Trigeminal neuralgia INTRODUCTION — Trigeminal neuralgia (TN) is the most well defined and one of the most common causes of facial pain. The International Association for the Study of Pain (IASP) defines TN as sudden, usually unilateral, severe, brief, stabbing or lancinating, recurrent episodes of pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve. ANATOMY — The trigeminal nerve is the sensory supply to the face and the sensory and motor supply to the muscles of mastication. It has three major divisions: Ophthalmic (V1) The nerve starts at the midlateral surface of the pons, and its sensory ganglion (gasserian ganglion) resides in Meckel's cave in the floor of the middle cranial fossa. EPIDEMIOLOGY — The annual incidence of TN is 4/100,000 to 5/100,000; approximately 15,000 new cases occur in the United States each year. TN is one of the most frequently seen neuralgias in the elderly. The majority of idiopathic cases begin after age 50, although onset may occur in the second and third decades or, rarely, in children. The male to female ratio is about 1:1.5 ; this slight female predominance is likely related to the increased longevity of women compared with men. Rare familial cases have been reported, but the vast majority of patients have sporadic disease. ETIOLOGY/PATHOGENESIS — Most cases of TN are caused by compression of the trigeminal nerve root, usually within a few millimeters of entry into the pons (the root entry zone). Compression by an aberrant loop of an artery or vein is thought to account for 80 to 90 percent of cases. Other causes of nerve compression include vestibular schwannoma (acoustic neuroma), meningioma, epidermoid or other cyst, or rarely a saccular aneurysm or arteriovenous malformation . The mechanism by which compression of the nerve leads to symptoms appears to be related to demyelination in a circumscribed area around the compression. Precisely how demyelination results in the symptoms of TN is not entirely clear. Demyelinative lesions may set up ectopic impulse generation, possibly causing ephaptic transmission. Ephaptic cross-talk between fibers mediating light touch and those involved in pain generation could account for the precipitation of painful attacks by light tactile stimulation of facial trigger zones. Furthermore, alteration of afferent input may disinhibit pain pathways in the spinal trigeminal nucleus. Evidence for a role of central pain mechanisms includes the presence of refractory periods after a triggered episode, trains of painful sensations after a single stimulus, and latency from the time of stimulation to the onset of pain. Demyelination of one or more of the trigeminal nerve nuclei may also be caused by multiple sclerosis (MS) or other structural lesions of the brainstem. In MS, a plaque of demyelination typically occurs in the root entry zone of the trigeminal nerve although vascular compression also has been noted in these patients. CLINICAL FEATURES — The pain of TN tends to occur in paroxysms and is maximal at or near onset. The pain has been described as "electric shock-like" or "stabbing." V2 and/or V3 are involved more frequently than V1. (V1 is most commonly affected by postherpetic neuralgia, Unlike some other facial pain syndromes, TN typically does not awaken patients at night. The pain usually lasts from one to several seconds, but may occur repetitively. A refractory period of several minutes during which a paroxysm cannot be provoked is common. TN is unilateral in most cases. Occasionally the pain is bilateral, but not on both sides simultaneously. There may also be a coexisting continuous, deep, dull pain. Facial muscle spasms can be seen with severe pain. This finding gave rise to the older term for this disorder, "tic douloureux." Some patients have a history of "pretrigeminal neuralgia," which is said to be dull, continuous, aching pain in the jaw evolving eventually into TN. This brief, milder pain is sometimes suspected to have a dental origin and unnecessary dental procedures have been performed in many cases. On the other hand, TN can be precipitated by dental procedures (eg, dental extraction), resulting in increased confusion about the precise etiology of this problem. Trigger zones in the distribution of the affected nerve may be present; lightly touching these areas often triggers an attack, leading patients to protect these areas. Other triggers include chewing, talking, brushing teeth, cold air, smiling, and/or grimacing. The course of TN is variable. Episodes may last weeks or months, followed by pain-free intervals. Recurrence is common, and some patients have continuous