confined to the trigeminal zone. 4. The pain in TN is unilateral. 5. In a patient with TN, the clinical sensory examination is normal. The strength and importance of such diagnostic criteria became quickly apparent as effective TN therapies were introduced. Patients who met the above criteria strongly benefited from anticonvulsants and a number of specific surgical procedures. However, patients who did not meet all the above criteria rarely benefited. [31-34] 4 This was one of the first examples of a precise research/clinical definition of an important diagnostic syndrome. The criteria were a major advance that facilitated subsequent research and enabled early and accurate clinical recognition of the syndrome. Comments on the Sweet criteria. Despite the wide acceptance of the Sweet criteria, however, few studies have actually critically analyzed the scientific foundations of this, or any other, TN diagnostic scheme. In most cases, diagnostic criteria for clinical syndromes develop gradually, based on the shared knowledge of experienced practitioners. The Sweet criteria are an example of this type of consensus, empirical approach. The Pain in TN is Paroxysmal. Paroxysmal attacks of pain are the key feature, and invariantly the presenting complaint, of patients with TN. The pain has an electric shock-like quality. It is sudden in onset and often severe in intensity, usually resulting in a facial grimace. Most published descriptions of TN report a pain duration between one second and two minutes for each attack. However, this duration probably includes both the patient’s initial pain and immediate response to the attack. On more careful questioning, essentially all of the patients report an instantaneous electric shock sensation that is over in much less than a second. The pain is frequently described as a "lightning strike," an instantaneous electric jolt sensation. In patients who describe pain that lasts for one or two minutes, particularly those who report a gradual buildup and decrement of pain symptoms are very atypical in TN. Even though such patients may meet the other diagnostic criteria listed above, such patients deserve a very thorough evaluation. It's important to emphasize another diagnostic feature of the pain in TN: between the paroxysmal attacks of pain, patients are pain-free. Some patients with classical trigeminal neuralgia develop a persistent background pain in addition to their paroxysmal pain. This presentation is referred to as atypical trigeminal neuralgia in much of the past and current literature. Many studies report that these patients are significantly less responsive to pharmacologic and intervetional therapies than those with CTN. This may be due to central facilitation of trigeminal nociceptive processing in these patients in accordance with recent electrophysiological findings. (30) Patients with significant dull pain as part of their clinical presentation do not cleanly fit the diagnostic criteria for TN. On further evaluation, such patients often have a different syndrome, or more than one pain diagnosis. An additional syndrome reported initially in 1949 by Symonds is pretrigeminal neuralgia. In these patients, a dull aching or burning pain involving a part of the upper or lower jaw develops for hours, days or weeks and may be triggered by jaw movements or liquids. They may have several bouts of this pain with remissions for weeks months or years followed by sudden onset of the paroxysmal pain of classical trigeminal neuralgia which is responsive to carbamazepine and/or baclofen in most cases. Unfortunately, some patients undergo multiple dental procedures before the syndrome is recognized as an early sign of trigeminal neuralgia.(44,45,46) 5 It is worth commenting on the intensity of pain associated with attacks of TN. Many descriptions of the syndrome emphasize the severe intensity of pain associated with the disorder, to the point where "excruciating" pain becomes part of the diagnostic criteria. Pain is a personal, subjective experience. It is difficult to meaningfully gauge and compare pain intensity between patients and across diagnoses. The clinical report of pain severity reflects not only the sensory symptom, but also the patient’s psychological state and their cumulative past experience. Depression and "learned pain behavior" can amplify the subjective pain complaints of any patient with legitimate pain symptoms, including those of TN. The pain in TN may be provoked by light touch to the face. A TN “trigger zone” is a localized trigeminal sensory area (facial skin or oral cavity), often only a few millimeters in size, where low intensity mechanical stimulation (such as light touch, an air puff, or even bending a facial hair) can trigger a typical pain attack. Trigger zones are commonly present in TN [16], but are not essential for the diagnosis. However, if present, a trigger zone is virtually pathonemonic of TN. In two large series of patients with trigeminal neuralgia, trigger zones were reported to be present in 91%.(41,42) TN trigger zones are nearly exclusively found in the perioral region or nasolabial fold, and can be located in either the second or third trigeminal division. In occasional cases, a second division trigger zone can elicit pain that occurs exclusively in the third division. First-division trigger zones are rare.(figure 66-1) The detailed studies of Kugelberg and Lindblom [46] demonstrated a number of additional interesting features that are typical of TN trigger zones: 1. A low threshold stimulus provokes an attack more effectively than a noxious stimulus. 2. There is a short delay between the trigger point stimulus and the evoked pain response. 3. Low threshold trigger point stimulation demonstrates temporal summation. After a pain attack, the trigger zone becomes relatively refractory for several seconds. During the refractory period, trigger zone stimulation is ineffective. The "trigger zone" in TN is occasionally confused with the diagnostic "trigger point" frequently described in so-called myofascial pain disorders. The two findings are very different and should be easily distinguished by most, if not all clinicians. 6 The pain in TN is confined to the trigeminal zone. Pain paroxysms in TN are confined to the sensory distribution of the trigeminal nerve on one side. Patients who report significant pain that extends outside the trigeminal distribution do not have TN. Even within the trigeminal distribution, the location of pain attacks is circumscribed. The lancinating attacks of pain typical of TN most frequently occur in the third trigeminal division, radiating along the mandible. Less frequently, pain occurs in the second division, or includes both divisions. First-division pain is rare in TN. In individual patients, the pain attacks are "stereotyped." In other words, they share similar features, with the same quality, location, and intensity. In some patients, the location of typical paroxysmal pain can "drift" over time within the second or third trigeminal division. However, it is rare for individual patients to experience paroxysms of pain in different trigeminal locations. The pain in TN is unilateral. Paroxysmal pain attacks in TN are exclusively unilateral. Pain occurs on the right side of the face more often than on the left with predominance ranging from 59-66%. Reviews have reported a 3-5% occurrence of bilateral pain. Pain rarely occurs on both sides simultaneously. Rather, the painful paroxysms occur on one side for weeks or months and then, following a period of remission, occur on the opposite side,(34, 36, 37, 38). Pain occurring on both sides simultaneously or in the presence of an abnormal neurologic exam should raise concerns of a secondary etiology such as tumor or MS. (39, 40). Pccirremce pf spontaneous remission of pain for weeks, months or years is another feature of trigeminal neuralgia which may complicate accurate assessment of therapies. (35) The clinical sensory examination is normal in TN. A number of clinical series describe subtle impairment of facial sensation in a minority of patients with TN [16, 28, 46-48]. However, this deficit is not usually apparent at the bedside or on a standard clinical examination. A patient who demonstrates a trigeminal sensory deficit combined with pain reminiscent of TN should raise strong clinical suspicions of another underlying disease process affecting the trigeminal system. CLASSIFICATION At the present time, clinical cases of TN fall into two groups: "classical" and "symptomatic" forms of TN. “Classical TN” refers to the “idiopathic” syndrome, meaning that the underlying cause of the disorder is not known. Over 90% of TN patients fall in this category. Symptomatic TN identifies a group of patients that exhibit the clinical syndrome of TN as a symptom of another disease process. The most common disorders associated with symptomatic TN are multiple sclerosis and benign tumors of the Gasserian ganglion or trigeminal root. 7 This common clinical distinction between classical and symptomatic forms of TN is included in the recent International Headache Society diagnostic criteria for TN, discussed below. The ICHD-II diagnostic criteria. The International Headache Society recently established new clinical diagnostic criteria for TN as part of the International Classification of Headache Disorders, Second Edition (ICHD-II) [49]. These criteria have gained wide acceptance, and reflect a significant advance that should facilitate communication and stimulate research regarding TN. The ICHD-II establishes trigeminal neuralgia (diagnostic code 13.1) as a discrete clinical diagnosis under the general classification of "cranial neuralgias and central ca uses of facial pain (13.)." The diagnostic term "trigeminal neuralgia" replaces the earlier term "tic douloureux." The ICHD-II further subdivides TN into two disorders. "Classical trigeminal neuralgia (13.1.1)," is the most common, "idiopathic" form (although this classification also includes cases associated with vascular compression). "Symptomatic trigeminal neuralgia (13.1.2)," on the other hand, has the same key features of TN, but results from another disease process (such as multiple sclerosis or a cerebellopontine angle tumor). Classical trigeminal neuralgia 13.1.1 Classical trigeminal neuralgia is defined by IHS as: "…a unilateral disorder characterized by brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve. Pain is commonly evoked by trivial stimuli including washing, shaving, smoking, talking and/or brushing the teeth (trigger factors) and frequently occurs spontaneously. Small areas in the nasolabial fold and/or chin may be particularly susceptible to the precipitation of pain (trigger areas). The pains usually remit for variable periods." The ICHD-II lists the following diagnostic criteria for classical trigeminal neuralgia: A. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting one or more divisions of the trigeminal nerve and fulfilling criteria B and C: B. Pain has at least one of the following characteristics: 1. intense, sharp, superficial or stabbing 2. Precipitated from trigger areas or by trigger factors C. Attacks are stereotyped in the individual patient. D. There is no clinically evident neurological deficit. E. Not attributed to another disorder. Symptomatic trigeminal neuralgia 13.1.2 Symptomatic trigeminal neuralgia is defined by IHS as: “Pain indistinguishable from 13.1.1 Classical trigeminal neuralgia but caused by a demonstrable structural lesion other than vascular compression.” 8 The ICHD-II lists the following diagnostic criteria for symptomatic trigeminal neuralgia: A. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve and fulfilling criteria B and C B. Pain has at least one of the following characteristics: 1. Intense, sharp, superficial or stabbing 2. Precipitated from trigger areas or by trigger factors C. Attacks are stereotyped in the individual patient D. A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration. The above criteria are accompanied by two comments: There may be sensory impairment in the distribution of the appropriate trigeminal division. 13.1.2 Symptomatic trigeminal neuralgia demonstrates no refractory period after a paroxysm, unlike 13.1.1 Classical trigeminal neuralgia. Comments on the ICHD-II criteria. The ICHD-II consensus clinical criteria for trigeminal neuralgia represent an impressive effort that will undoubtedly facilitate uniform diagnostics, clear clinical communication, and research in TN around the world. Since the underlying basic mechanisms that cause the TN syndrome are not well understood, any diagnostic criteria or classification system has inherent limitations. Pain Characteristics Clinical pain has five major dimensions: location, quality, intensity, temporal pattern, exacerbating factors, and remitting factors. TN, like any other pain syndrome, is identified by a distinct pattern of findings across all these dimensions. The ICHD-II criteria group pain descriptors in a potentially confusing way. The ICHD-II definition requires least one of the following 2 criteria for a diagnosis of TN. 1. Intense, sharp, superficial or stabbing 2. Precipitated from trigger areas or by trigger factors However, the first criterion mixes intensity, location, and quality descriptors together. The second criterion includes exacerbating factors. It is difficult to appreciate the logic behind these criteria in a diagnostic algorithm. 9 Distinctions between classical and symptomatic trigeminal neuralgia. ICHD-II attempts to set clear criteria that define the classical and symptomatic forms of trigeminal neuralgia. This is more difficult than it might first appear. For example, ICHD-II defines 13.1.2 symptomatic trigeminal neuralgia as: “Indistinguishable from 13.1.1 Classical trigeminal neuralgia” (except for the presence of) “a causative lesion other than vascular compression demonstrated by special investigations and/or posterior fossa exploration.” As discussed at length in the next section, compression of the trigeminal root is a potential inciting injury that results in chronic neurologic changes producing the symptoms of trigeminal neuralgia. Compression by a cerebellopontine angle tumor might result in "symptomatic" TN by ICHD-II criteria. It is interesting to note that the exact same initial injury produced by a blood vessel would be classified as “13.1.1 classical trigeminal neuralgia." This aspect of the definition is uncomfortably arbitrary, and emphasizes the fact that the clinical criteria are not based on primary pathophysiologic mechanisms. Refractory periods. The presence of a “refractory period” between paroxysmal attacks is a consistent feature in TN and provides strong clues to the underlying pathophysiology of the disorder. It is interesting that the ICHDII criteria state: “13.1.2 Symptomatic trigeminal neuralgia demonstrates no refractory period after a paroxysm, unlike 13.1.1 Classical trigeminal neuralgia.” If the refractory period were reliably absent in symptomatic trigeminal neuralgia, that observation would be a strong argument that the basic mechanisms of classical and symptomatic TN are fundamentally different. There is no reason to think that the actual underlying pathophysiology of TN is fundamentally different in MS, CPA compression, or classical “idiopathic" TN cases. In fact, as discussed in the next section below, the limited pathologic studies on the trigeminal nerve in TN show surprising similarities in the vascular compression, tumor, and MS cases. In addition, the absence of a refractory period would provide a simple clinical indicator to distinguish which TN patients have MS or tumors. Unfortunately, patients with symptomatic trigeminal neuralgia are often truly indistinguishable clinically from those with classical TN. The large majority of these patients demonstrate a refractory period following an evoked paroxysm. Triggers. It’s important to note that the ICHD-II criteria for trigeminal neuralgia uses the terms "trigger area" and "trigger factors" instead of "trigger zone." The ICHD-II comments that "In some cases a paroxysm may be triggered from somatosensory stimuli outside the trigeminal area, such as a limb, or by other sensory stimulation such as bright lights, loud noises or tastes.” 10 This definition is significantly broader than the concept of “trigger zone” discussed above, and potentially strongly conflicts with much of the prior clinical and basic research on TN trigger zones. As noted above, the details of the clinical diagnostic criteria for TN should be considered a work in progress. Disagreements and confusion will always be present in such consensus criteria, until the underlying pathophysiology of the disorder is well established. Etiology and Pathophysiology The basic pathophysiology responsible for the signs and symptoms of TN is not known, although there is increasing evidence that partial injury to the Gasserian ganglion or trigeminal nerve roots may be an important initiating factor [19]. Any basic theory of TN would need to adequately explain the unique and characteristic features of TN [39,108], including: Stereotyped attacks of lancinating pain that occur in a limited part of the trigeminal territory; The absence of any significant motor or sensory deficit between pain attacks; The frequent presence of TN trigger zones that provoke pain attacks; The association of TN with a series of specific disorders, including: o benign tumors in the cerebellopontine angle or Gasserian ganglion; o multiple sclerosis The therapeutic efficacy of anticonvulsants; and The therapeutic efficacy of a variety of surgical procedures on the ganglion and nerve root. In the 20th century, Dandy, Gardner and Miklos recognized the presence of a groove or distortion of the trigeminal nerve root by vessels or rarely tumors.