Trigeminal Neuralgia
(tic douloureux)
(Review article for physicians; please also see this blog post about the use of Botox for trigeminal neuralgia)
Alexander Mauskop, M.D.
Director, New York Headache Center
From Journal of Pain and Symptoms Management, 1993.
Abstract
Trigeminal neuralgia is not a common but a debilitating pain syndrome. After the diagnosis is established, a stepwise approach to treatment is recommended. Carbamazepine is the drug of choice. When carbamazepine fails to relieve pain baclofen and then phenytoin are used. A number of second-line drugs, such as clonazepam, divalproex sodium, chlorphenesine carbamate and pimozide can also be tried. A large number of patients will respond to one or another drug or to a combination of 2 drugs. When medical treatment fails several surgical procedures have been found to be effective. Percutaneous radiofrequency gangliolysis is the most widely used procedure with a high success rate. An experienced physician must perform all surgical procedures in order to achieve the lowest possible rate of serious complications.
Key Words: trigeminal neuralgia, carbamazepine, baclofen, phenytoin, clonazepam, divalproex sodium, pimozide, radiofrequency gangliolysis, microvascular decompression.
Trigeminal neuralgia (TN) or tic douloureux is associated with one of the most severe types of pain. The incidence of this condition according to the published studies seems to be too low, judging from personal experience. This may be in part because each patient leaves a strong and lasting impression. Their suffering is unusually intense and frightening. Fortunately, majority of these patients can be helped by pharmacological or surgical means.
Epidemiology
According to one study (1) the prevalence of TN is 155 cases per 1,000,000 which translates into 40,000 patients in the USA at any particular time. Another recent study (2) determined an incidence of 4.3 cases per 100,000. For women the rate was 5.9, while for men – 3.4 per 100,000. A similar rate was found by a different group of researchers (3). In women the incidence was 5.0 per 100,000, in men – 2.7, and the average was 4.0 per 100,000. It has been estimated that 15,000 new cases are diagnosed each year (4). A study in England (5) determined the annual incidence of new cases of TN to be 2.1 per 100,000 but under-reporting was suspected.
The average duration of TN is between few months and 7 years; spontaneous remissions occur. The age of onset is frequently in the 6th and 7th decades. When trigeminal neuralgia occurs in a young person, especially a woman, multiple sclerosis is a suspected cause. Multiple sclerosis and hypertension are the only 2 risk factors for TN identified in epidemiological studies (3). Approximately 1% of patients with multiple sclerosis has trigeminal neuralgia, while 3% of patients with trigeminal neuralgia have multiple sclerosis.
Clinical features
The definition of TN according to the classification by International Headache Society (IHS) is provided in Table 1. In clinical studies it is important to use as homogeneous groups of patients as possible, and this definition serves the purpose of such selection. In clinical practice such precise definition is less important. Several studies, however, indicate that patients with atypical trigeminal neuralgia are less responsive to treatment than ones with typical features. These atypical patients can often have symptomatic trigeminal neuralgia due to other treatable causes.
Some patients develop aching pain in the face for months or years before they go on to develop a typical TN (6). This, so-called pre-trigeminal neuralgia can be diagnosed only retrospectively.
Many patients with TN have very intense pain and grimace each time they have this lightning-like pain. Others are able to maintain their composure and may not appear to be in severe pain. Some patients can continue to function despite the pain, while others become disabled, malnourished and depressed.
In addition to the usual triggers, which include chewing, talking, brushing teeth and touching the face, some patients have attacks that are provoked by vigorous physical activity, by lowering their head with blood rushing into the face and even by wind blowing at the face. Most commonly trigger areas are situated around the mouth and nose.
The right side is affected more frequently than the left. When a single branch of the trigeminal nerve is affected most frequently it is the 2nd branch (44%); the 3rd is involved in 36% and the 1st in 20%. More common is involvement of 2 or 3 branches together. About a third of all patients with TN have involvement of both the 2nd and 3rd divisions. In 3-5% of patients pain occurs bilaterally. Family clustering of this condition is rare, but when present tends to increase the risk of bilateral involvement (7). The other side is involved not by extension of pain from one side but due to an independent neuralgia.
Differential diagnosis
A multitude of conditions can cause severe facial pain. Differential diagnosis of facial pain is listed in Table 2. Some of these conditions are easily distinguished from trigeminal neuralgia, while others may pose a great challenge. Many of the conditions listed do not cause lancinating electric-like pain. Those that can mimic typical pain of TN include posterior fossa tumors, aneurysms and arterio-venous malformations. On surgical exploration of posterior fossa in patients with TN tumors are found in up to 2.7% of cases (8).