pain. The differential diagnosis includes short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), cluster-tic syndrome, jabs and jolts syndrome, and other neuralgias. DIAGNOSIS — The diagnosis of TN is suspected clinically based upon the characteristic features described above, primarily paroxysms of pain in the distribution of the trigeminal nerve. Trigger zones may be demonstrated on physical examination; these are often located near the midline. Once the diagnosis is suspected on clinical grounds, a careful search for ipsilateral dental pathology should be undertaken, but unnecessary surgical or dental procedures must be avoided. Imaging studies — Magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) can identify demyelinating lesions, a mass lesion in the cerebellopontine angle, or an ectatic blood vessel in patients with TN. The sensitivity and specificity of MRA for identifying neurovascular compression as the cause of TN were 89 and 50 percent, respectively, in a study of 27 patients with TN, using surgical findings as the standard. The greatest benefit of MRI may be in identifying the small percentage of patients that have a potentially serious structural lesion (eg, tumor, multiple sclerosis). However, the precise indications for MRI are not clear .One retrospective study found that it was not possible to reliably identify patients at high risk for a structural lesion based upon the history and physical examination alone. In this report, 6 of 42 patients (14 percent) with TN had an associated structural lesion identified on MRI: the mean age of this group was 53 years; all had a typical pain history and unilateral involvement of a single division of the trigeminal nerve; two had other cranial nerve abnormalities; three had complete, two had partial, and one had a poor response to medical therapy. None of these variables differed from the group without structural lesions (although other cranial nerve abnormalities were not compared), leading the others to conclude that all patients with TN may benefit from MRI to exclude a structural lesion. On the other hand, a second study of 51 patients with TN was able to identify clinical features that were suggestive of the presence of a structural lesion. MRI identified 17 (33 percent) nonvascular abnormalities and 27 (53 percent) vascular contacts or compressions of the trigeminal nerve. Of the patients younger than 29 and 29 to 39 years of age, 100 and 45 percent, respectively, had a tumor or multiple sclerosis compared with 20 and 18 percent of those 40 to 60 and older than 60 years of age, respectively. One-third of patients with pain in more than one branch of the trigeminal nerve had a tumor. The authors concluded that it may be reasonable to obtain an MRI in patients who have failed to respond to initial conservative therapy, particularly if they are young and have pain in more than one branch of the trigeminal nerve. In summary, while specific evidence-based recommendations regarding the indications for MRI in patients with TN cannot be made, it appears that MRI should be obtained in the following groups to rule out a mass lesion or multiple sclerosis: Patients with sensory loss As mentioned, there are some investigators who obtain an imaging study in all patients with TN MEDICAL THERAPY — Pharmacologic therapy is the initial treatment of most patients with TN that is not caused by a structural lesion (eg, MS or a mass lesion). Surgery is reserved for patients who are refractory to medical therapy. A variety of medications have been studied in the treatment of TN. Carbamazepine is believed to be most effective; a response to carbamazepine is considered diagnostic for TN by some experts. Baclofen, phenytoin, valproate, pimozide, and clonazepam have utility as well, alone or in various combinations. Misoprostol (15-methyl-PGE1 analogue) appears to be effective in TN due to MS. More recently, newer antiepileptic drugs such as gabapentin, lamotrigine, and topiramate have been reported to be useful, although there is less clinical experience with these agents. Oxcarbazepine, a keto derivative of carbamazepine, has had reported success in treating TN in small studies. Although there are no controlled data regarding the efficacy of opioids in TN specifically, we have used opiates in patients with acute exacerbations of pain lasting for days to weeks. Opiates may help make the pain bearable while other, more effective and long-term, treatments take effect. Our experience with opiates suggests partial analgesia with central side effects (particularly sedation) when these drugs are used alone, as