(11) Based on the tumorcompression evidence, Dandy [36] theorized in 1934 that compression by vessels or other structures adjacent to the nerve, might account for many cases of apparent "classical” TN.(35 SS reference) He proposed that the symptoms of TN might result from partial axonal injury and demyelination at the site of nerve compression. . Jannetta produced convincing evidence that this was the cause of TN by his large series of effective microvascular decompression surgeries using the operating microscope and demonstrated the absence of trigeminal nerve compression in patients undergoing suboccipital craniotomy for other reasons and in a series of fresh cadaver studies.(11,20,21) He also demonstrated that surgical decompression of the nerve root often effectively alleviates TN symptoms without producing any new sensory or motor trigeminal deficits[95, 125-128]. Jannetta’s review of 4400 operative procedures from 1969 to 1999 revealed a rostroventral superior cerebellar artery loop, compressing the trigeminal nerve either at the brainstem or distally, to be the most common cause of vascular compression. (22) Compression by the posterior inferior cerebellar, vertebral, and anterior inferior cerebellar arteries has been also been found. Other reported causes of compression of the trigeminal nerve have included meningioma, epidermoid cyst, arachnoid cyst, and schwannoma arising from the nerve root itself.(22) Malis proposed petrous ridge and fibrous dural band compression as a cause of TN and demonstrated successful alleviation of TN in a case series of 43 patients undergoing decompression of these fibrous bands. (24) Kerr and King further argued a peripheral versus a central mechanism for trigeminal neuralgia. Kerr's peripheral hypothesis, based on epidemiology, surgical resections, cadaver and animal studies, suggested that the paroxysmal neuralgic pain of trigeminal neuralgia with associated trigger zones is 11 consistent with minor mechanical or pulsatile compression superimposed upon predisposing axonal degenerative changes due to hypertension, atherosclerosis or disease such as multiple sclerosis. He also noted that with aging, replacement of the bony roof of the carotid canal with connective tissue is known to occur. He argued that that these degenerative bony changes would permit pulsatile contact with areas of the ventral ganglion which correlate with the anatomical area in which most trigger zones are known to occur. . [This needs to be referenced- ?] ( 21,25) King argued a central etiology for trigeminal neuralgia based on injections of alumina gel into the spinal nucleus of the fifth nerve in cats which resulted in a syndrome of dysesthesia of the face with over reaction to tactile stimulation.(21,25) The compression theory How does mild compression of the trigeminal nerve result in TN? Cutting or compressing the trunk of an undamaged nerve elicits, at most, only a brief discharge in sensory axons [29-30]. However, following a partial nerve injury, a cascade of changes takes place over time in the sensory neurons as part of the repair process [19, 29-33]. It seems likely that several of these changes contribute to the signs and symptoms observed in clinical neurogenic pain disorders, including TN. Focal areas of axonal demyelination due to nerve compression generate spontaneous action potentials that travel in either direction along the nerve. In some cases, single action potentials may evoke sustained afterdischarges [34-36]. Spontaneous activity, evoked afterdischarges, and abnormal coupling between primary afferents may all be important mechanisms in TN. Devor’s group [37] analyzed trigeminal root surgical biopsy specimens taken from the site of presumed vascular compression. Their cases again showed evidence of demyelination and close apposition of axons in the area of compression. These anatomic findings demonstrate the right anatomic substrate for ephaptic transmission [32]: a substantial loss of myelin, as well as abnormal close apposition of trigeminal axons in the area of injury. Love[38] has examined trigeminal nerve specimens from six MS patients undergoing rhizotomy for intractable TN, obtaining data that strongly supports the above view. In all of Love’s MS cases, the trigeminal roots revealed areas of demyelination and axons in close apposition. These findings are similar to the changes seen in TN cases with vascular compression, even though the etiology of nerve injury in MS is quite different. It should also be noted that ephaptic crosstalk provides a plausible mechanism to explain the "trigger zone” phenomenon. In TN, often a minimal intensity cutaneous stimulus, (such as hair-bending, drinking a cool liquid, or air blowing over a small area of skin), will reliably evoke typical TN pain attacks. The trigger phenomenon is strongly consistent with interaction between large, rapidly conducting cutaneous afferents, and the smaller caliber A-delta and C- fibers that carry pain information. Ephaptic interaction between low threshold, large caliber sensory afferents and nociceptive sensory axons could account for this observation. . Experimental studies also indicate that this anatomical arrangement favors the ectopic generation of spontaneous nerve impulses and their ephaptic conduction to adjacent fibers, and that spontaneous nerve activity is likely to be increased by deformity of the nerve and frequently associated pulsatile vasculature. (27,28,29,30) Based on these morphologic and physiologic changes following partial nerve injury, Devor [19, 33, 37] has proposed an "ignition hypothesis" to explain the principal signs and symptoms in TN. In this model, a partial injury to the trigeminal roots or ganglion results in a group of hyperexcitable and functionally linked primary sensory neurons. The spontaneous or evoked discharge of individual 12 neurons can quickly spread by ephaptic and other means to excite an entire population of adjacent sensory neurons, resulting in the sudden jolt of pain characteristic of TN. This model is attractive, not only because it explains many of the key features of TN listed at the beginning of this section, but also because it encourages specific, testable hypotheses that should stimulate advances in both basic science and clinical investigation related to TN More conclusive evidence of the peripheral versus central etiology of TN can be found in recent electrophysiological studies. One such recent study has revealed evidence of peripheral damage to small fibers of the trigeminal nerve near the root entry zone in the brainstem due to demyelination and axonal degeneration or isolated advanced axonal damage on the symptomatic side in patients with CTN. In patients with CTN and concomitant chronic facial pain, facilitation of central trigeminal processing at the supraspinal level was found. This is consistent with divergent results of MVD in these two groups of patients. Outcome data from MVD in patients with CTN shows excellent or good pain relief in 97% immediately postoperatively and in 80% of those with 5-year follow-up. In patients with TN and concomitant persistent facial pain, (previously defined as "atypical"), only 51% show good or excellent pain relief at 5 years.(30.31) Pre- and post-operative electrophysiological recording sessions revealed that relief of pain correlates with normalization of previously prolonged trigeminal reflex responses. Electrophysiological testing has also been able to differentiate CTN from STN with a high degree of sensitivity and specificity, (92% and 95%).(32,33) Although not practical for routine patient diagnostic purposes, this research is helpful in understanding the decreased response rates in these distinct groups of patients. Although substantial advances have been made in our understanding of the pathophysiology of TN over the past two decades, it's important to emphasize that many basic questions and problems remain and to re-emphasize that the etiology and pathophysiological mechanism for TN is still unknown. Problems with Current Theories. Although substantial advances have been made in our understanding of the pathophysiology of TN over the past two decades, it's important to emphasize that many basic questions and problems remain. A few of these include: There is no objective test for TN. The diagnosis of classic TN is based on a history of characteristic symptoms, in the absence of any objective pathology or clinical exam findings. The lack of an objective test to confirm the diagnosis is a significant stumbling block for research and therapy. In other common painful compression neuropathies (such as carpal tunnel syndrome or lumbar disc herniation), clinical electrophysiologic studies (including nerve conduction, EMG, and evoked responses) demonstrate physiologic changes that at least partially correlate with clinical findings. These tests have substantial value for diagnosis, clinical correlation, and research. However, at the present time there are no physiologic tests that sufficiently correlate with TN symptoms to make them helpful in the diagnosis or investigation of TN. Recent studies demonstrate fMRI abnormalities in patients with TN. These findings are encouraging and the present authors believe this line of investigation may prove useful in the near future. 13 TN patients have no clinical sensory abnormality. Many forms of clinical or experimental nerve compression commonly result in a sensory deficit. If nerve compression is an important factor in the pathophysiology of TN, why isn't a trigeminal sensory loss more commonly found in the disorder? This is an obvious, significant concern. However, for unclear reasons, a nerve compression injury producing facial pain does not appear to produce a sensory deficit in the trigeminal system as readily as it does at spinal levels. For example, in a retrospective study of facial pain patients with CPA meningiomas, Nguyen et al .[99] found very few patients who exhibited an associated sensory deficit. The Vos, Maciewicz et al. [152] infraorbital nerve compression model discussed above is also notable for an absence of any sensory loss, despite major evidence that the nerve injury results in a neurogenic pain disorder. These observations are particularly interesting since the physiologic changes following experimental nerve compression (ectopic impulse generation and afterdischarges) are most prominent in large, myelinated sensory fibers rather than the small diameter fibers that code for pain. Large myelinated sensory afferents convey light touch, joint position, and muscles spindle information. It is surprising that nerve compression would result in a painful disorder without evidence of large fiber damage, such as paresthesias or sensory loss. The lack of sensory deficit in patients with TN remains a puzzling, and very interesting feature of the disorder. Trigeminal compression does not produce TN in animals. The Vos animal model discussed above [152, 153] provides strong experimental evidence that chronic, mild compression of the infraorbital nerve results in a trigeminal neuropathic pain disorder. However, the experimental model also shows that localized allodynia and hyperalgesia are consistent findings following ION compression; these sensory abnormalities are virtually never found in human clinical TN. The Vos animal model is potentially more consistent with the clinical findings of human painful trigeminal traumatic neuropathy. It's appropriate to emphasize that much of the above criticism regarding TN is based on a comparison with other neuropathic pain disorders. However, most of these other disorders result from nerve injuries that are peripheral to the sensory ganglion; TN seems to result from injuries to the segment proximal to the brain (the central segment and dorsal root entry zone). The biology of the peripheral and central trigeminal sensory axons segments is quite different. It's possible that the unique features of TN may, in some fashion, result from selective chronic compression of the central trigeminal axon segments. 14 .. Differential Diagnosis The diagnosis of Trigeminal Neuralgia is essentially clinical. The importance of differentiating classical trigeminal neuralgia from symptomatic TN and other causes of facial pain is of great relevance in treating underlying disease or lesions and for instituting effective medical or surgical therapy. This requires a thorough history to obtain the patient's detailed description of defining characteristics, frequency and duration of pain, exacerbating factors, presence or absence of triggers and associated symptoms. A complete physical exam is necessary to confirm the presence or absence of neurologic deficits. Appropriate tests, including more advanced testing with CT or MRI/MRA is often indicated to confirm the suspected diagnosis and exclude secondary causes. Since trigeminal neuralgia is itself a rare disease, rare presentations of other disease processes fulfilling the diagnostic criteria of trigeminal neuralgia may require close examination. Reports of rare cases of sinusitis presenting as classical trigeminal neuralgia involving first and second division of the trigeminal nerve have been reported with one report of fatal progression in a diabetic patient. (47,48) Since involvement of the ophthalmic branch occurs in less than 5% of trigeminal neuralgia patients, a high degree of suspicion is indicated in such cases. As the example above illustrates, it is important to differentiate classical and symptomatic TN since STN may be secondary to a progressive lesion or disease process. Expedient treatment of the underlying disease process or lesion in these cases may limit patient morbidity and mortality and improve overall patient outcome. Although most patients with malignant and benign tumors present with sensory deficit or persistent idiopathic facial pain, the literature does contain reports of patients with tumors initially presenting with TN and no neurologic deficits. Nguyen, Maciewicz and colleagues [17 ] at the Massachusetts General Hospital evaluated patients with facial pain and atypical findings and found cerebellopontine angle tumors in 4%. They reported three tumors: meningiomas, with variable pattern of cranial nerve V, VII, VIII deficits; acoustic neuromas, with primarily cranial nerve VII deficits; and epidermoid tumors, with few signs or symptoms other than facial pain. Cheng, Cascino, and Onofrio [16] at the Mayo Clinic reported a “Comprehensive Study of Diagnosis and Treatment of Trigeminal Neuralgia Secondary to Tumors.” They evaluated 5,058 patients from 1976-1990 with the diagnosis of TN in 2,972 patients. Tumors were found in 296/2,972 (9.95%), consisting of meningiomas, schwannomas, pituitary tumors and others; glioma, lymphoma, arachnoid cyst, and squamous cell carcinoma. Neurological deficits were seen in 47%. Mathews and Scrivani [18], at the Massachusetts General Hospital reported on 575 patients from 1992-1996 with chronic neurogenic facial pain They also noted structural pathology in many patients that fit the diagnosis of TN. Brainstem auditory evoked potential and blink reflex testing are sensitive methods for examining patients with TN. When the patient's neurologic exam is abnormal or if the patient does not respond to standard medical therapy, increasingly sensitive methods of imaging with computed tomography or magnetic resonance imaging and magnetic resonance angiography result in accurate diagnosis in almost all cases. (49,50,51,52,53) Multiple sclerosis is another common cause of symptomatic TN, presumably probably resulting from a demyelination plaque at the level the trigeminal root as it enters the brainstem. MS should be considered in any person under 50 who presents with TN, since the average age of patients with classical TN is usually older. Bilateral TN is also strong evidence for multiple sclerosis. Multiple sclerosis often goes undiagnosed in patients who have relatively mild or infrequent exacerbations. A TN evaluation can be the first opportunity for the clinician to diagnose MS. 15 The cranial neuralgias covered in greater depth later in this chapter must also be differentiated from trigeminal neuralgia. Glossopharyngial neuralgia presents with paroxysmal, electrical pain, spontaneous remissions, and triggers associated with swallowing, chewing, coughing and talking in some patients. Pain occurs most frequently in the ear, tonsils, larynx and tongue and may radiate to the neck, shoulder or face. In less than 10 % of cases there is an association with trigeminal neuralgia. Glossopharyngial neuralgia is also rarely found in patients with multiple sclerosis.