Trigeminal Neuralgia

Women are more at risk than men of trigeminal neuralgia, but the association is not as strong if correction is made for women living longer than men. The strongest association of having trigeminal neuralgia is with multiple sclerosis, which has been seen in both epidemiological data and in data for multiple sclerosis. There may be an association with hypertension and stroke, but this could be due to chance association.

Strong empirical evidence indicates that vascular compression of the trigeminal nerve root is associated with trigeminal neuralgia in about 95% of patients. However, the exact pathophysiology of how vascular compression leads to trigeminal neuralgia remains speculative. Popular hypotheses include a combination of central demyelination of the nerve root entry zone and reinforcing electrical excitability (the ignition hypothesis). Recent studies suggest that this demyelination then leads to an impairment of the nociceptive system. Those patients with more background pain seem to have a loss of central inhibition of the nociceptive system; even after successful surgery, some form of abnormality of somatosensory function remains.

Other factors including predisposing biology on a genetic basis are likely to be important because although rare, familial clusters do exist.

The remaining small subset of trigeminal neuralgia cases are associated with multiple sclerosis plaques or lacunar infarctions within the brain stem trigeminal system or cerebellopontine mass lesions.

Trigeminal neuralgia often starts suddenly with a memorable onset. The periods of remission tend to get shorter with time and the attacks of pain often get longer; 65% of patients newly diagnosed with trigeminal neuralgia will have a second episode within five years, and 77% within 10 years. Fifty per cent of patients will have remissions of at least six months’ duration. Patients can have as few as three or four attacks a day, but they could have as many as 70 per day. At times the attacks of pain come so quickly that it is impossible to determine whether there is a gap between each attack. There is often a refractory period when the pain cannot be triggered. Pain can occur at night in a third of patients. It is unusual to have trigeminal neuralgia in the first ophthalmic division of the trigeminal nerve only.

Some patients continue to have a background pain of lower intensity for 50% of the time. This condition has variously been called atypical trigeminal neuralgia, type 2 or—in the new International Classification for Headache Disorders—trigeminal neuralgia with concomitant persistent facial pain. Some patients might also have autonomic features such as conjunctival injection, lacrimation, nasal congestion or rhinorrhoea, eyelid oedema, ptosis, or facial sweating. In the presence of autonomic symptoms, it can be difficult to determine whether this is still trigeminal neuralgia or a variant known as short unilateral neuralgiform pain with autonomic symptoms (SUNA) or short unilateral neuralgiform pain with conjunctival injection and lacrimation (SUNCT).

Trigeminal neuralgia itself is a purely clinical diagnosis. However, investigations could be required especially if red flags are present. These investigations are targeted towards identifying other craniofacial pain syndromes within a differential diagnosis of trigeminal neuralgia and identifying non-vascular compressive causes of trigeminal neuralgia.

The most useful investigation is an MRI scan of the brain with and without contrast, which is used to rule out other potential causes of pain if the diagnosis is not clear cut or if red flags are present.

MRI is the most sensitive screening and diagnostic test available for detecting multiple sclerosis and has the highest positive predictive value. Although rare, brain tumours can be associated with trigeminal neuralgia. Posterior fossa tumours are the tumours most likely to be associated with typical trigeminal neuralgia pain characteristics, and are most commonly vestibular schwannomas, meningiomas, or epidermoid cysts.

Pharmacological treatment

Anti neuropathic drugs are the mainstay of management in trigeminal neuralgia. Carbamazepine remains the drug of choice, though this is based on small randomized controlled trails of poor quality. However incidence of side effects, is high , mainly central nervous system effects such as tiredness and poor concentration and there is a high risk of drug interactions. The second drug of choice is oxcarbazepine, a keto derivative of carbamazepine that has shown similar efficacy to carbamazepine but increased tolerability and fewer drug interactions.

Carbamazepine should be started at 100 mg up to twice daily, and titrated in steps of 100 – 200 mg every two weeks, until pain is relieved. In the majority of people a dosage of 200 mg three or four times a day is sufficient to prevent paroxysms of pain (maximum dosage 1,600 mg daily). Modified release preparations may be useful at night if the person experiences breakthrough pain. Once pain is in remission, the dosage should be gradually reduced to the lowest possible maintenance level, or the drug can be discontinued until a further attack occurs.

Do not prescribe carbamazepine to people:

• With a known hypersensitivity to carbamazepine or structurally related drugs (for example tricyclic antidepressants) or any other component of the formulation.
• With atrioventricular block.
• With a history of bone marrow depression.
• With a history of hepatic porphyrias.
• Taking a monoamine oxidase inhibitor.

Prescribe carbamazepine with caution to people:

• At risk of suicide.
• With cardiac disease.
• With a history of haematological reactions to other drugs.
• With a history of absence and myoclonic seizures.
• Who are susceptible to angle-closure glaucoma.

Adverse effects of Carbamazepine

Common adverse effects of carbemazepine include nausea and vomiting, sedation, dizziness, and ataxia.

• These adverse effects are dose related and are most common at the start of treatment and in older people.
• Switching to a modified-release preparation of carbamazepine may help to reduce the incidence of central nervous system adverse effects, such as sedation.