high doses of morphine, hydromorphone or oxycodone are usually required. In combination with other neuropathic analgesics, opiates seem to be more effective at lower doses. Carbamazepine (Tegretol) — Carbamazepine (CBZ) appears to decrease neuropathic pain by blocking sodium and potassium conductance. ). Its utility in patients with TN was first reported in 1962 . A number of randomized, controlled trials subsequently proved the efficacy of CBZ, with a response rate over 70 percent. A systematic review also concluded that approximately 70 percent of patients achieve significant pain relief with CBZ .In various comparative studies in patients with TN, CBZ was found to be more effective than tizanidine (an alpha-2 adrenergic agonist), have the same efficacy as tocainide and was less effective than pimozide. The usual starting dose of CBZ is 100 to 200 mg twice daily. The dose can gradually be increased by 200 mg until side effects of pain relief occurs, with a typical maintenance dose of 600 to 1200 mg. Adverse effects of CBZ include drowsiness, dizziness, nausea and vomiting; slow titration may minimize these effects. Carbamazepine-induced leukopenia is not uncommon, but it is usually benign; aplastic anemia is a rare side effect. There are reports of eventual loss of efficacy of CBZ monotherapy over time; these patients may respond to combination pharmacotherapy including gabapentin, lamotrigine, topiramate, or other newer antiepileptics. Baclofen (Lioresal) — Baclofen may depress excitatory synaptic transmission in the spinal trigeminal nucleus. It can be used as monotherapy for TN, but is more commonly used in combination with carbamazepine. 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, and the drug should be discontinued slowly since seizures and hallucinations have been reported with upon withdrawal. Phenytoin (Dilantin) — Phenytoin was the first anticonvulsant used to treat TN. It blocks sodium channels and inhibits presynaptic glutamate release. Phenytoin has been shown to effectively treat TN, and has antinociceptive properties. Intravenous phenytoin (15 mg/kg) was effective in reducing acute exacerbations of neuropathic pain in one report, making it a useful treatment for acute therapy in patients with severe symptoms. Fosphenytoin, a prodrug of phenytoin that is better tolerated intravenously, also appears to be effective in acutely ill patients Valproic acid (Depakote, Depakene) — Approximately 50 to 80 percent of patients have relief of TN symptoms with valproic acid therapy. Valproic acid increases the amount of GABA, binds GABA receptors, and prolongs the repolarization of voltage-gated sodium channels. Lamotrigine (Lamictal) — Lamotrigine (400 mg) was successful in treating 11 of 13 patients with TN that was refractory to carbamazepine and phenytoin in a double-blind, placebo-controlled study. It reportedly acts by blocking voltage-dependent sodium channels resulting in the inhibition of glutamate release. Gabapentin (Neurontin) — Gabapentin is an attractive drug for the treatment of neuropathic pain syndromes because it has fewer side effects than other antiepileptics and little interaction with other anticonvulsants. In a brief communication, gabapentin was effective in relieving pain for 6 out of 7 patients with refractory TN and multiple sclerosis . The doses of gabapentin ranged from 900 to 2400 mg per day in this study. Clonazepam (Klonopin) — Clonazepam has been reported to provide partial analgesia in small studies in TN but no large, randomized, controlled study has been published in the peer-reviewed literature. Clonazepam is a benzodiazepine and can be habit forming and has substantial sedative side effects. Oxcarbazepine (Trileptal) — Oxcarbazepine, the dihydroketo analogue of carbamazepine, was developed to retain the antineuralgic effect of carbamazepine while reducing side effects. A study of 13 patients with TN found that improvement in symptoms occurred in all treated with oxcarbazepine. In a second study of six patients with TN refractory to carbamazepine, all had a good therapeutic response to oxcarbazepine and reported fewer side effects than with carbamazepine. Topiramate (Topamax) — Topiramate is a novel antiepileptic approved for adjunctive therapy of partial seizures. In a report of six patients with TN and multiple sclerosis, topiramate led to complete resolution of pain. However, the pain relief may have been related to improvement of the underlying MS. Pimozide (Orap) — Pimozide, a dopamine receptor antagonist, was found to be effective in one study of patients with refractory TN. However, the drug has