(54) Intense and stabbing pain localized in the depth of the ear canal is also described in by patients with geniculate ganglion or nervus intermedius neuralgia (NIN), a rare disorder affecting the sensory branch of the facial nerve. Other cranial neuralgias which may be confused with TN include:"Tic convulsif" and hemifacial spasm. Patients with "tic convulsif" present with severe otalgia combined with unilateral facial spasm. This rare neuralgic disease is thought to be due to vascular compression of the sensory and motor components of the facial nerve at their junction with the brainstem. Hemifacial spasm is a neuralgia involving the facial nerve which is characterized by intermittent, involuntary, irregular unilateral, contractions of muscles supplied by the ipsilateral facial nerve. (55, 56,57) Pain arising from a group of disorders known as trigeminal autonomic cephalgias may also be confused with trigeminal neuralgia. These include cluster headaches, chronic paroxysmal hemicranias and short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing, (SUNCT). Knowledge of their epidemiology and a careful history will assist with accurate diagnosis. Cluster headache pain is unilateral and usually occurs in the ocular, frontal and temporal areas, (though it may occur in the infraorbital and maxillary regions). It usually presents initially in men who are between 18 and 40 years old. Pain is severe, constant, stabbing, burning and throbbing with associated ipsilateral ptosis, miosis, tearing and rhinorrhea. Bouts often occur for several weeks to months with 1-3 attacks in a 24 hour period. Patients will not infrequently be woken from sleep with an attack. Pain-free intervals of several months may occur between bouts of attacks. These headaches tend to respond to ergot preparations, prednisone and methysergide. (58) Chronic Paroxysmal hemicrania usually occurs in women. It generally involves the ocular, frontal, and temporal areas. Occasionally it may involve the occipital, infraorbital, aural, mastoid and nuchal areas on the same side. Attacks vary in frequency in duration but may last 5-45 minutes. Pain is excruciating and is associated with ipsilateral conjunctival injection, lacrymation, nasal stuffiness and rhinorrhea. These headaches respond well to indomethacin. (59,60) [This needs a reference] Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT ) is a rare syndrome which typically affects males between age 23 and 77years of age. It is characterized by unilateral burning, stabbing or electric pain which is usually near the eye. Episodes generally last from 15 to 120 seconds and multiple episodes can occur daily. Patients present with cutaneously triggered attacks in up to 75% of cases. These attacks are differentiated from trigeminal neuralgia by lack of a refractory period and presence of associated conjunctival injection, tearing, rhinorrhea, and facial sweating or flushing. As in trigeminal neuralgia, primary and secondary forms occur. Secondary forms may be due to cerebellopontine angle arteriovenous malformation, infection and pituitary tumors. (61,62) Painful opthalmoplegia such as seen in Tolosa-Hunt syndrome, ocular diabetic neuropathy, ophthalmic herpes zoster and opthalmoplegic migraine must also be differentiated from trigeminal neuralgia. Tolosa-Hunt syndrome is a painful opthalmoplegia due to a granulomatous inflammation in the 16 cavernous sinus. It is characterized by episodic unilateral or bilateral orbital pain associated with paralysis of one or more of the third, fourth or sixth cranial nerves. Involvement of the V2 and V3 divisions of the trigeminal nerve, the optic nerve and the facial nerve has been reported. The pain is typically described as steady gnawing or boring. Spontaneous resolution may be followed by remissions and relapses of symptoms. Involvement of the optic, facial, acoustic or trigeminal nerves has been reported. Treatment with corticosteroids results in resolution of pain and paresis in most cases within 72 hours. Failure of response to steroids or recurrence of symptoms should prompt further work-up. Ocular diabetic neuropathy may present as eye and forehead pain associated with ocular cranial nerve paresis, (usually CN III). As in other diabetic neuropathies, pain improves with glucose control, treatment with tricyclics and anticonvulsant medications. Herpes Zoster involving the trigeminal ganglion affects the ophthalmic division in the majority of cases. Ophthalmic herpes may be accompanied by palsies of the 3rd, 4th and/or 6th cranial nerves or with facial palsy. Burning pain, sometimes accompanied by neuralgic pain is followed by vesicular eruption typically within 7 days. Pain may resolve or persist as post herpetic neuralgia. Opthalmoplegic migraine is a rare clinical entity presenting as recurrent migraine like headaches accompanied by paresis of one or more of the ocular cranial nerves in the absence or other intracranial lesion. There may be a latent period of up to 4 days from onset of headache to onset of ocular cranial nerve paresis. Demonstration on magnetic resonance imaging of thickening and enhancement of the cisternal part of the occulomotor nerve in these patients suggests the etiology of recurrent deyelinating neuropathy. (2) Other common causes of facial pain include pain caused by sinusitis or other inflammatory conditions involving the eyes; tumors of the nose or sinuses, disorders of the teeth, jaws or related structures such as TMJ pain and posttraumatic pain of the peripheral branches of the trigeminal nerve. Sinusitis presents with pain involving the periocular, frontal nasal and maxillary areas. It is generally described as deep and constant and is associated with purulent discharge, fever and fullness of the nose and ears. CT reveals opacification of the sinuses. In older patients or immunocompromised individuals, tumors or mycoses should be ruled out. (63) Pain related to the teeth is often triggered by chewing or by hot, cold, sweet and sour substances. It may have occasional sharp and shooting characteristics but usually will also have a diffuse, continuous aching, throbbing or burning component which is difficult to localize. This type of pain is also differentiated from TN by lack of trigger zones or periods of spontaneous remissions. TMJ pain and myofascial pain related to the jaw is described as aching, burning or cramping pain associated with use of the jaw or muscles of mastication. Clicking and other signs of joint dysfunction along with radiation to the scalp and neck are associated features.(64,65) These are all discussed in further detail in the facial pain chapter of this text. Trauma to peripheral branches of the trigeminal nerve after surgery, blunt or penetrating trauma or dental procedures generally presents as constant pain with burning, tingling or stabbing components as well as a dull background pain. In one study comparing patients with facial pain after nerve injury to patients with pain of spontaneous origin, found decreased temperature and tactile thresholds and abnormal temporal summation of pain in patients with nerve injury but not in patients with spontaneous pain. (66) Persistent idiopathic facial pain is typically described as a continuous, dull ache that is poorly localized. It fluctuates in intensity and is generally unresponsive to analgesics. It occurs most frequently in women with a mean age of 44.6 years and range of 17-87 years. Most of these patients have multiple diagnosis including depression, headache, neck and back pain and irritable bowel disease. Neurologic and radiologic exams are normal by definition. These patients often have undergone multiple dental 17 procedures.(67) Treatment of Trigeminal Neuralgia Medical management The use of the antiepileptic medications for the treatment of trigeminal neuralgia was first suggested by Bergouigan in 1942.(68) His trial of phenytoin in these patients was based on Trousseau's theory that the paroxysmal pain of trigeminal neuralgia was similar to the paroxysmal brain activity occurring in patients with epilepsy.(69) The medical therapy of trigeminal neuralgia is based on the efficacy of drugs that have undergone double–blind evaluation. This is particularly important in light of the need to obtain expedient relief of the excruciating pain of the paroxysms suffered by these patients with proven therapies. Randomized controlled trials are essential in the evaluation of the treatments for TN. Because of the occurrence of unpredictable periods of prolonged spontaneous remission, there is a greater likelihood of attributing successful treatment of this disease to ineffective agents. Surgical consultation should be sought early for patients with structural lesions and in patients refractory to medical treatment. For patients unresponsive to medical therapy who are not good surgical candidates due to coexisting medical conditions, treatment with radiation or percutaneous therapies may be effective. Of the medications studied in the treatment of TN, carbamazepine is considered the drug of choice according to the European Federation of Neurological Societies and the Quality Standards Subcommittee of the American academy of Neurology.(70) Current evidence suggests that oxcarbazepine should be the first line agent in patients with intolerable side effects, or inadequate pain control with carbamazepine.(70) [This needs a reference]The combination of Carbamazepine with Baclofen or lamotrigine has been shown to be effective in cases where patients do not respond to carbamazepine alone or in whom it loses efficacy. .(70) [This needs a reference] Carbamazepine is a tricyclic antiepileptic agent which acts at the same site targeted by the tricyclic antidepressant imipramine in the cytochrome P450 isoenzyme center. Carbamazepine [Authorplease revise – this must be a typo – you migt say that CBZ is a tricyclic agent?] slows the recovery rate of voltage-gated sodium channels, modulates activated calcium channel activity and activates the descending inhibitory modulation system. Although it is one of the oldest antiepileptic drugs and many new drugs in this class exist with fewer side effects and fewer drug-drug interactions, 4 placebocontrolled studies and a systematic review have established its effectiveness in reducing the intensity and frequency of attacks and the number of triggers with a combined number needed to treat (NNT) of 1.7.(71-75) Although carbamazepine has been shown to have an initial response rate of over 70% in TN patients, one long term study which evaluated its efficacy over a 16 year period, reported that by 5-16 years only 22% of participants continued to have effective relief with 44% requiring additional or alternative treatment.(76) The recommended starting dose is 100 to 200 mg twice daily with gradual increase by 200 mg until intolerable side effects or pain relief occurs. The typical maintenance dose of carbamazepine is 600 to 1200 mg daily in divided doses. Side effects occur initially in up to 40% of patients initially but generally subside in most patients after a few weeks. The biologic half-life of carbamazepine is 30-35 hours when first administered. This decreases to 12 hours with autoinduction of liver enzymes with occurs after a few weeks. Since pain relief appears to be closely related to serum level, slow-release formulations may be effective in maintaining serum drug concentration.(77 ) The efficacy of carbamazepine is limited by side effects that include drowsiness, dizziness, constipation, nausea and ataxia. More severe adverse effects include rashes, leucopenia, abnormal liver function, and rarely, aplastic anemia and hyponatremia due to inappropriate secretion of ADH. Compared with placebo it has a number needed to harm (NNH) of 3. Monitoring of CBC, liver function 18 and sodium is recommended. (78) Oxcarbazepine is the 10-keto analogue of carbamazepine. A large double-blind, crossover trial comparing oxcarbazepine with carbamazepine and three multicenter, double-blind randomized trials comparing oxcarbazepine to carbamazepine revealed equal efficacy with fewer adverse effects. Tolerability was reported as "good" to "excellent" by 62% of patients receiving oxcarbazepine, compared with 48% of patients receiving carbamazepine.(79-80) Lamotrigine is also a relatively new anticonvulsant drug which decreases repetitive firing of sodium channels by slowing the recovery rate of voltage-gated channels. In a small double-blind crossover RTC evaluating patients on carbamazepine or phenytoin who were refractory to treatment with these medications, lamotrigine (400 mg) versus placebo increased the number of patients who improved after 4 weeks of treatment.(81) A case series also suggests its efficacy as monotherapy for TN. Side effects include dizziness, constipation, nausea and drowsiness. Stevens-Johnson's syndrome has been reported to occur in 1 in 10,000 patients taking lamotrigine. Its utility as a single agent may be limited by its long titration schedule.(82,83) Phenytoin is an older anticonvulsant with a molecular structure similar to the barbiturates. It acts by blocking sodium channels in rapidly discharging neurons and by inhibiting presynaptic glutamate release. Although it is has been used longer than any other antiepileptic drug in the treatment of trigeminal neuralgia, there are no controlled trials supporting its efficacy. Uncontrolled observations report that it is effective in relieving symptoms in 23 of 30 patients and when 3-5 mg/kg is given intravenously for acute therapy.(84,85,86) Phenytoin interacts with many drugs including digoxin and warfarin. Severe rashes can occur in 1 of 10 to 20 patients. There is also a possibility of rise in blood glucose, hepatotoxicity, and gingival hyperplasia and megaloblastic anemia. Fosphenytoin, a prodrug of phenytoin that is better tolerated intravenously, also appears to be effective in acutely ill patients.(87) Baclofen is an analog of the neurotransmitter gamma-aminobutyric acid. Its effectiveness in the treatment may be due to depression of excitatory synaptic transmission in the spinal trigeminal nucleus. (88) In three small RCTs, baclofen was shown to be effective as both monotherapy and add-on therapy to carbamazepine in the treatment of patients with TN.(89-91) The starting dose is 5 to 10 mg TID, with gradual titration to a maintenance dose of 50 to 60 mg per day. Sedation, dizziness, and dyspepsia can occur with treatment. The dose should be adjusted in patients with decreased renal function since baclofen is excreted primarily by the kidneys. Baclofen has CNS and cardiovascular depressant effects and thus careful titration should occur in patients on other sedating medications and on antihypertensive agents. Antidiabetic medications may need to be adjusted secondary to increases in blood glucose. Baclofen should be discontinued slowly since seizures and hallucinations have been reported with upon withdrawal. Other medications which have shown efficacy in recent trials include subcutaneous sumatriptan and intranasal lidocaine. Two randomized, placebo controlled crossover studies with a total of 38 patients show significant relief of painful paroxysms after subcutaneous sumatriptan but not placebo. Continuation of oral sumatriptan, 50 mg PO BID, resulted in continuous analgesia following the subcutaneous injection in one of the studies.(92,93) Intranasal 8% lidocaine spray was examined in twenty-five patients with V2 division TN in a RCT crossover study with resulting moderate or better pain relief lasting from 0.5-24 hours with lidocaine but not placebo.(94) Uncontrolled observations and case studies have shown efficacy in the treatment of TN with valproic acid, clonazepam and pimozide. The efficacy of pimozide is severely limited by its significant side effects which include parkinsonism, mental retardation and memory impairment.(95-98) The newer anticonvulsant drugs gabapentin and topiramate have been shown to be effective in the treatment of neuropathic pain however, there is little evidence of their effectiveness in the treatment of TN. Small 19 case series report their effectiveness in the treatment of symptomatic TN secondary to MS.