The work-up of a patient with trigeminal neuralgia should include an MRI scan of the brain. If an MRI scanner is not available a contrast-enhanced CT scan can be done with thin cuts through the posterior fossa. Depending on the associated symptoms a variety of other tests may be necessary to rule out the conditions listed in the Table 2.
Pathophysiology
Vascular compression of the root of the trigeminal nerve is seen in many patients who undergo posterior fossa surgery. The high efficacy of microvascular decompression suggests that a peripheral lesion causes TN. Some features of TN, however, indicate a central mechanism. These features include triggering of pain by a stimulus outside the area of pain, latent period between the triggering event and pain, as well as a refractory period after the pain when another paroxysm of pain cannot be provoked. Not surprisingly, a theory combining these 2 mechanisms is the one most widely accepted (9). It is thought that a peripheral anatomical lesion leads to segmental demyelination of the nerve with development of ephaptic transmission, or cross-talk, that eventually leads to secondary changes in the spinal trigeminal nucleus. These changes include reduction in the mechanism of surround inhibition with activation of a larger than normal number of wide-dynamic-range neurons that leads to perception of pain from a tactile stimulus (10,11). Carbamazepine is thought to relieve pain of TN by facilitating inhibition in the spinal trigeminal nucleus.
Medical therapy
First-line drugs.
Carbamazepine (CBZ) is the drug of first choice for the treatment of TN. The medication is started at a low dose of 100 mg twice a day in order to avoid nausea and somnolence that can be intolerable at a higher starting dose. The dose is increased by 100 mg every day to the point of pain relief or development of unacceptable side effects. The daily amount is given in 3 or 4 doses. Monitoring blood levels is necessary when high doses are used, malabsorption, non-compliance or toxicity is suspected. Correlation between the blood level and the analgesic effect in TN has been established (12). It is common to see a decline in the efficacy of CBZ on a steady dose. This often is due to the phenomenon of autoinduction of metabolism of CBZ. By increasing the dose of CBZ and bringing the drug level up again pain control can be regained. Unfortunately, patients often develop tolerance and pain may recur even with a high therapeutic blood level. The much feared blood dyscrasias due to CBZ are less common than it was originally believed. They are also believed to be idiosyncratic reactions and monitoring the blood cell count may not always prevent them. Some decline in the white cell count is common after the initiation of carbamazepine therapy. Various schedules of blood monitoring can be found in the literature, while the manufacturer of CBZ no longer advises a certain frequency of testing. It is reasonable to check blood cell count prior to the treatment and then 2 weeks, 1 month and 3 months after the initiation of treatment. At the same time hepatic functions should also be checked because of potential hepatotoxicity, although it is very rare. It is more important to warn the patient to contact a physician in cases of a fever, sore throat, bruises, stomatitis or other symptoms.
A small number of patients does not respond to CBZ or does not tolerate it. Some of those who do respond initially develop tolerance and stop responding after a period of months or years. These patients should placed on baclofen.
Baclofen
Baclofen is recommended by some (13) as the initial therapy because of lack of serious side effects. It had 74% effectiveness in a double-blind study of 50 patients (14). This drug is an analog of GABA, an inhibitory neurotransmitter. It is used for the treatment of spasticity in multiple sclerosis and spinal cord injuries. The usual starting dose is 5 mg 3 times a day with a gradual increase up to 20 mg 4 times a day. Although, 80 mg is the highest recommended dose, the use of much higher doses have been reported for spasticity of multiple sclerosis (15). The most common side effects are transient drowsiness, dizziness and fatigue. The effectiveness of baclofen, like that of CBZ, can also decline with time. In such patients combination of baclofen with carbamazepine or phenytoin can be synergistic and can provide better relief than either one of these drugs alone.
Phenytoin
The first reports of phenytoin efficacy in TN appeared soon after its introduction as an anticonvulsant (16). Phenytoin is somewhat less effective than CBZ but it has certain advantages. As with CBZ, general principles of phenytoin use as an anticonvulsant apply to its use for TN. Titration of the daily dose is necessary in many cases, but there is no need to start with a low dose. The usual daily amount of 300 mg can be given in a single dose if Dilantin brand or extended phenytoin sodium capsules are used. Phenytoin has the advantage of being available parenterally for patients who are in a crisis or are unable to take medications by mouth. Side effects of phenytoin include drowsiness, nausea and, with long term use gingival hyperplasia and hirsutism. Dose-related side effects include nystagmus, slurred speech, ataxia and confusion.