many side effects including mental retardation, memory impairment, and parkinsonism. Recommendations — A number of medications can be used to treat TN. The current literature favors carbamazepine (CBZ) as first-line therapy. The drug is highly effective, and side effects are generally manageable, particular if low doses are prescribed initially with gradual titration. Patients with symptoms that are refractory to CBZ monotherapy may benefit from combination therapy with gabapentin, lamotrigine, topiramate, baclofen, or tizanidine. Intravenous infusion of phenytoin, fosphenytoin or lidocaine may provide rapid analgesia while oral medications are titrated. Phenytoin or fosphenytoin is dosed at 250 to 1000 mg intravenously at no more than 50 mg/minute and lidocaine is given at 100 to 300 mg over one-half hour while monitoring pulse and blood pressure. This maneuver may also enable the physician to better examine the patient with a sensitive face. Occasionally, there are reported spontaneous permanent remissions of TN. More often, the illness tends to wax and wane in severity and frequency of pain exacerbations. Periodic attempts to gradually withdraw these drugs are warranted in patients achieving relief of pain with oral medications. SURGICAL THERAPY — A variety of surgical procedures may relieve symptoms in patients refractory to drug therapy. Microvascular decompression — Microvascular decompression involves the removal or separation of various vascular structures, often an ectatic superior cerebellar artery, away from the trigeminal nerve. Long-term follow-up suggests that 60 to 70 percent of patients have good outcomes: Thus, microvascular decompression is an effective, relatively safe, though invasive intracranial procedure for patients with TN. Radiofrequency rhizotomy — Percutaneous radiofrequency rhizotomy creates a lesion in the gasserian ganglion of the trigeminal nerve by application of heat. The lesion is thought to selectively destroy pain impulses carried by unmyelinated or thinly myelinated fibers. The ganglion is approached in Meckel's cave through the foramen ovale. The lesioning is performed in cycles of 45 to 90 seconds at 60 to 90 degrees Celsius . Percutaneous rhizotomy is less invasive than microvascular decompression, is associated with a low rate of morbidity and mortality, and has a higher initial success rate but a recurrence rate of 25 to 50 percent within 2 to 3 years . Creation of large lesions are more effective in preventing recurrence, but are associated with a higher likelihood of facial numbness and dysesthesia. Several series have evaluated the outcome of radiofrequency rhizotomy. One prospective study of 154 patients found that 99 percent obtained initial pain relief . Dysesthesia occurred in 31 patients (23 percent) and motor weakness in 22 (14 percent); the paresis resolved within one year in 19 of the latter patients. The authors estimated that the 14-year recurrence rate was 25 percent. A second study in 1000 patients found that pain relief was achieved in 95 percent; permanent complications included masseter weakness in 105 patients, oculomotor palsies in 5 patients, weakening of the corneal reflex in 197 patients (6 of whom requested an ocular operation for keratitis), and painful dysesthesia in 52 patients. It is possible for patients who have a recurrence of symptoms after rhizotomy to undergo microvascular decompression. In the study cited above, having undergone a previous ablative procedure did not lessen the likelihood of symptom relief after microvascular decompression, but the rates of burning and aching facial pain were higher if a trigeminal ganglion lesion had been created with radiofrequency before microvascular decompression . Glycerol rhizolysis — Retrogasserian glycerol rhizolysis involves the injection of 0.1 to 0.4 mL of glycerol into the trigeminal cistern . A tingling or burning sensation is felt on the face, and pain relief is usually immediate (although may require up to seven days). Sensory loss can occur and is not necessary for pain relief, although long-term relief may be greater in patients who experience some sensory loss. Pain recurrence is common after glycerol rhizolysis, with recurrence rates by six years as high as 92 percent. A single-center case series of 92 patients (including 50 with previous surgery for TN) reported that 23 patients (35 percent) received either no benefit or experienced recurrent pain and required additional surgery at a mean of 7.5 months after rhizolysis. Excellent facial pain outcome (defined as no pain and no medications) was noted in 48 patients (50 percent) at