(99-101) A case report and case series demonstrate statistically significant relief of refractory TN with injection of botulinum toxin, 16-100 units,(102,103) and intravenous lidocaine, in doses ranging from 2 to 5 mg/kg body weight resulted in partial or complete relief of pain paroxysms provoked by vibratory symptoms. (104,105) In summary, the current literature supports carbamazepine as first-line therapy for TN. Patients with symptoms that are refractory to CBZ monotherapy or who have intolerable side effects should be given oxcarbazepine as first line therapy. Those patients who do not respond to monotherapy may benefit from combination therapy with gabapentin, lamotrigine, topiramate or baclofen. The newer anticonvulsant medication, pregabalin, has been shown to be effective in treating neuropathic pain; however its use has not been reported in patients with trigeminal neuralgia. Intravenous phenytoin, fosphenytoin, lidocaine, subcutaneous sumatriptan or botulinum toxin injections may be effective in refractory cases of TN. Due to reports of spontaneous intermittent or permanent remissions of TN; periodic withdrawal of medications is warranted in patients who have prolonged pain free periods on oral medications. Treatment of Acute Attacks Occasionally, patients may present in acute attacks, with frequent spontaneous, or easily triggered, high intensity jolts of pain. In this situation, some form of acute intervention is warranted because the patients functioning is generally severely affected by the pain attacks and if it continues, may alter their ability to be able to properly eat or drink. In such cases, the present authors have had some success with local anesthetic trigeminal division nerve blocks typically with a long-acting local anesthetic (bupivicaine). Occasionally, the application of a topical amide local anesthetic preparation (lidocaine 2-5%) may be effective. However, there is little good data that shows that local anesthetic applications are consistently effective in stopping acute attacks and/or eliminating recurrence of pain after the duration of the applied anesthetic. Further, some patients may benefit from intravenous administration of fosphenytoin (Cerebyx), valproic acid (Depacon), or lidocaine. These infusions need to be conducted in a carefully monitored setting with appropriate medical attention and emergency equipment available (outpatient surgical center or in hospital). Nerve Blocks Local anesthetic by injection or infusion has been used for diagnostic purposes and for temporizing treatment in patients with unbearable pain refractory to medical therapy and awaiting MVD.(106) No controlled studies of nerve blocks for relief of TN have been reported. Small case series include significant reduction of pain and triggers in 5 elderly patients for a median of 2 months subsequent to injection of infraorbital nerve in patients with second division TN with combination of 4% tetracaine dissolved in 0.5% bupivicaine. Another study looking at relief of pain following injection of the infraorbital nerve, [Is this at the same infrarbital location?] reported greater than 3 months of relief with 4% tetracaine and 0.5% bupivacaine (compared to 3 days or less with 0.5% bupivicane or 1% mepivacaine alone,),(107,108 ) Similar pain relief and duration was reported following a series injections of symptomatic peripheral trigeminal nerve branches [Which ones?], in patients with TN, with a combination of ketamine, morphine, and bupivacaine.(109 ) A case report of stimulator guided mandibular and maxillary division nerve blocks [Which 20 Nerves?] using a combination of lidocaine, bupivacaine, clonidine and fentanyl at monthly intervals for 1 year in 2 patients describes prolongation of relief after 3 months and pain free status with no recurrence at 9 month follow up. No sensory or motor disturbances were reported.(110) Peripheral injections are of value in elderly patients who have not responded to medical or other surgical therapies. Standard precautions to avoid intravascular injection of drugs should be taken and care should be taken when performing V3 and V3 blocks. Total brainstem anesthesia with respiratory arrest following extraoral trigeminal V2-V3 blocks has been reported.(111) Careful aspiration, flouroscopic guidance when available and use of contrast, (when no contraindication exists), and digital subtraction , can decrease the risk of intravascular or intrathecal injection. Controlled studies are needed to validate the efficacy of nerve blocks in the treatment of trigeminal neuralgia. Neurolytic Block Alcohol, phenol or glycerol injection has long been reported in the treatment of trigeminal neuralgia. Percutaneous gangliolysis using glycerol is discussed under surgical techniques. A retrospective case audit of patients who received peripheral alcohol injections for trigeminal neuralgia from 1994-1999 found a mean duration of effect for of 11 months.(112) In a comparison of efficacy of 68 peripheral alcohol blocks with 22 peripheral glycerol injections and peripheral cryotherapy, peripheral alcohol injections gave complete relief for a median of 13 months which compared to cryotherapy. Glycerol injections provided a mean of 7 months of pain relief.(113) A retrospective analysis of 157 cases of intractable idiopathic trigeminal neuralgia treated with peripheral glycerol injections reported an initial 98% success rate with 60 patients having recurrent pain between 25 and 36 months. The study reports complete or near complete pain relief in 154 patients at 4 years, (with inclusion of patients with recurrent pain who were reinjected).(114) Post injection facial swelling, discomfort numbness and are reported complications of alcohol injections. More serious complications occurred in 3 of 413 injections over a 20 year period.(115) A small case series of sixty peripheral injections in 18 patients of the infraorbital, supraorbital and mandibular nerves using 10% phenol in glycerol reported and initial 87% initial marked or total pain relief with a median of 9 months of continued relief. Most patients with recurrent pain requested a repeated procedure rather than surgery or a ganglion nerve block. No serious complications or dysesthetic pain was reported. In patients with facial sensory loss, sensation was recovered within 6 months and was well tolerated. (116) [Authors- do you think there should be a statement about potential post injection dysaesthesia or deafferentiation?] SURGICAL THERAPY Surgical therapies are aimed at either damaging or destroying pain transmitting nerve fibers or relieving pressure on the nerve from vascular loops, fibrous bands or mass lesions. Radiation therapy may relieve pain in patients who are not surgical candidates and who are refractory to medical management of TN. Microvascular decompression Microvascular decompression is performed under general anesthesia using a microscope to visualize the trigeminal nerve as it leaves the pons via a suboccipital craniectomy. Compression of the nerve by a vein or artery is relieved by repositioning the artery or coagulating the vein. Although microvascular decompression is invasive, it is associated with the best long term outcome and overall mortality and complication rates are low. A recent analysis of long-term follow-up data of 1,324 patients with TN who underwent MDV between 1976 and 2000 revealed an increase in the post operative cure rate from 92.9% to 96.7% in patients operated on after 1986. Incomplete cure rate dropped from 7.1% to 3.3% and recurrence rate decreased from 10.2 to 6.5%.(117) Barker et al [128] present the long-term results of 21 1185 patients who underwent MVD for medically intractable TN during a 20 year period. Of the 1185 patients, 1155 patients (97%) were followed for 1 year or more after the operation. The median follow up was 6.2 years. Most postoperative recurrences took place within the first 2 years after surgery. Thirty percent of patients had recurrences of tic pain during the study period, and 11% underwent second operations for the recurrence of pain. Ten years after surgery, 70 percent (as determined by Kaplan-Meier analysis) had excellent final results; that is, they were free of pain without medications. An additional 4% had occasional pain that did not require long-term medication. Ten years after the procedure, the annual rate of the recurrence of tic was less than 1 percent. Female sex, symptoms lasting more than eight years, venous compression of the trigeminal root entry zone, and the lack of immediate postoperative cessation of pain were significant predictors of eventual recurrence. Having undergone a previous ablative procedure did not lessen a patient’s likelihood of having a cessation of tic after MVD. Major complications included two deaths shortly after the operation and one brainstem infarction. Sixteen patients (1%) had ipsilateral hearing loss. They concluded that MVD is a safe and effective treatment for TN, with a high rate of long-term success. The rate of complications was significantly reduced and no deaths occurred after intraoperative monitoring of brainstem evoked response began in 1980.(118) Barker et al [125] address these issues in a review of 1204 patients that underwent MVD for TN during a 20-year period. It has been contended that in patients suffering with TN, relief from pain can only be obtained at the price of nerve damage and, therefore sensory loss. In their group of 1204 patients, followed by questionnaire (minimum 2 years), 17% of patients reported some degree of persistent facial numbness. Decompression of a vein at MVD and failure to find compression by the superior cerebellar artery, independently predicted postoperative facial numbness, which in turn predicted postoperative facial burning and aching facial pain (odds ratio, 5.2-5.9). A trend toward worse outcome was noted in patients with numb faces (p= 0.3). Similar findings were noted in subgroups of patients in whom the superior cerebellar artery was compressed at MVD (n= 381) and in whom a superior cerebellar artery with vein was found (n= 120). In the latter subgroup, facial numbness (5.8% of patients) significantly predicted worse long-term outcome (p= 0.03). They concluded that they found no evidence that postoperative numbness predicts relief of typical tic after MVD. Trigeminal numbness was related to operative findings at MVD and predicted postoperative burning and aching facial pain. To minimize postoperative facial dysesthesia, trauma to the trigeminal root during MVD should be avoided when possible. Broggi et al [262] presented 148 patients, including 10 with MS that underwent MVD for TN with a mean follow-up of 38 mo. (1-7 yrs.). They report immediate pain relief in 84.7% with a recurrence rate of 15.3%. In the MS cases, 5/10 (50%) were pain free. Their negative outcome variable was TN > 84 mo. In a Nationwide Inpatient Sample database, Kalkanis et al [264, 265] at the Massachusetts General Hospital evaluated mortality, morbidity and effect of hospital and surgeon volumes in 1326 patients that underwent MVD for TN from 1996 – 2000. The overall mortality rate was 0.3% with volume and mortality not statistically related. The rate of discharge other than to home was 3.8%, with low volume hospital and/or surgeon being 5.1%, as compared to 1.6% for high volume. Neurological complications were 1.7% and less frequent at high vol. hospital (p=0.04) or by high vol. surgeons (p=0.01). Tyler-Kabara et al [263] reported on 2675 patients that underwent MVD, 2003 with TN and 672 atypical TN (ATN). Complete postoperative pain relief was reported in 80% with TN and 47% ATN. Longterm pain relief (> 5 yrs.) was reported in the TN group as 73% being excellent and 7% good (overall = 80%) and in the ATN group as 35% being excellent and 16% good (overall= 51%). Recent onset of 22 symptoms and trigger points were predictors of better postoperative pain relief, while preoperative sensory loss was a negative predictor for satisfactory long-term pain relief. In a retrospective comparative analysis of 225 patients who underwent MVD and 206 having undergone percutaneous trigeminal radiofrequency rhizotomy, 64% of patients who underwent MVD remained completely pain free 20 years postoperatively versus 50% risk of recurrence of pain 2 years after radiofrequency rhizotomy. (119) Gangliolysis Percutaneous rhizotomy or gangliolysis is useful in treating the elderly or debilitated patient who is refractory or intolerant to medical therapy and for whom surgery is not warranted due to risk factors. Gangliolysis is performed under fluoroscopic guidance, by placing a needle percutaneously, through the foramen oval and advancing it to the trigeminal cistern.(275) [ preceding is not clear] (see changes) The three techniques currently used include percutaneous radiofrequency ablation or thermocoagulation, trigeminal ganglion compression and retrogasserian glycerol rhysolysis. Percutaneous radiofrequency trigeminal gangliolysis involves the use of radiofrequency to create anatomically distinct lesions in cycles of 45-90 seconds at 60 to 90 degrees Celsius. Percutaneous trigeminal ganglion compression is performed under general anesthesia. Utilizing a Fogarty catheter is inserted via a 14 gauge catheter into the trigeminal cistern and inflated with radiocontrast to compress the gasserian ganglion. Careful observation of heart rate and blood pressure is required due to the possibility of severe bradycardia and hypotension which may require treatment with atropine and vasopressors. Percutaneous glycerol rhyzolysis is performed in a sitting position. After confirmation of needle location with radiocontrast, 0.1 to 0.4 mls of anhydrous glycerol is injected into the cistern of Meckel's cave. Electrocoagulation was initially reported in 1932 by Kirshner and underwent numerous modifications leading to the current modality which was invented and popularized by Sweet and White in the 1960’s and 1970’s. These advances led to electrical stimulation of the nerve for more precise localization prior to thermal lesioning, reliable radiofrequency generated current for thermal lesioning and computerized temperature monitoring and timing controlled lesion configuration with built in safety overrides. The theoretical basis for this procedure producing pain relief is based on the work of several investigators about the same time that demonstrated that the compound action potentials of A-delta and C fibers in nerves is blocked at lower temperatures than those of the larger and more myelinated A-alpha and Abeta fibers[215-217]. This gives the clinical picture of loss of nociceptive input with preservation of touch and other sensory modalities. Currently, radiofrequency rhizotomy is performed with continuous flouroscopic imaging guidance with a balanced sedation and controlled general anesthetic technique that allows the procedure to be performed in a safe, comfortable outpatient setting. This procedure is currently the most common surgical treatment and has the largest patient follow-up statistics from numerous series. Tew and Taha [222] have reported their experience managing TN, including 1200 cases with RTR over a 20 year period (mean follow up = 9 years). Their patients were all subjected to a trial of pharmacologic management prior to surgical consideration. Eventually, 75% of patients required a 23 surgical procedure because of either pain recurrence or the side effects of medications. This lack of pharmacologic success is quite different from our present series reported above (further discussion to follow). Using their rating scale for early results of RTR, they reported 93% excellent or good results, 4% fair results and 1% poor results because of severe denervation dysesthesias. The procedure failed in 2% of patients, predominately those with significant preoperative denervation. Pain recurred in 20% of patients; pain was minor in 5% and did not require medication or reoperation, pain was moderate in 5%, but was well controlled with medication, and pain was severe in the remaining 10% and required reoperation. Complications of the 1200 cases included primarily; dysesthesias (20%), masticatory muscle weakness (23%), absent corneal reflex (6%), keratitis (2%), diplopia (1.2%), anesthesia dolorosa (1%) and meningitis (0.2%). The authors comment that the first 700 of these cases were performed with a straight electrode and the following 500 were performed with the Tew curved electrode. They report a significant decrease in the complication rates with the curved electrode. Mortality and major morbidity do occur with RTR despite it success and popularity. Sweet reported on over 10,000 cases and found 13 deaths and four cases of major morbidity. Ten patients had suffered intracranial hemorrhage of whom 5 died and one had permanent hemiplegia. Eight other deaths had been due to intracranial hemorrhage. Sweet hypothesized that while during RTR temporary rises in blood pressure are common and this coupled with many patients being on drugs that cause prolonged bleeding, that this was the reason for these events. While this might be so, currently our patients are monitored closely for blood pressure changes by the anesthesia team and antihypertensive therapy is given early and aggressively if necessary. Also, all drugs that commonly prolong bleeding are discontinued for an appropriate time interval prior to the surgical procedure. As already reported [222] other neurological complications do occur, yet they are rare and often transient. As mentioned earlier, there is a lack of controlled studies of surgical treatment for TN and until recently, also a lack of long-term, prospective follow up data. Taha et al [222] present results in 154 consecutive patients with TN treated by RTR and prospectively followed for 15 years. Ninety-nine percent of the patients obtained intial relief after one RTR. Dysesthesia occurred in 23%; in 7% with mild initial hypalgesia; in 15% with dense hypalgesia; and in 36% with analgesia. Dysesthesias were mild and did not require treatment in most patients. The corneal reflex was absent or depressed in 29 patients (19%), and keratitis developed in 3 patients (1.9%). Twenty-two patients (14%) developed trigeminal motor weakness, and in 19 of 22 patients (86%) the paresis resolved within 1 year. The authors estimated using Kaplan-Meier analysis that the 14-year recurrence rate was 25% in the total group: 60% in patients with mild hypalgesia, 25% in those with dense hypalgesia, and 20% in those with analgesia. Of the 100 patients all of whom were followed for 15 years after one or two RTR procedures, 95 patients (95%) rated the procedure excellent (77) or good (18). The authors concluded that RTR is an effective, safe treatment for TN. Dense hypalgesia in the painful trigger zone, rather than analgesia, should be the target lesion. Our technique of performing RTR in this study also utilized the goal of lesioning to be hypalgesia and not analgesia / anesthesia. 