2nd line drugs
Less frequently used drugs include clonazepam, pimozide chlorphenesine carbamate, divalproex sodium, corticosteroids, oral local anesthetics, and narcotic analgesics.
Clonazepam has been reported to be effective in two thirds of patients with TN (17,18,19). Clonazepam is a benzodiazepine with a potential for addiction, although in patients with a typical trigeminal neuralgia it is rarely a valid concern. The most common side effect of clonazepam is sedation, but gradual escalation of the dose allows time for the development of tolerance to this side effect. The usual starting dose is 0.5 mg three times daily. The maximum recommended daily dose is 20 mg.
In a double-blind crossover study comparing pimozide with CBZ all 48 patients with TN improved on pimozide, while only 56% improved on CBZ (20). Pimozide is a neuroleptic drug approved as a second-line drug for treatment of tics in patients with Tourette’s Disorder. Because of the potential for serious side effects, such as tardive dyskinesia, this drug should be reserved for patients who failed other medical approaches and are not willing to undergo surgery.
Divalproex sodium is another anticonvulsant that can be used with some success (21). Again, the same principles used for the treatment of seizures apply when treating TN. The initial dose is 250 mg a day with rapid escalation to 250 three times a day and much higher, depending on the response, side effects and blood levels. The average therapeutic level of 50-100 mcg/ml can be exceeded if the patient tolerates it. Common side effects include nausea, sedation and tremor. Occasionally transient hair loss and weight gain can occur.
Chlorphenesine carbamate, which is used as a muscle relaxant, has been recommended for TN when the main 3 drugs are ineffective (22). The usual dose is 400-800 mg 3 or 4 times a day. This drug has few side effects.
A large intravenous bolus of corticosteroids (for example, 20-40 mg of dexamethasone) can be tried in a patient who is in a crisis with an attack of very frequent and severe tics. Corticosteroids should not be used for any length of time because of their potential for serious side effects and low efficacy.
Opioids are rarely effective without producing sedation and should be also reserved for unusually severe and refractory cases when a short period of sedation is desirable.
Local anesthetics given orally are known to be helpful in some pain syndromes. Tocainide has been shown to relieve pain of TN (23) but it has a high incidence of hematological side effects. Mexiletine is another local anesthetic, antiarrhythmic agent that can relieve pain of diabetic neuropathy (24) and thalamic pain (25) but it failed to relieve pain of TN in 4 patients (26). Because only 4 patients were studied no conclusions about its efficacy can be made and a trial of this drug is reasonable when other medications fail. Cardiac status must be assessed before initiating this medication.
Surgical approaches
Peripheral procedures
A variety of procedures involving the peripheral branches of the trigeminal nerve have been attempted (27). This is a logical first step after the failure of medical therapy. The relief is usually not sustained but many patients prefer to repeat these procedures rather than undergo more risky gangliolysis or microvascular decompression. Usually, a block of the trigger zones is done using local anesthetics. If this procedure provides some temporary relief alcohol injection or cryotherapy can produce a remission that in some patients will last for 3-6 months. Nerve avulsion has been done by some surgeons but the rate and duration of success of this procedure is not known.
Glycerol injection
Percutaneous glycerol injection into the gasserian ganglion is thought to destroy large myelinated fibers that conduct triggering impulses. Another possible explanation of its effect is destruction of the partially demyelinated fibers involved in ephaptic transmission (28). This procedure has a high initial success rate of 75-90% but also a high recurrence rate (29). Its proponents, however, claim that it produces less sensory loss than other destructive procedures. Some patients are unable to tolerate radiofrequency gangliolysis because of pain or anxiety. They may prefer glycerol injection, which does not require patient cooperation and can be done under general anesthesia or with intravenous sedation.
Radiofrequency gangliolysis (RFG)
Percutaneous radiofrequency lesioning of the gasserian ganglion is probably the most popular surgical procedure with over 14,000 cases published in 33 reports (30). Although a selective destruction by graded heating of A-delta and C fibers has been assumed, the evidence for this selectivity in humans is not convincing. Initial pain relief occurs in 88-99% of patients but the recurrence rate is 20-30% (30, 31). The electrode is introduced into the ganglion under fluoroscopic guidance as in all percutaneous procedures. Mild stimulation is used to position the electrode. When this stimulation produces paresthesias in the affected branch of the nerve the current is turned up. The surgeons are cautioned to undertreat in order to reduce the chance of anesthesia dolorosa and sensory loss. Such undertreatment by reducing the temperature and duration of thermocoagulation produces lower success rate but the treatment can be repeated.