• Allergic skin reactions (including urticaria, which may be severe) are also common:
  • Withdraw carbamazepine if the skin reaction worsens, or is accompanied by other symptoms.
• Rarely, serious dermatological adverse effects, including Stevens-Johnson syndrome and exfoliative dermatitis, can occur.
  • People who are of Han Chinese, Hong Kong Chinese, or Thai origin should be screened for the presence of the HLA–B*1502 allele before taking carbamazepine. Those who test positive should not start carbamazepine unless there is no other treatment option.
  • Testing for this allele should also be considered in people originating from Malaysia and the Philippines.
• Hyponatraemia occurs in 20% of people taking carbamazepine. It is usually mild but in rare cases can lead to water intoxication accompanied by lethargy, vomiting, headache, and confusion.
  • Consider hyponatraemia if the person develops dizziness, drowsiness, confusion, nausea, muscle cramps, or seizures.
  • If hyponatraemia is suspected, reduce the dose or stop carbamazepine and manage according to severity of symptoms, duration, and state of hydration.
• Leucopenia (very common) and other blood disorders (including thrombocytopenia, agranulocytosis, and aplastic anaemia) may occur with carbamazepine treatment.
• Advise people taking carbamazepine to seek immediate medical attention if they develop symptoms indicative of blood, hepatic, or skin disorders (for example fever, sore throat, rash, mouth ulcers, bruising, or bleeding).
• There is a small risk of suicidal thoughts and behaviour associated with antiepileptic drugs, which may be seen as early as one week after starting treatment.
  • People taking carbamazepine and healthcare professionals should be alert to any mood changes, distressing thoughts, or feelings about suicide or self-harm at any point during treatment.

• A full blood count should ideally be done before starting treatment, and periodically thereafter.
  • If the white blood cell or platelet count is low or decreased during treatment, the person should be closely monitored.
  • Stop treatment if leucopenia develops that is severe, progressive, or accompanied by clinical symptoms (e.g. fever or sore throat), or if there is any evidence of significant bone marrow depression.
• Liver function tests should also be performed before commencing treatment and periodically thereafter, particularly in patients with a history of liver disease and in elderly patients.
  • The drug should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease.
  • Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase.

Other drugs that have been used in management of trigeminal neuralgia include:

• Gabapentin
• Pregabalin
• Amitriptyline
• Nortriptyline
• Lamotrigine
• Baclofen

• Antispasmodic agents. Muscle-relaxing agents such as baclofen may be used alone or in combination with carbamazepine. Side effects may include confusion, nausea and drowsiness.

Microvascular decompression. This procedure involves relocating or removing blood vessels that are in contact with the trigeminal root to stop the nerve from malfunctioning. Microvascular decompression can successfully eliminate or reduce pain most of the time, but pain can recur in some people. Microvascular decompression has some risks, including decreased hearing, facial weakness, facial numbness, a stroke or other complications. Most people who have this procedure have no facial numbness afterward.

Brain stereotactic radiosurgery (Gamma knife). In this procedure, a surgeon directs a focused dose of radiation to the root of your trigeminal nerve. This procedure uses radiation to damage the trigeminal nerve and reduce or eliminate pain. Relief occurs gradually and may take up to a month.Brain stereotactic surgery is successful in eliminating pain for the majority of people. If pain recurs, the procedure can be repeated. Facial numbness can be a side effect.

Radiofrequency lesioning of trigeminal nerve and glycerol injection can also be used in management of trigeminal neuralgia.

Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, mostly by acting on neurogenic inflammatory mediators and controlling the neurotransmitter release of sensory and autonomic nerve terminals that are involved in many chronic painful conditions as chronic intractable trigeminal neuralgia.

The analgesic effect of BTX-A has been investigated through a series of open-labeled studies as well as a few randomized controlled trials (RCTs), with an increasingly strong evidence that botulinum toxin injections are efficacious, thus placing it as a treatment option either before surgery or for those with intractable trigeminal neuralgia and unwilling to undergo surgery, however, a more placebo-controlled clinical trials are still needed to confirm these findings.

The role of BTX-A in the treatment of drug-refractory trigeminal neuralgia has been evaluated by some authorities and it was found to be an effective treatment with the majority of the patients reporting a reduction or even disappearance of the pain. BTX-A was found to be effective in combination with pharmacotherapy, prior to considering more invasive therapies such as surgery or gamma knife radiosurgery. As such, BTX-A is a particularly valuable treatment for elderly patients and those with adverse anesthetic comorbidities. However, these studies included small patients number or of low-quality RCTs.

The mechanism by which BTX-A exerts its antinociceptive effect is poorly understood; whether or not BTXA can change sensory perception in those patientsremains unknown. Cui et al demonstrated that subcutaneous BTX-A injection is associated with the inhibition of formalin-induced glutamate release; an important mediator for the induction and maintenance of central sensitization of pain. BTX-A may also reduce the peripheral nociceptive input by inhibiting the release of substance P and calcitonin-gene-related peptide (CGRP), both of which would play a very important role in neurogenic inflammation. Moreover, BTX-A can reduce the release of other neurotransmitters and neuromediators including epinephrine and norepinephrine.

Regarding safety of BTX-A, injection-related side effects have been reported: facial asymmetry and edema/ hematoma at the site of injection, both of which are generally well tolerated and transitory in nature. Overall botox injections are well tolerated and any side effects are transient.