24 Mathews and Scrivani [33] present results of 258 patients (1991-1997) treated with RTR. Early pain relief (0-6 months) was excellent or good (successful) in 224/258 (87%), fair (unsuccessful) in 21/258 (8%), and poor (failures) in 3/258 (5%). There were 11% recurrences that underwent reoperation and 16% with recurrence that did not undergo reoperation. Long-term overall pain relief (12 mo.-80 mo.) was 83%. Side effects included dysesthesia (13%), corneal anesthesia (2%), keratitis in only 2 patients that was adequately treated. Retrospective analysis of patients undergoing percutaneous glycerol rhizolysis (GR) showed complete [Author – did you mean complete or incomplete?] (yes, the paper states “complete”) pain relief in 84% of patients with or without medication at 6 months following treatment. This dropped to a median of 54% at 3 year follows up. There was insufficient good quality data to compare pain relief from percutaneous balloon compression of the gasserian ganglion with the other ablative techniques. Complications included dysesthetic disturbances in 4 to 10 % of patients treated with any ablative technique The complication rate was highest in patients undergoing RFT though most complications were transient.(120) Ablative procedures are less invasive than MVD and are generally associated with a high initial response rate. Recurrence is common however, and the incidence of facial numbness is higher than with microvascular decompression. Patients who have a recurrence of TN after an ablative procedure can successfully undergo microvascular decompression. Peripheral Neurectomy Surgical destruction of the peripheral branches of the trigeminal nerve is indicated for patients who have failed medical therapy, who have failed gangliolysis, who have severe cardiopulmonary disease and are unable to tolerate a suboccipital craniectomy and MDV Duration of good to excellent relief varies from less than 1 year to a range of 2-5 years in reported series. The median pain free period among 88 patients in one series was 41 months with a mean of 52.5 months. A more recent analysis of 40 patients reported excellent to good results in all patients for a period of time ranging from 2-5 years.(121,122) The procedure can be repeated, however, the risk of neuroma increases with repeated procedure as well as the risk of diminished success. Dense numbness in the distribution of the eradicated nerve results following neurectomy. Cryoneuroablation of the peripheral branches of the trigeminal nerve can be performed using a 1.4 to 2 millimeter probe which incorporates a nerve stimulator to test both sensory and motor function as well as a thermistor to identify temperature at the tip of the probe. A 3.5 to 5.5 millimeter ice ball is produced which results in disruption of the nerve structure with wallerian degeneration while leaving the myelin sheath and endoneurium intact, (axonotmesis). (123) The use of cryotherapy to successfully treat patients with trigeminal neuralgia has been reported by several authors to provide relief of pain for periods of time ranging from 6-13 months. There was no permanent sensory loss though up to 1/3 of patients developed atypical facial pain following the procedure in one review. (124-126) Stereotactic Radiosurgery The first radiosurgical device was developed in the 1950's by Professor Lars Leksell at the Karolinska Institute in Stockholm, Sweden. Professor Leksell's work resulted in the development of the Gamma knife which is able to precisely irradiate small intracranial targets with gamma ray photons. The patient's head is immobilized by the use of an external metal frame which is attached to the skull by four screws. A large helmet with 201 fixed ports allows radiation from radioactive cobalt-60 sources to converge on the intracranial target. 25 The goal of radiosurgical treatment of trigeminal neuralgia is the delivery of energy to the proximal trigeminal root with minimal injury to surrounding structures. (127,128) Improved targeting with MR imaging has resulted in pain free results in 21.8-75% of patients and pain improvement in 65 to 88%. Gamma knife therapy produces lesions aimed at target area with the use of a stereotactic frame. (129) Data on radiosurgery for trigeminal neuralgia is predominantly observational and of generally poor quality.(130-132). In a recent outcome study reviewing 151 patients treated with gamma knife surgery (GKS), patient age, and right sided pain and previous neurectomy correlated with pain free outcome. One study found that treatment response did not correlate with the dose of radiation. (133) Treatment response correlated with vascular compression of the trigeminal nerve, as visualized on high resolution MRI, in some (134), but not all (133,135), reports. Pain relief with gamma knife surgery occurs after a lag time of about one month. (136,137). A systematic review of this data found that approximately 75 percent of patients report complete relief within three months, and 50 percent of patients can permanently stop drug therapy after surgery. Sensory disturbances (e.g., numbness, paresthesias, and dysesthesias) are the most frequent complications. (138) A multi-institutional study using GKR has been undertaken and is continuing in order to establish the short- and long-term outcomes of radiosurgery, the appropriate radiosurgery dose and to determine the risks of complications [273]. This group initially reported on 50 patients from 5 centers that underwent gamma knife radiosurgery for trigeminal neuralgia. The target dose of the radiosurgery used varied from 60-90 Gy. The mean follow-up period was 18 months (range 11-36). Twenty nine patients (58%) responded with excellent control (pain free), 18 patients (36%) obtained good control (50-90% relief), and 3 patients (6%) were treatment failures. The median time to pain relief was 1 month (range 1 day-6.7 months). Responses remained consistent for up to 3 years post-radiosurgery in all cases except three (6%) in which the patients had recurrence of pain at 5, 7, and 10 months. At 2 years, 54% of patients were pain free and 88% had 50-90% relief. A maximum radiosurgery dose of 70 Gy or greater was associated with a significantly greater chance of complete pain relief (72% versus 9%). Three patients (6%) developed increased facial paresthesia after radiosurgery, which resolved totally on one case and improved in another. No patient developed other deficits or deafferentation pain. Young et al [265], recently published a follow-up series of 60 patients that underwent GKR for TN. Fifty one patients had idiopathic TN and 9 patients had tumor related TN. The 51 patients with nontumor related disease were all treated with a standard protocol utilizing a maximum isodose of 70 Gy. to the trigeminal root. Within a latency period of one day to 4 months following treatment, 38 of 51 patients (74.5%) were completely free of pain and eventually tapered off medications. An additional 7 patients (13.7%) experienced reductions in pain from 50-90% and utilized little or no medications. At follow-up, a mean of 16.3 months (range 6-36 months) after treatment, 41 patients (80.4%) remained pain free or had marked pain reduction. There were four patients with recurrent pain. All 26 patients with classical symptoms of TN with no atypical features and no prior surgery, had complete or nearly complete pain relief. None of these patients had recurrent pain. Nine patients with the tumor related TN received standard radiosurgical treatment directed at their tumors and 8 of the 9 (88.8%) had pain relief. Of the total of 60 patients treated for TN, 49 (81.7%) experienced complete or nearly complete pain relief at last follow-up. Only one patient with preexisting facial sensory loss due to tumor had a mild increase in facial numbness. No other patient experienced neither loss of facial sensation nor any other 26 complication. This multi-institutional study and follow-up study at one institution with a standardized protocol [265], have both found GKR to be minimally invasive, safe and effective treatment for trigeminal neuralgia. Recently, there have been several groups that have reported on longer follow-up with GKR for TN with changing patterns of data. Rogers et al [274] at the Barrow Neurological Institute treated 54 patients between 1997-2000 with only 35-40 Gy. They reported results as excellent/good/fair/poor (BNI pain index) as 52/54 (96%) experienced pain relief, 19/54 (35%) as excellent, 3/54 (6%) as good, 26/54 (48%) as fair, and 4/54 (7%) as poor. The mean follow-up time was 12 months with a range of 3-28 months. Brisman [275] at Columbia-Presbyterian Medical Center in New York reported on GKR for primary management of TN. Eighty-two patients underwent GKR as their first neurosurgical intervention (Group A), and 90 patients underwent GKR following a different procedure (Group B). All GKR patients were treated with a maximum dose of 75 Gy. The single 4-mm isocenter was placed close to the junction of the trigeminal nerve and the brainstem. Six-month follow up was available for 126 patients and 12-month follow up for 84 patients. Excellent (no pain and no medicine) or good (at least 50% reduction in pain and less medicine) relief was more likely to occur in Group A than in Group B patients 6 and 12 months following GKR for TN (p = 0.058). Excellent or good results were also more likely in patients with TN without multiple sclerosis (MS) (p = 0.042). The number and type of procedures performed prior to GKR, the interval between the last procedure and GKR, and the interval from first symptom to GKR (within Groups A and B) did not affect 6-month outcome. The interval between first symptom and GKR was shorter in Group A patients without MS (87 months) than in Group B (148 months; p < 0.004). There were no significant differences between Group A and B patients with regard to sex, age, or laterality. He concluded that patients with TN who are treated with GKS as primary management have better pain relief than those treated with GKS as secondary management. Patients are more likely to have pain relief if they do not have MS. As a follow-up, Brisman and colleagues [276] evaluated the relationship of the trigeminal nerve and blood vessel proximity as revealed by MRI and its effect on pain relief after GKR for TN. T1-weighted, axial 1-mm-thick volume acquisition magnetic resonance imaging scans were obtained through the area of CN V at its exit from the brainstem after injection of 15 ml of gadolinium. The BV-CN V relationship on the symptomatic side that was treated with GKR was categorized into the following groups: Group 1 (no close relationship), Group 2 (BV close to CN V but not touching it), and Groups 3 and higher (BVCN V contact). A total of 181 symptomatic nerves were studied in 179 patients with TN who were treated with GKR. In BV-CN V Groups 1, 2, and 3 and higher, respectively, were 43 sides (24%), 31 sides (17%), and 107 sides (59%). In 100 sides where there was no surgical procedure before GKR, 50% or greater pain relief was more likely in those with BV-CN V contact (51 [88%] of 58 sides) than in those without BV-CN V (29 [69%] of 42 sides) (P = 0.024). BV-CN V contact was observed more often in men (55 [69%] of 80 sides) than in women (52 [52%] of 101 sides) (P = 0.023) and more often in patients who had unilateral TN (104 [62%] of 169 patients) rather than bilateral TN (2 [20%] of 10 patients) (P = 0.016). They concluded that in patients who have not undergone previous surgery for TN, BV-CN V contact revealed by high-resolution magnetic resonance imaging may indicate a particularly favorable response to GKR. 27 Although radiosurgery is less effective than MVD, it is an effective, minimally invasive treatment option for patients refractory to medical therapy who are not surgical candidates or who wish to forego the risks of surgery. Patients who fail to respond to radiosurgery or who have recurrence of symptoms may respond to repeat treatment. (139,140) Linear accelerator radiosurgery is an alternative to the Gamma Knife developed in the mid 1980s. Unlike the radioactive cobalt-based Gamma Knife, liniac systems use x-ray beams generated from a linear accelerator. This system also uses a metal head frame which is attached to the patient's skull. Recent developments include Intensity Modulated Radiation Therapy (IMRT) which use computer controlled "beam-shaping" to more precisely conform the beam to the shape of the target.(141) A case series of 22 patients who had failed medical therapy and either declined or were unsuitable to undergo a surgical procedure found that radiosurgery by this technique was safe and effective.( 142) More recently, there have been reports of the use of Cyberknife Radiosurgery (CKR) for TN. CKR differs from GKR in several ways. It is the only system to incorporate a miniature linear accelerator mounted on a flexible, robotic arm.to treat tumors anywhere in the body. CKR utilizes a single source linear accelerator to deliver the radiotherapy as opposed to GKR which delivers gamma radiotherapy with 201 computer focused colbalt source beams. CKR offers superior targeting accuracy without the need for the invasive head frame which rigidly position the patients head for TN treatments. It is generally felt that GKR, with over 30 years of clinical use, remains the “gold standard” for stereotactic radiosurgery for TN and possibly for other structural pathology. Romanelli and colleagues (2003) [280] at Stanford University Medical Center reported on ten patients with medically refractory TN who were deemed unsuitable for conventional surgery and underwent CKR using CT cisternography for localization. Pain relief was achieved in 7 patients, in 5 of them within 24-72 h after irradiation. They concluded that CKR can achieve early-onset pain relief in a subset of TN patients. Improvements using this technique include the absence of a stereotactic ring; potentially improved targeting accuracy produced by CT cisternography and improved dose homogeneity over initial reports with CKR. Lim and colleagues (2005) [281] also from Stanford University Medical Center reported on forty-one patients that were treated between May 2002 and September 2004 for idiopathic TN at Stanford University and the Rocky Mountain CyberKnife Center. Patients with atypical pain, multiple sclerosis, or previous radiosurgical treatment or a follow-up duration of less than 6 months were excluded. Patients were evaluated for the level of pain control, response rate, time to pain relief, occurrence of hypesthesia, and time to pain recurrence with respect to the length of the nerve treated and the maximum and the minimum dose to the nerve margin. Thirty-eight patients (92.7%) experienced initial pain relief at a median of 7 days after treatment (range, 24 hours-4 months). Pain control was ranked as excellent in 36 patients (87.8%), moderate in two (4.9%), and three (7.3%) reported no change. Six (15.8%) of the 38 patients with initial relief experienced a recurrence of pain at a median of 6 months (range 2-8 months). Long-term response after a mean follow-up time of 11 months was found in 32 (78%) of 41. Twenty-one patients (51.2%) experienced numbness after treatment. They concluded that CKR for TN has high rates of initial pain control and short latency to pain relief compared with those reported for other radiosurgery systems. The doses used for treatment were safe and effective. Higher prescribed 28 doses were not associated with improvement in pain relief or recurrence rate. The hypesthesia rate was related to the length of the trigeminal nerve treated. Symptomatic Trigeminal Neuralgia Symptomatic trigeminal neuralgia is differentiated from classical trigeminal neuralgia through demonstration by special studies of a causative lesion other than vascular compression. Sensory impairment and bilaterality may be present as well as lack of a refractory period after a paroxysm.