Percutaneous microcompression
Percutaneous microcompression of the ganglion is done by introducing a balloon into the Meckel’s cave and inflating it (32, 33). The degree of inflation and its duration determine the extent of damage to the ganglion and correspondingly the success rate as well as the degree of sensory loss. The advantages of this technique include relative simplicity compared to RFG. It is painless as it is done under general anesthesia. It is claimed to be as safe as RFG, although it obviously has the added risk of general anesthesia.
Complications of percutaneous procedures
Percutaneous techniques are all considered to be much safer than microvascular decompression. Morbidity and mortality, however is not zero as some authors claim. Percutaneous glycerol injection has been reported to cause cardiac arrest in 2 patients (34). One patient developed it immediately after penetration of the needle into the foramen ovale. That patient was quickly resuscitated and the procedure was completed. The second patient developed cardiac arrest after the procedure and could not be resuscitated. Six patients have been reported to die from an intracranial hemorrhage induced during RFG (30). Other complications include meningitis, abscess as well as cranial nerve injuries, including ophthalmic. These complications occur despite fluoroscopic guidance. Corneal anesthesia may occur and if no preventative measures are taken, it can lead to corneal ulceration. Anesthesia dolorosa is an extremely unpleasant and painful complication of destructive procedures that is very difficult to treat. Possible approaches to the treatment of anesthesia dolorosa include tricyclic antidepressants and anticonvulsants but frequently a long list of various medications is tried before some relief is obtained. Successful treatment of anesthesia dolorosa was reported using dorsal root entry zone (DREZ) lesioning of the nucleus caudalis which is a part of the spinal trigeminal nucleus (35). This procedure has been also used for the treatment of pain of postherpetic neuralgia.
Microvascular decompression
Proponents of this technique claim to address the etiology of this condition, which they assume to be compression of the trigeminal nerve by a blood vessel. Large numbers of patients treated by this method were found to have various blood vessels compress the trigeminal nerve. However, the role of such compression in producing TN remains unclear. The major disadvantage of this approach is the need for craniotomy. The long-term response rate is about 80%. Major complications in the most experienced hands include death in less than 1%, hematoma or infarction (1%), pneumonia and meningitis (8). Like with any other surgical procedure less experienced surgeons have much higher incidence of complications (30). All TN patients should be referred only to surgeons who perform a large number of these operations, rather than to a local neurosurgeon.
Table 1.
Diagnostic criteria according to the International Headache Society’s classification (x)
A. Paroxysmal attacks of facial or frontal pain which last a
few seconds to less than two minutes.
B. Pain has at least 4 of the following characteristics:
1. Distribution along one or more divisions of the
trigeminal nerve
2. Sudden, intense, sharp, superficial, stabbing or
burning in quality
3. Pain intensity severe
4. Precipitation from trigger areas, or by certain daily
activities such as eating, talking, washing the face
or cleaning the teeth
5. Between paroxysms the patient is entirely asymptomatic
C. No neurological deficit.
D. Attacks are stereotyped in the individual patient.
E. Exclusion of other causes of facial pain by history,
physical examination and special investigations when
necessary.
Table 2
Causes of facial pain
Dental
acute pulpitis
acute periodontitis
periodontal abscess
cracked tooth syndrome
denture trauma
TMJ syndrome
atypical odontalgia
Diseases of the jaw
acute osteomyelitis
fractures
infected cysts
malignant tumors
Disease of salivary glands
salivary calculi
acute infection
Sjogren’s syndrome
tumors
Sinus disease
sinusitis
viral
bacterial
fungal
mucocele
malignant tumors
carcinoma
sarcoma
lymphoma
Ear pain
injury
squamous cell carcinoma
infections
otitis
mastoiditis
cellulitis
perichondritis
chondritis
herpes simplex
herpes zoster
Ophthalmic
glaucoma
optic neuritis
iritis and uveitis
orbital pseudotumor
orbital tumor
Intracranial
glossopharyngeal neuralgia
trigeminal neuralgia
cluster headache
ice-pick pain
inflammation
infections
aneurysm
stroke
tumor
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