a mean follow-up of 28.7 months. Balloon compression — Balloon compression is performed using a Fogarty catheter to compress the gasserian ganglion. The balloon is inflated with 0.5 to 1.0 mL of contrast dye for 1 to 6 minutes.This produces immediate pain relief but there may be persistent discomfort from dysesthesias. Gamma knife radiosurgery — Gamma knife therapy produces lesions with focused gamma radiation . The therapy is aimed at the proximal trigeminal root since therapy of the gasserian ganglion produced poor results. The aiming of the beams is carried out with a stereotactic frame and MRI. The doses used are 70 to 90 Gy. The beams cause axonal degeneration and necrosis . Data on radiosurgery for trigeminal neuralgia are predominantly observational and of generally poor quality. One study found that treatment response did not correlate with the dose of radiation . Treatment response correlated with vascular compression of the trigeminal nerve, as visualized on high resolution MRI, in some, but not all [, reports. Pain relief with gamma knife surgery occurs after a lag time of about one month. A systematic review of these data found that approximately 75 percent of patients report complete relief within three months, but this number decreases to 50 percent by three years. Less than 50 percent of patients can permanently stop drug therapy after surgery. Sensory disturbances (eg, numbness, paresthesias, dysesthesias) are the most frequent complications. New or worsened facial sensory impairment occurred in 20 percent of patients in one series with a median latency to onset of 35 months after treatment. Patients who fail to respond to radiosurgery or who have recurrence of symptoms may respond to repeat treatment. These outcomes are similar to those achieved with other ablative techniques. However, while these findings suggest that many patients have a good outcome with radiosurgery, the efficacy of this technique should be studied in a randomized, controlled trial. In addition, long-term results are still unknown. Linear accelerator radiosurgery — Dedicated linear accelerators provide a means for noninvasive, outpatient treatment of trigeminal neuralgia, without patient sedation. Linear accelerator radiosurgery is a similar modality to gamma knife radiosurgery but with a different source of radiation. 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. Another series of 32 patients reported overall good or excellent results of 78 percent of patients with a median time to pain relief of six weeks. Further study of this technique is warranted. Peripheral neurectomy — Peripheral neurectomy can be performed on the branches of the trigeminal nerve: supraorbital, infraorbital, alveolar, and lingual nerves. Neurectomy is accomplished by incision, alcohol injection, radiofrequency lesioning, or cryotherapy. Cryotherapy involves freezing of the nerve using special probes, in theory to selectively destroy the pain fibers. Summary — Patients with TN who are unresponsive or suffer intolerable adverse effects with medical therapy are candidates for surgery. The two most commonly performed procedures are radiofrequency rhizotomy and microvascular decompression. Microvascular decompression is invasive, although the overall mortality and complication rate are low, and the procedure is associated with the best long-term outcome. Rhizotomy is less invasive and associated with a high initial response rate, but recurrence is common and the incidence of facial numbness is higher than with microvascular decompression. Patients who have undergone rhizotomy and had a recurrence can successfully undergo microvascular decompression. |
A study of 1185 patients who had the procedure
performed during a 20-year period (median follow-up 6 years) found that immediate
postoperative relief was complete in 82 percent of patients, partial in 16 percent, and
absent in 2 percent. One year after surgery, 75 percent of the patients had complete
relief after the first operation (excellent outcome), and 9 percent had partial relief
(good outcome). Ten years after the procedure, 64 percent had excellent results and 4
percent had partial relief. 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 recurrence. Major complications included
two deaths shortly after the operation (0.2 percent) and one brain-stem infarction (0.1
percent). Sixteen patients (1 percent) developed ipsilateral hearing loss and 11
experienced severe facial numbness. The rate of complications was significantly reduced
and no deaths occurred after intraoperative monitoring of brainstem evoked response began
in 1980.