(2) Multiple Sclerosis and benign or malignant neoplasms are the most common cause of symptomatic trigeminal neuralgia although fungal infection and bacterial sinusitis with intracranial extension, scrub typhus, hardened felt from previous microvascular decompression surgery and trigeminal neuralgia as the first manifestation of mixed connective tissue disorder have also been reported. (143-148) Multiple Sclerosis Multiple Sclerosis(MS) is an inflammatory autoimmune systemic disease which is characterized by demyelinating lesions and plaques within the brain. Widespread neuronal loss with periods of remyelination may be associated with periods of remission. The diagnosis of MS is made by the occurrence of nervous system lesions spread in an individual over time and in different spaces. MS affects women more than men with a cumulative ratio of females to males of 1.77 to 1.0. Median and mean age of onset of multiple sclerosis is 23.5 and 30 years of age, respectively. (149) Trigeminal neuralgia occurs in up to 2% of patients with MS though this represents only about 0.5% of patients presenting with trigeminal neuralgia.(150,151) These patients can present with symptoms which mimic classical trigeminal neuralgia but often present with bilateral symptoms and persistent background facial pain.(151) The pathophysiology of trigeminal neuralgia in multiple sclerosis continues to be debated. Although demyelinating lesions affecting the trigeminal root entry zone have been found on autopsy and on magnetic resonance imaging, twenty four MS patients out of series of 851 studied at one institution were found to have entry zone lesions which were clinically silent.(152) Although microvascular decompression was once thought to be contraindicated in MS patients with STN, a recent report of MVD performed in 35 MS patients with severe neurovascular compression at the REZ resulted in a 39% excellent and 22% fair to good long-term pain relief. Seventy-four percent of these patients had demyelinating lesions affecting the brainstem trigeminal pathway on the painful side in addition to neurovascular compression.(153) In a series of 5 patients with STN and MS who were refractory to medical treatment and had undergone multiple unsuccessful percutaneous procedures, those patients undergoing MVD combined with partial sectioning of the nerve did better than those undergoing MVD alone.(154) In general, patients with STN secondary to MS respond less favorably to medical and interventional therapies and may require significantly more treatment than their cohorts with CTN.(155) Neoplasm The presentation of CTN does not rule out the presence of a tumor. Some authors advocate advanced imaging of all patients presenting with CTN due to delayed neurologic symptoms in patients with space-occupying lesions. (156) Among 2,972 patients diagnosed with TN at the Mayo Clinic between 1976-1990, tumors were the cause of facial pain in 296 patients. Gender and pain distributions paralleled those in CTN; however patients presenting with tumors were younger than those with CTN. Delay in tumor diagnosis averaged 6.3 years. The development of neurological deficits prompted further imaging and diagnosis of tumor in 47% of these patients. These patients were often successfully treated medically for many years prior to onset of neurological symptoms. (156,157) Meningioma, epidermoid and acoustic neuroma are the most frequent posterior fossa tumors associated with symptomatic trigeminal neuralgia. In a review of 161 and 80 consecutive posterior fossa 29 tumors from 1993-1999 and 1979-2003 at separate institutions, cranial nerve dysfunction was the most common neurological sign on admission. Intracranial hypertension and disturbance of gait also presented in up to 44% of these patients.(158,159) Twenty cases of trigeminal neuralgia caused by contralateral tumors of the posterior fossa have been reported. Only 4 of these cases symptomatically conformed to CTN. The mechanism of contralateral tumor causing TN is thought to be distortion and displacement of the brain stem and compression of the contralateral Meckel’s cave. (160,161) Pain in all three divisions of the trigeminal nerve is the first symptom of a tumor in Meckel’s cave in over 65% of cases. The most common cavernous sinus tumors are trigeminal schwannomas and meningiomas. Tumors in this location make up only 0.5% of all intracranial tumors.(162) Case reports of metastatic disease to Meckel’s cave presenting as trigeminal neuralgia include: colorectal cancer, esophageal cancer, breast cancer, renal cell carcinoma and lymphoma.(162-166) Primary melanoma, adenocarcinoma and lymphoma involving Meckel’s cave and associated with trigeminal neuralgia have also been reported. (168-170) Trigeminal neuralgia with sub acute onset of numbness in one or more divisions of the trigeminal nerve is thought to be associated with rapidly expanding tumor in this region.(166) Other reported causes of symptomatic trigeminal neuralgia include platybasia, (a skull base deformity)(171), sarcoid granuloma of the trigeminal nerve and infarction of the root entry zone of the trigeminal nerve in the pons. (171-173) Trigeminal neuralgia has also been seen in adults and children as the only manifestation of chiari type I malformations.(174-176) Patients with hydrocephalus from remote causes such as a lumbar myxopapillary ependymoma and a quadrigeminal arachnoid cyst have also presented with trigeminal neuralgia.(177,178) Shunting and relief of hydrocephalus resulted in resolution of symptoms in these cases. 5-10 % of trigeminal neuralgia has been reported to be symptomatic trigeminal neuralgia secondary to brain tumors. (179) Although persistent pain, numbness, palsies, and gait disturbances along with other neurological signs often differentiate these patients from those with classical trigeminal neuralgia, delay in the presentation of neurological deficits are not infrequent. Expedient work up including advanced imaging is indicated in cases of TN with new onset of neurological signs such as numbness or palsies. Herpes Zoster and Post Herpetic Neuralgia Acute herpes zoster results from the reactivation of the varicella zoster virus which is referred to as “chicken-pox” in children or “shingles” in adults. The virus remains dormant in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection. As cellular immunity wanes with disease, chemotherapy or age, the virus is reactivated and is transported along peripheral nerves producing an acute neuritis. In a recent population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction, the incidence of HZ was found to be 3.6 per 1000 person-years. The Herpes Zoster, (HZ), and the rate of HZ-associated complications increased with age, with 68% of cases occurring in those aged 50 years and older. Postherpetic neuralgia occurred in 18% of adult patients with HZ and in 33% of those aged 79 years and older. (180) In herpes zoster involving the trigeminal nerve, neuronal spread of the virus occurs along the ophthalmic (1st) and less frequently the maxillary (2nd) division of the fifth cranial nerve. Vesicular eruptions occur at the terminal points of sensory innervation, causing extreme pain. Zoster opthalmicus, herpes zoster involving the ophthalmic ganglion of the trigeminal nerve, accounts for as many as 10-25% of herpes zoster cases. Nasociliary involvement will most likely cause ocular inflammation. Inflammation of the eye can lead to impairment of vision and in some cases 30 temporary blindness. Prompt treatment is required to prevent chronic inflammation or long term vision loss. Contiguous spread of the virus may lead to the involvement of other cranial nerves, resulting in optic neuropathy (cranial nerve II) or isolated cranial nerve palsies (cranial nerve III, IV or VI). Ramsay-Hunt syndrome follows herpes zoster infection of the geniculate ganglion of the facial nerve. The vesicular eruption occurs in the external auditory canal. Pain is felt within the ear or posterior pharynx. Hearing or balance problems can also manifest with this syndrome. Acute herpes zoster typically presents with prodrome consisting of hyperesthesia, paresthesias, burning dysesthesias or pruritus along the affected dermatome(s). This prodrome is usually accompanied by fever and general malaise. It generally lasts one to two days but may precede the appearance of skin lesions by up to three weeks. Manifestation of prodromal symptoms without development of the characteristic rash may occur in some patients. This presentation is known as "zoster sine herpete," and may delay correct diagnosis and treatment. Following the prodromal period, a vesicular skin rash appears along the affected nerve. Involvement of the trigeminal nerves characteristically respects the vertical midline. The vesicles will discharge fluid and begin to scab over after about one week. The pain is extreme during the inflammatory stage. Vesicles at the tip of the nose are known as Hutchinson's Sign and signal a 75 percent likelihood of ocular sequelae which may include follicular conjunctivitis, epithelial and/or interstitial keratitis, dendritic keratitis, uveitis, scleritis chorioretinitis, optic neuropathy and palsies of the third, fourth and sixth cranial nerves. Pain that persists beyond healing of the rash but which resolves within four months of onset is referred to as subacute herpetic neuralgia. Postherpetic neuralgia (PHN) refers to pain persisting longer than four months from initial onset of rash.(181) Affected patients usually report constant, severe, burning, lancinating pain in the distribution of the affected nerve(s). Patients may also complain of pain in response to non-noxious stimuli. Even the slightest pressure from clothing, bed sheets or a slight breeze may elicit severe pain. Treatment The goals of treatment of acute herpes zoster include treatment of the acute viral infection, treatment of the severe acute pain associated with herpes zoster infection and prevention of post herpetic neuralgia. Acute herpes zoster infection should be treated with antiviral medication within 72 hours of vesicular eruption to reduce the duration and severity of pain associated with the infection (182) The use of antivirals may produce a moderate reduction in the risk of development of postherpetic neuralgia. (183) Oral steroids may also be beneficial in reducing the severe pain of acute herpes zoster. (184) Acute treatment of AHZ with tricyclic antidepressants or anticonvulsants starting within 48 hours of onset of rash may also reduce acute pain and incidence of PHN. (185, 186) Patients with ocular involvement should be referred to a specialist for evaluation and treatment of ophthalmic complications. The VZV vaccine, (Zostavax), approved in May 2006 by the Food and Drug Administration, was found to reduce incidence of shingles by 51 percent in a randomized double-blind study. Pain was reduced by 61% in those who received the vaccine but still developed the infection and post herpetic neuralgia was reduced by two-thirds compared with placebo.(187) Nutritional counseling may also be indicated in populations at risk for herpes zoster. In a review of 243 herpes zoster cases, it was determined that individuals, particularly those over age 60, who ate less than one serving of fruit or vegetables weekly, had a three-fold greater risk of zoster compared to those who ate more than three servings daily independent of vitamin supplement intake.(188) An association between deficiency of vitamin A,(a key immune modulator involved in the synthesis of 31 lymphocytes, neutrophils, cytokines and immunoglobulins), and increased risk of herpes zoster has also been observed.(189) Systematic reviews of the literature have concluded that pharmacologic therapies shown to be more effective than placebo for post herpetic neuralgia include tricyclic antidepressants, potent opioids, gabapentin, pregabalin, tramadol, capsaicin and lidocaine 5% patch. Intrathecal methylprednisolone was shown to be of benefit in patients refractory to pharmacologic therapies.(190,191) A thorough discussion of treatment of post herpetic neuralgia may be found in chapter ____. Safety and tolerability should be considered when selecting pharmacologic treatments. Older patients may have more intolerable side effects at standard doses and thus may require smaller doses and more gradual titration. They may also be on multiple medications for co-existing medical conditions with potential for drug-drug reactions. NERVUS INTERMEDIATE NEURALGIA Nervus intermedius neuralgia is an uncommon disorder affecting the sensory branch of the facial nerve, (cranial nerve VI) It is located between the motor component of the facial nerve and the vestulocochlear nerve (cranial nerve VIII). Sensory fibers contained in the nervus intermedius or intermediate nerve, carry afferent sensory input from the skin of the external auditory meatus, mucous membranes of the nasopharynx and nose and taste from the anterior two-thirds of the tongue, floor of the mouth and the palate. The geniculate ganglion contains the cell bodies of the sensory fibers of the nervus intermedius. The Cell bodies of parasympathetic axons within the nervus intermedius are contained within the superior salivatory nucleus. These axons synapse with neurons which supply parasympathetic innervations to the lachrymal gland as well as the submandibular and sublingual glands. Nervus intermediate neuralgia or geniculate neuralgia involves severe pain deep in the ear which may radiate to the outer ear, mastoid or eye region. The syndrome was reported as “Tic Douloureux of the sensory filaments of the facial nerve” by Clark and Taylor in 1909. Rare cases continue to be reported. (192) Etiology Jannetta described relief of geniculate and other cranial neuralgias following microvascular decompression in 1976. (193) He more recently reviewed 14 cases of nervus intermedius neuralgia, who having failed conservative treatment, underwent MVD. Over seventy one percent experienced an excellent outcome, over twenty one percent experienced partial relief and seven percent had no relief following MVD. Good long term results were seen in ninety percent of patients. In a 1991 review of 18 cases of “primary otalgia” seen over a 15 year period, vascular loops, adhesions, thickened arachnoid and benign osteoma were among abnormalities involving the nervus intermedius. The authors report decompression of cranial nerves V, IX, X, the tympanic nerve and the chorda tympani in addition to the nervus intermedius in many of these cases. (194,195) Existence of nervus intermedius as a unique entity has been questioned due to the similarity of its presentation to that of glossophayngeal neuralgia. Symptoms and Signs The pain of nervus intermedius is sharp, lancinating and paroxysmal. Painful attacks are unilateral and can be triggered by cold, noise, swallowing or touch. Patients may also experience symptoms such as increased salivation, better taste, tinnitus and vertigo during paroxysms. Patients with nervus intermedius neuralgia may also rarely have pain in the trigeminal distribution. This may be due to cross compression of cranial nerve V in addition to the nervus intermedius, (as has been seen on surgical exploration). (196) Diagnosis 32 Sensation is supplied to the area of the ear by the Vth, VIIth, VIIIth, IXth and Xth cranial nerves and the 2nd and 3rd cranial nerves. A thorough history should be taken to ascertain the exact distribution and character of the pain as well as any triggers or precipitating factors. A comprehensive examination should be done to rule out other causes of otalgia before the diagnosis of geniculate ganglion neuralgia can be made. This should include examinations of the nose, paranasal sinuses, mouth, teeth, nasopharynx, pharynx and larynx to rule out other causes of pain, audiogram, auditory evoked response potentials and vestibular tests. MRI with gadolinium enhancement of the brain, cerebellopontine angle and facial nerve and MRA should be performed. As described above, vascular compression or other pathology may involve more than one of the cranial nerves in the middle fossa. As described in the previous section, geniculate neuralgia can be caused by herpes zoster infection. The pain from acute herpes zoster involving the geniculate ganglion is usually constant and burning as opposed to the lancinating paroxysmal pain of nervus intermedius neuralgia. Onset of the pain of caused by acute herpes zoster (AHZ) is generally followed by a vesicular eruption involving the ear drum and external auditory canal. Treatment Pharmacologic treatment of nervus intermedius neuralgia is similar to that of trigeminal neuralgia. When conservative management fails, a thorough workup to exclude other causes of pain should be investigated. The nervus intermedius or geniculate ganglion cannot be injected with local anesthetic or other solution, however, blockade of other nerves supplying the area of the ear can be anesthetized to exclude them as causes of the otalgia. Surgical management consists of microvascular decompression or section of the nervus intermedius. Excision of the nervus intermedius and geniculate ganglion has also been advocated along with selective retrolabyrinthine Vth nerve section in complex cases. (195) GLOSSOPHARYNGEAL NEURALGIA Glossopharyngeal neuralgia is a rare neuralgia with a reported relative frequency of 0.75% to 1% compared to trigeminal neuralgia.(197,198) It is defined as paroxysmal pain in the areas supplied by the IXth and Xth cranial nerves. The glossophayngeal or ninth cranial nerve exits the upper medulla just rostral to the vagus nerve. Sensory fibers carried in the glossophayngeal nerve supply the posterior onethird of the tongue, the tonsils, pharynx, the middle ear and the carotid body. The glossophayngeal nerve also supplies parasympathetic fibers to the parotid gland via the otic ganglion, motor fibers to the stylopharyngeus muscle and contributes to the pharyngeal plexus. The symptoms associated with glossophayngeal neuralgia can be better understood upon review of its branches, which include the tympanic nerve, stylopharyngeal nerve, tonsillar nerve, nerve to the carotid sinus, branches to the posterior third of the tongue, lingual branches and a communicating branch to the vagus nerve. Etiology Classical or Idiopathic and secondary or symptomatic forms of glossophayngeal neuralgia exist, similar to trigeminal neuralgia. Symptomatic causes include tumors, peritonsillar abscess, carotid aneurysm, chiari type I malformations and Eagle syndrome (in which CN IX is compressed against an ossified stylohyoid ligament). (199-201) Idiopathic glossophayngeal neuralgia occurs most commonly from vascular compression of CN IX, (often in association with CN X) at the nerve root entry zone. The vertebral artery or posterior inferior cerebellar arteries are most often implicated on surgical exploration. Symptoms and Signs The character of pain in the patient with glossophayngeal neuralgia is similar to that of trigeminal neuralgia. The unbearable, electrical, lancinating pain is located unilaterally in the ear, larynx, tonsillar fossa or base of the tongue. It is rarely bilateral. It may radiate toward the ear, the angle of the jaw or the upper and lateral aspect of the neck. Paroxysms of pain are often triggered by swallowing, 33 yawning, coughing or talking. Diagnosis A careful history and physical exam is essential in the evaluation of a patient suspected of suffering from glossophayngeal neuralgia. MRI/MRA should be performed to rule out a mass lesion or vascular pathology. An ossified stylohyoid ligament (consistent with Eagle syndrome) may be identified on roentogram. As in trigeminal neuralgia, the paroxysms of glossophayngeal neuralgia may last from seconds to minutes. Dozens of attacks may occur daily with episodes lasting from weeks to months followed by periods of remission. The patient is generally free from pain between attacks though in some patients a dull background pain may persist. Investigation should also exclude MS in younger patients with bilateral symptoms or neurological deficits. The branch of the glossophayngeal nerve to the carotid sinus is involved in maintenance of blood pressure and is thought to play a role in the profound cardiac arrhythmias and even asystole which occur in some patients in association with pain paroxysms. The differential diagnosis includes geniculate or nervus intermedius neuralgia. Rare glossophayngeal zoster has been reported. (202) Treatment The pharmacologic treatment of glossophayngeal neuralgia is similar to trigeminal neuralgia. When conservative therapy has failed, surgical exploration and vascular decompression has been shown to be highly effective on long-term follow-up with a low complication rate.(203,204) When a source of neurovascular compression is not found, successful relief of symptoms has been obtained with section of the glossophayngeal nerve together with the upper fibers of the vagus nerve. (205,206) VAGAL AND SUPERIOR LARYNGEAL NEURALGIA The two sensory branches of the vagus nerve, the auricular branch and the superior laryngeal nerve are involved in this rare neuralgia. The auricular branch of the vagus nerve or Alderman’s nerve, divides into two branches: the posterior auricular nerve and the nerve supplying the auricula and posterior part of the external acoustic meatus. The superior laryngeal nerve descends behind the internal carotid artery and divides into the internal and external laryngeal nerves. The internal laryngeal nerve supplies sensation to the base of the tongue, epiglottis and the larynx to above the vocal cords. The external laryngeal nerve supplies the cricothyroid muscle, the inferior pharyngeal constrictor and communicates with the superior cardiac nerve behind the common carotid artery. Etiology Idiopathic or classical superior laryngeal neuralgia is characterized by lack of a known precipitating lesion or by vascular compression of the upper fibers of the vagal nerve as they leave the brainstem. Secondary or symptomatic superior laryngeal neuralgia has been reported to be secondary to multiple causes including deviation of the hyoid bone, lateral pharyngeal diverticulum and as a complication following carotid endarterectomy.(207-209) Symptoms and signs Vagus or superior laryngeal neuralgia is characterized by severe pain paroxysms in the submandibular region, throat and/or under the ear. Attacks are triggered by swallowing, talking, yawing coughing or straining and turning the head. A trigger zone is generally present in the larynx or lateral aspect of the throat overlying the hyoid bone. Compression of the vagus nerve has also reported to be associated with intractable hiccups, coughing, spontaneous gagging and dysphagia.(210,211) Diagnosis The diagnosis of vagus or superior laryngeal neuralgia is based on a thorough history to define the distinct characteristics and precipitating factors of the patient’s pain. A careful exam of the head and neck should be performed to rule out other pathology. MRI/MRA should be performed to rule out compressive mass lesions or neurovascular compression. Hoarseness of speech and a trigger point 34 superolateral to the thyroid cartilage may be noted on exam of the patient. Differential diagnosis includes glossophayngeal neuralgia, geniculate neuralgia and carotidynia. Treatment Pharmacologic therapy of vagus neuralgia is identical to that of trigeminal neuralgia. Successful treatment of superior laryngeal neuralgia with high concentration lidocaine injections after carbamazepine treatment failure has been reported. (212) Surgical treatment following pharmacologic therapy failure is warranted. Microvascular decompression has been successful when neurovascular compression of the vagus is identified. When no compressive lesion is identified, relief of pain can be obtained following section of the glossopharyngial nerve and the upper rootlets of the vagal nerves. The medial aspect of the descending trigeminal tract has also been sectioned in refractory cases to produce loss of pain and temperature sensation in the pharynx. (213) OCCIPITAL NEURALGIA Occipital neuralgia is defined as pain in the distribution of the greater and lesser occipital nerves. The pain starts in the suboccipital region and may radiate to the vertex with occasional radiation to the supraorbital or retroorbital region. True neuralgic pain is rare and thus occipital neuralgia is often diagnosed in cases of tension headaches, cervical facet arthopathy and migraines. Etiology As with the cranial neuralgias, occipital neuralgia may be divided into idiopathic, or, and secondary occipital neuralgia. Secondary forms include trauma, cervical tumors involving the 2nd and 3rd cervical roots and degenerative C1-C2 osteoarthritis. Various entrapment syndromes of the greater and lesser occipital nerves have also been reported in patients suffering from occipital neuralgia. These include inferior oblique muscle entrapment, atlanto-epistrophic ligament entrapment and neurovascular compression. Herpes zoster and postherpetic neuralgia involving the occipital nerve may also occur. (214-217) Symptoms and Signs Occipital neuralgia is characterized by paroxysmal stabbing pain, with or without persistent aching between paroxysms, in the distribution of the greater, lesser and/or third occipital nerves. Although the pain is not spontaneously triggered by light touch or vibration as in trigeminal neuralgia, the area of the nerve(s) affected is tender on exam, and light pressure over the nerve may reproduce the patient’s usual pain. The typical pattern of radiation of occipital neuralgia is to the vertex and supraorbital or retroorbital areas. If the lesser occipital nerve is involved, radiation to the lateral scalp behind and above the ear may occur. Perhaps due to the communication of the C2 and C3 dorsal rami, (which make up the occipital nerve), with the trigeminovascular system, some patients with occipital neuralgia present with concurrent migraine like symptoms with development of scalp allodynia and autonomic changes similar to those seen in cluster headaches. Diagnosis Occipital neuralgia must be differentiated from referred pain from the upper cervical zygapophyseal joints or referral from neck muscle trigger points. Diagnostic blocks of the occipital nerve(s) involved with local anesthetic should provide temporary relief of pain. Migraines involving the occipital region are usually characterized by discrete attacks of throbbing, vice like or exploding pain associated with photophobia, phonophobia, nausea and vomiting with or without aura. Patients with migraines will generally respond to ergot alkaloids or tryptans. Muscle tension headaches are frequently associated with chronic neck muscle tension and must be differentiated from occipital neuralgia. They are generally associated with emotional or physical stress or overuse patterns. Tender areas in the suboccipital muscles and trapezius are easily identified on 35 palpation. Herpes zoster involving the occipital nerves is typically constant, burning and followed by vesicular lesions in the distribution of the affected nerve(s). If neurologic exam leads to suspicion of a structural lesion, radiographic studies including CT or MRI/MRA may be useful in identification of pathologic lesions. Treatment Patients with lancinating neuralgic pain may respond to treatment with antiepileptic medications or GABA agonists. Those with a persistent background pain similar to persistent idiopathic facial pain may respond to tricyclic antidepressants, oral local anesthetic agents or alpha 2 agonists. If muscle spasm and entrapment is thought to be a significant contributor, muscle relaxants, transcutaneous electrical nerve stimulation, physical therapy and manipulation may be beneficial. Local anesthetic with steroid injection may provide days to weeks of relief. Botulinum A toxin injections of the occipital nerve have been shown to provide a median of 16 weeks of relief, (median VAS decreased from 8.5 to 1 and median pain disability index from 56 to 17.5).(218) If patients do not respond to pharmacologic therapies, other treatment modalities are available. An initial case report of pulsed radiofrequency for treatment of intractable occipital neuralgia reported 70% relief for 4 months followed by an additional 5 months of 70 % relief with repeat pulsed radiofrequency. (219) Three small series of peripheral electrical nerve stimulation with non surgical (2 studies) and surgical leads (1 study) has shown promising results with greater than 50% relief at 3 and 12 month follow up. (220) Well designed long-term studies comparing the efficacy and risk of peripheral nerve stimulation with other surgical approaches is needed. Reports of surgical treatment of occipital neuralgia include successful relief of refractory occipital neuralgia with decompression of the C1 and C2 dorsal roots by the posterior inferior cerebellar artery and by a fenestrated vertebral artery.(215, 221) After partial posterior rhizotomy, 10 of 14 patients rated pain as good or excellent. (222) C2 ganglionotomy provided relief in 4 of 4 patients treated. An improvement of mean VAS scores from 80/100 to 20/100 was found in 10 patients who underwent neurolysis of the greater occipital nerve and sectioning of the inferior oblique muscle. Mean follow-up was 37 months in this series. (214) OTHER TERMINAL BRANCH NEURALGIAS Rare neuralgias involving branches of the trigeminal nerve have been reported. These include supraorbital neuralgia, nasociliary neuralgia, infraorbital neuralgia and nummular headache. Injury or entrapment of other peripheral branches of the trigeminal nerve such as the lingual, alveolar or mental nerves may result in pain in the area supplied by that branch. Supraorbital neuralgia is characterized by paroxysmal or constant pain in the region of the supraorbital notch. It is unilateral and radiates to the medial aspect of the forehead in the area supplied by the supraorbital nerve. It can be caused by injury or entrapment of the supraorbital nerve at its outlet. The pain is transiently relieved by injection of a small volume of local anesthetic at the supraorbital notch. Medical treatment is often unsuccessful when entrapment of the nerve is present. Successful treatment with cryoneuroblation and surgical release of the nerve at its outlet has been reported. (223, 224) Nasociliary neuralgia or Charlin’s neuralgia is a rare condition characterized by stabbing pain, lasting seconds to hours, in one side of the nose. The pain radiates to the medial frontal region and is triggered by touching the lateral aspect of the ipsilateral nostril. Temporary relief form pain following local anesthetic blockade of the nasociliary nerve is diagnostic. Inflammatory cutaneous lesions and chronic sinusitis have been implicated as secondary causes of nasociliary neuralgia.(225, 226) Relief following surgical section of the nasociliary nerve, turbinectomy and septoplasty has been 36 described.(227) Infraorbital neuralgia has been reported most frequently in association with post traumatic entrapment syndromes.( 228) If pain is not successfully alleviated by reduction of zygomatic fracture and mobilization of surrounding soft tissue and bone, Pharmacologic therapy with antiepileptic agents alone or combined with antidepressants such as the tricyclics or serotonin norepinephrine reuptake inhibitors may be effective. Nummular headache is thought to be neuralgia of a terminal cutaneous branch of the trigeminal nerve. It has been described as a primary disorder characterized by head pain felt exclusively in a small round area generally 2-6 cm in diameter. The pain is not attributed to another disorder and neurological and neuroimaging exams are normal by definition. A constant background pain may be described as well as exacerbations which are spontaneous or triggered by combing the hair or touch in the affected area. In patients refractory to pharmacologic therapy, reduction of pain was reported for an average of 14 weeks was reported after initial and repeat injection with botulinum toxin A.(229) In all cases of idiopathic neuralgia of the terminal branches of the trigeminal nerve, a careful history and physical exam to rule out other causes of facial pain the is imperative. Age less than 40 and presence of neurological deficit should prompt further diagnostic radiologic exams to rule out compressive lesions. NECK-TOUNGUE SYNDROME Neck-tongue syndrome is a rare disorder which results in simultaneous and sudden onset of pain in the occiput or upper neck in concert with pain and paresthesias of the tongue. Etiology Neck-tongue syndrome is categorized as idiopathic or secondary to inflammatory or degenerative arthritis of the cervical spine. There is surgical and clinical evidence that the sudden occipital or neck pain associated with paroxysmal tongue paresthesias with head turning is secondary to compression of the C2 spinal nerve root. This may follow subluxation of the atlantoaxial joint or compression by arthritis affecting the C1-C2-C3 articulation. The paroxysmal tongue and neck pain is explained by the route of the afferent fibers from the tongue as they travel via the hypoglossal nerve to the second cervical root. Symptoms and Signs The pain of neck-tongue syndrome is acute in onset and paroxysmal. It may last seconds to minutes. The pain occurs in the distribution of the lingual nerve and the second cervical nerve root. It is generally accompanied by numbness, paresthesia or sensation of involuntary movement of the tongue. Diagnosis Neck-tongue syndrome must be differentiated from other causes of pain of the neck and throat such as acute carotidynia, which can also be caused by head movement. The acute form of carotidynia can be evaluated by laboratory tests such as an ESR and an MRI/MRA to evaluate the anatomy of the carotid arteries. The pain of carotidynia is relieved by corticosteroids. The paroxysmal pain of glossopharyngial, superior laryngeal or vagus neuralgias may also involve the area of the tongue but are associated with triggers such as coughing, swallowing or speaking. A complete history and careful physical exam should be performed to determine the character of pain, associated triggers and exacerbating factors. Radiographic tests should be performed to rule out inflammatory or arthritic changes of the upper cervical spine and compressive pathology. Treatment Conservative therapy includes stretching exercises and avoidance of abrupt turning of the head. 37 Associated muscle spasm can be managed by muscle relaxants. In incapacitating cases, surgical decompression has resulted in partial relief of symptoms.(230) Persistent Idiopathic Facial Pain The International Headache society has defined persistent idiopathic facial pain (PIFP) as ”persistent facial pain that does not have the characteristics of cranial neuralgias and is not attributable to another disorder". In general, however, according to the IHS criteria, a diagnosis of persistent idiopathic facial pain is possible when the pain in the face is present daily and persists for most or all of the day.(2) Etiology The etiology of persistent atypical facial pain is obscure. Pain may be initiated by operation or injury to face, teeth or gums but persists without any demonstrable local cause. By definition, no structural pathology or specific cause of facial pain is found. Frequently patients have undergone multiple dental procedures and surgical therapies. Electrophysiological studies illustrate facilitation of central trigeminal processing which appears to follow injury to peripheral branches of the trigeminal nerve. Central sensitization following peripheral nerve injury may be an underlying pathophysiologic mechanism for the development of chronic facial pain. (231,232) Support for this mechanism is further increased by recent studies which demonstrate that central processing of nociceptive input is more easily upregulated into pathological hyperexitability in women versus men exposed to experimental pain. This may account for the higher prevalence of various chronic pain conditions among women. (233) Diagnosis Persistent idiopathic facial pain is ill defined and not confined to known anatomical distribution. The pain is initially confined to a limited area on one side of the face, often in the nasolabial fold or side of the chin and may spread to the upper or lower jaw or a wider area of the face of neck. It is described as constant, aching, cramping or burning. It is typically described as deep and is poorly localized. It is not associated with sensory loss or other physical signs. Although a high association with psychological disorders such as depression or somatization is reported, depression may also be a consequence of living with pain rather than a precursor to it. (234) Many different disorders may be included in this diagnostic category, making differential diagnosis very complex. These include TMJ, pain of dental origin, chronic sinusitis and pain from invasive or metastatic tumors. The diagnosis of PIFP is therefore one of exclusion. A targeted history and an accurate examination are crucial to correctly classify this facial pain. Laboratory investigations including X-ray of face and jaws should not demonstrate relevant abnormality. A thorough dental examination should take place to rule out occult dental pathology. A Head MRI should be performed with special attention to the base of the brain. If the patient is a smoker, a lung roentogram should be performed to rule out lung cancer which can present with referred pain to the face, (presumably via CN X). (235) Treatment High quality randomized clinical trial data for the treatment of persistent idiopathic facial pain is limited. Patients with persistent atypical facial pain typically respond poorly to analgesics and anticonvulsants. (236) Antidepressants with norepinephrine and serotonin reuptake inhibition have more consistently been associated with positive treatment results in this patient group. Amitriptyline was found to be significantly more effective than placebo in reducing pain independent from effect on mood. Low dose amitriptyline, (10 to 30 mg daily), was as effective as high dose, (50 mg to 150 mg daily. (237) In a mixed group of TMD and persistent idiopathic facial pain patients, dothiepin, a tricyclic antidepressant not available in the United States, resulted in 71% excellent (pain free) pain relief in the 38 dothiepin group compared to 46% in the placebo group independent of effect on mood. At 12 month follow up, 81% of patients on dothiepin were pain free. (238) Low dose, (75 mg) venlafaxine did not decrease pain intensity in patients with persistent idiopathic facial pain but did result in a statistically significant decrease in use of rescue medication compared with placebo. (239) Cognitive behavior therapy in combination with pharmacologic therapy has been shown to decrease the pain’s interference with life and increase feelings of control over life in patients with chronic facial pain. (240) In a prospective study using validated self-report instruments at initial and follow up visits, use of cognitive coping strategies was found to be associated with positive outcome for patients suffering from chronic orofacial pain. (241) Other therapies showing effectiveness in chronic orofacial pain include acupuncture and transcutaneous nerve stimulation. (242) A subset of PIFP patients have been successfully treated with stellate ganglion blocks suggesting a role of sympathetically mediated pain in some patients.(243) Surgical procedures such as trigeminal microvascular decompression are aimed at treatment of the peripheral portion of the trigeminal nerve and are ineffective in treating persistent idiopathic facial pain. Bullard and colleagues as well as Kanpolat et al have reported pain relief in patients with atypical facial pain after caudalis dorsal root entry zone operations and CT guided, percutaneous trigeminal tractotomy-nucleotomy, suggesting pain of central origin in this group of patients. (244-246) OTHER CENTRAL CAUSES OF FACIAL AND HEAD PAIN Anesthesia Dolorosa Etiology Anesthesia dolorosa is defined as perception of pain in an area that is anesthetic. It is a dreaded complication of trigeminal nerve surgery, including partial nerve sections, microvascular decompression, percutaneous gangliolysis, neurolytic injections and stereotactic radiosurgery. It has also been reported after penetrating cranial injury. (247) The area of persistent and painful anesthesia is in the distribution of the injured nerve. Symptoms and signs The patient with anesthesia dolorosa complains of burning, pulling or stabbing pain which can also include a sharp, stinging, shooting or electrical component. The pain often increases with cold or with rapid temperature changes. Diagnosis As it pertains to the head and face, anesthesia dolorosa involves the territory of a specific branch or branches of the trigeminal nerve or the occipital nerve. Quantitative sensory testing may be used to confirm lack of sensation. Treatment There are no controlled trials evaluating pharmacologic therapy of anesthesia dolorosa. Empiric treatment of pain by clinical characteristics has led to use of anticonvulsants in patients with lancinating and electrical pain, tricyclic antidepressants and serotonin, norepinephrine inhibitors in patients with burning pain and intravenous lidocaine and ketamine infusions in patients unresponsive to other pharmacologic therapy. Motor cortex stimulation was the recommended surgical treatment of choice for facial anesthesia dolorosa according to authors of a recent review of literature on central and neuropathic pain over the last 15 years. Motor cortex stimulation may act by replacing nociceptive with non-nociceptive sensory input at the cortical, thalamic, brainstem and spinal level. It may also interfere with the 39 emotional component of nociceptive perception.(248) In a prospective study of 10 patients undergoing trial and treatment with motor cortex stimulation, patients with facial weakness and sensory loss regained both strength and discriminative sensation during stimulation. (249) Multicenter randomized studies are now in progress to further evaluate this modality of treatment. Anesthesia dolorosa did not appear to respond to deep brain stimulation according to one 15 year series of 141 patients. (250) Burning Mouth Syndrome Burning mouth syndrome is defined as oral mucosal or tongue pain persisting daily for most of the day with no medical or dental cause. A high incidence of anxiety, depression, somatization and personality disorders have been found in these patients.(251) Etiology Similar to the neuralgic syndromes, there may be primary or idiopathic burning mouth syndrome and BMS from secondary causes. Secondary causes which must be ruled out, include mucosal disease, nutritional deficiency, (e.g., vitamins B1, B2, B6, zinc deficiency), Sjögren’s syndrome, radiation therapy induced changes and cranial nerve injury. (252) The etiology of burning mouth syndrome is unknown. Other associations include the use of ACE inhibitors (253) and damage to the chorda tympani with resulting “taste phantoms” due to loss of central inhibition. (254) Symptoms and signs In addition to complaints of burning pain, patients may present with associated altered taste and dysesthesias or paresthesias. The tip and anterior two thirds of the tongue is usually involved however the lips and entire mouth may be symptomatic.(2) Diagnosis Reported general population prevalence of burning mouth syndrome rates vary from 0.75% to 15%. Onset before age 30 is rare. Eighty five percent of study subjects have been women with most frequent onset within 3 years prior to 12 years post onset of menopause. Because of this association hormonal changes have been implicated, however, replacement therapy has not resulted in significant treatment benefit.(255) Lack of response to hormonal and other replacement therapies may be due to neuropathic changes as suggested by electrophysiological studies, thermal quantitative sensory tests and tongue biopsies from burning mouth patients compared to controls.(256,257) Treatment There is insufficient evidence to show effectiveness of antidepressants, hormones or analgesics in the treatment of burning mouth syndrome. A 2005 Cochrane review found that of nine trials, eight of which were randomized controlled trials, three trials studying cognitive behavioral therapy, anticonvulsants and alpha-lipoic acid demonstrated a reduction in burning mouth syndrome symptoms. (258) CENTRAL POST STROKE PAIN Previously named thalamic pain, central post stroke pain refers to pain following an ischemic or hemorrhagic stroke. It is associated with sensory abnormalities in the painful part of the face and/or body. As opposed to pain and impaired sensation which correlate to the territory of the trigeminal or occipital nerves, central post stoke pain (CPSP) occurs as unilateral pain and dysesthesia of part or all of the face which cannot be explained by injury to the trigeminal or occipital nerves. Etiology Results of somatosensory evoked potentials in CPSP patients correlating severity of sensory abnormalities with stroke location, suggest that the lesions of the cortical spinothalamic pathways are essential for the development of CPSP. (259) Clinical studies also indicate that lesions at any level along the spino-thalamo-cortical pathway can result in CPSP independent of injury to the medial lemniscal 40 pathways, which carry essential information for vibration sensibility, tactile discriminatory functions and proprioception. (260) Although the exact mechanism of CPSP has yet to be elucidated, speculation based on clinical data is that dysesthesias may result from central misinterpretation of residual dorsal column system input in the absence of suppression via integrated spinothalamic system activity. (261) Symptoms and Signs Central post stroke pain may be vague or difficult for patients to characterize. Painful sensations may be poorly localized and my change over time. According to its first description in 1906 by Dejerine and Roussy, the syndrome includes disturbance of superficial and deep sensibility, hemiataxia and hemiastereognosia, intolerable pain, chreoathetoid movements and slight hemiplegia. (262) Post stroke pain may be constant, spontaneous and paroxysmal. It is typically described as burning, aching, pricking, lacerating or throbbing. In a population study of 207 stroke patients, CPSP was found in 8% of patients. 94% of patients had decreased temperature, touch and pain sensibility. Fifty six percent of patients reported allodynia to cold stimulation and another 56% allodynia to touch. (263) CPSP was found to occur in 11% of patients over age 81 suffering from stroke.(264) Diagnosis Diagnosis of CPSP is suggested by an area of sensory loss explained by a specific CNS lesion with MRI or CT showing at least one brain lesion affecting input to the thalamus contralateral to the affected side. Other causes of facial pain must be excluded including, tumor, MS, nociceptive pain, infection, neurogenic or psychogenic pain. In most patients pain occurs within one month after stroke but has been reported to occur 3 years following a stroke.(263,265) Treatment Amitriptyline and lamotrigine have been found to be effective in the treatment of CPSP in randomized controlled studies and should be regarded as the oral agents of first choice. Carbamazepine failed to show effectiveness in a placebo controlled study as did topiramate in a small open label study in doses up to 600 mg daily. Randomized controlled trials with opioids showed almost no effect with levorphanol versus placebo in the treatment of CPSP. Morphine reduced allodynia and sensory threshold but was no different than placebo in reducing pain and was discontinued in the majority of patients due to intolerable side effects. Short term effective relief of CPSP was seen in patients treated with intravenous lidocaine, propofol and ketamine in randomized controlled trials. Ongoing therapy with mexilitine following IV lidocaine therapy yielded negative long-term results. In a small open label study, Gabapentin was effective in alleviating pain in two patients with pain following thalamic infarction.(266) Spasticity associated with CPSP results in impaired function, range of motion and pain. Oral Tizanidine has been shown to reduce stroke-related spasticity and pain while preserving muscle strength.(267,268) Baclofen is effective for the treatment of spasticity and pain but may cause weakness at higher doses. (265)Intrathecal Baclofen and intrathecal baclofen are effective oral agents for the treatment of spasticity and spasticity related pain. Botulinum A toxin has been shown to reduce spasticity and improve arm function after stroke in an exploratory meta-analysis, including two randomized, controlled trials.(269) In patients with intractable pain not responding to medication who are surgical candidates, deep brain stimulation and motor cortex stimulation may offer relief. A meta-analysis of deep brain stimulation for pain relief over the period from 1966 to 2003 found DBS more effective for nociceptive than deafferentaiton pain with 63% versus 47% long term treatment success. Trial stimulation was successful in approximately 50% of patients with post-stroke pain. In patients who underwent permanent implantation, 58% reported ongoing pain relief. (270) 41 A second surgical modality used for treatment of intractable deafferentaiton pain is stimulation of the primary motor cortex. Since it was reported initially in 1990, 28 studies involving 271 patients have undergone epidural, subdural and central sulcus stimulation. 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Characteristics of facial pain syndromes Typical neuralgia Atypical Neuralgia Persistent Idiopathic facial Unilateral facial pain pain(formerly atypical facial pain) Intermittent: Constant, can fluctuate Constant, not much every few variation moments to once a day or less always Rarely Never Electric shock, stabbing, shooting location Unilateral; usually trigeminal, rarely nervus intermedius, glossopharyngial, vagus, upper cervical Sensory None or mild changes hypesthesia Precipitating Triggered by non factors noxious stimulation, often in anterior face and remote from face Autonomic none changes Local none tenderness Causative Vascular factors compression of nerve in subarachnoid space; rarely multiple sclerosis Common >50 age at onset (yr) Gender 60% female Burning, aching, can have superimposed shocks Trigeminal or upper cervical. Unilateral, rarely bilateral Burning, aching Often hypesthesia Common hypesthesia. Dysesthesia, paresthesias. Not triggered Rarely triggered; trigger usually in area of pain Not restricted to specific cranial nerve distribution. Intraoral or facial. Can extend to neck. Starts unilateral. May progress to bilateral. Rarely present None Rare Rare Tumor, infection, trauma or mechanical impingement on nerve; MS, often no cause found None Known 30 Variable 75%female 90% female 56 Legends Figure 66-1. The most likely sites of triggering for tic douloureux are in the anterior face. (use 3rd edition figure 47-2) 57