Trigeminal Neuralgia

Trigeminal neuralgia is a unilateral disorder of recurrent, brief, electric shock-like pain in one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. Incidence is 4 to 13 per 100,000 per year, the peak age is 50 to 70 years, and women are affected about 1.5 times more often than men.

Classification

• Classical: caused by neurovascular compression with morphological changes of the trigeminal root, usually the superior cerebellar artery loop at the root entry zone.
• Secondary: due to an identifiable structural disease such as multiple sclerosis (2 to 4% of cases, often younger and bilateral), cerebellopontine angle tumour (meningioma, schwannoma, epidermoid), or arteriovenous malformation.
• Idiopathic: no cause identified on MRI.

Each subtype is further described as purely paroxysmal or with concomitant continuous pain.

Pathophysiology

• Chronic compression produces focal demyelination of the nerve near the pons.
• Ectopic discharge and ephaptic transmission between damaged axons cause paroxysmal bursts evoked by touch.
• Central sensitisation contributes to the refractory period and, in some patients, to a persistent dull background pain.

Distribution

• Involvement of V2 and V3 is most common, V1 alone in under 5%, and the right side is affected slightly more often. Bilateral disease is uncommon in classical disease and raises the likelihood of multiple sclerosis.

Typical attack features

• Abrupt, severe, stabbing or electric pain lasting from a fraction of a second to 2 minutes, in clusters through the day.
• Pain confined to the trigeminal distribution, unilateral, and often along the lip, cheek, gums or chin.
• Triggers include light touch, washing, shaving, applying make-up, brushing teeth, chewing, speaking, and cold wind. Patients avoid eating and drinking, and can lose weight and become depressed.
• A refractory period follows each attack. Pain rarely wakes the patient from sleep.
• Remissions of weeks to months occur early, and shorten with time.

Neurological examination is normal in classical disease. Subtle sensory change suggests another cause.

Red flags indicating secondary disease

• Sensory deficit, reduced corneal reflex, or facial weakness.
• Onset below 40 years of age.
• Bilateral symptoms.
• Isolated V1 distribution.
• Continuous pain, with little relation to triggers.
• Hearing loss, vertigo, or other cranial neuropathy.
• Poor response to carbamazepine.
• Concurrent MS symptoms.

Differential diagnosis

• Dental pain, temporomandibular disorder, sinusitis.
• SUNCT and SUNA (autonomic features, very short bursts of 1 to 600 seconds, often periorbital).
• Cluster headache, post herpetic neuralgia and trigeminal neuropathic pain, persistent idiopathic facial pain, glossopharyngeal neuralgia, giant cell arteritis, and occipital neuralgia.

Diagnosis is clinical. Imaging establishes the cause rather than the diagnosis.

MRI is indicated in all patients at diagnosis

• High resolution 3D heavily T2 weighted sequences (CISS or FIESTA) show the root and compressing vessel. Add MR angiography (time of flight) for vessel relationships.
• Features supporting classical disease: neurovascular contact with root displacement or atrophy.
• Gadolinium enhanced MRI excludes tumours, demyelinating plaques in the pons or root entry zone, and AVM.

Other tests

• Trigeminal reflex testing (blink reflex, trigeminal evoked potentials) distinguishes symptomatic from classical disease when MRI is unavailable or ambiguous.
• Before starting carbamazepine, check sodium, full blood count, liver and renal function, and ECG if cardiac conduction disease is suspected.
• HLA-B1502 testing is advised in patients of Han Chinese, Thai, Malaysian and other Southeast Asian ancestry, and HLA-A3101 in patients of European and Japanese descent, because of the risk of Stevens-Johnson syndrome and drug hypersensitivity.
• ESR and CRP if giant cell arteritis is possible.
• Dental and ENT review when the pain description is atypical.

First line drug therapy

• Carbamazepine: start 100 mg twice daily (or 100 mg at night in the elderly), increasing by 100 mg every 1 to 3 days to pain control, usually 600 to 1200 mg/day in 2 to 4 divided doses. The maximum is 1600 mg/day. Controlled release tablets help adherence.
• About 70% respond initially. The number needed to treat is under 2.
• Monitor sodium, blood count and liver enzymes at baseline, at 2 to 4 weeks, then 3 to 6 monthly.
• Adverse effects include dizziness, ataxia, drowsiness, diplopia, hyponatraemia, rash, leukopenia, and hepatotoxicity.
• It induces CYP3A4 and reduces levels of warfarin, DOACs, oral contraceptives and many others. It is teratogenic.
• Oxcarbazepine: start 300 mg twice daily, increase by 300 mg every 3 days to 900 to 1800 mg/day (maximum 2400 mg/day). It causes less enzyme induction but has a higher risk of hyponatraemia.

Second line and add-on drugs

• Baclofen 5 mg three times daily, increasing by 5 mg every 3 days to 40 to 80 mg/day. Do not stop abruptly.
• Lamotrigine 25 mg daily, increasing every 2 weeks to 200 to 400 mg/day (slow titration to limit rash).
• Gabapentin 300 mg at night, titrated to 900 to 3600 mg/day. Pregabalin 75 mg twice daily increased to 150 to 300 mg twice daily.
• Phenytoin 100 mg three times daily, topiramate 50 to 200 mg/day, and botulinum toxin type A 50 to 100 units given intradermally or submucosally in the painful area, for refractory pain.
• Topical lidocaine on trigger zones gives temporary relief. Opioids are ineffective and best avoided.

Acute severe exacerbation

• Admit for hydration and nutrition.
• IV fosphenytoin 15 mg phenytoin equivalents per kg (maximum 150 mg PE/min), or IV lidocaine 1.5 to 2 mg/kg over 30 to 60 minutes with ECG monitoring. Sumatriptan 3 mg SC has also been used.

Surgical and interventional options Considered with refractory pain, drug intolerance, or patient choice:

• Microvascular decompression: the preferred option for classical disease in fit patients with a demonstrable vascular conflict. About 85 to 90% are initially pain free, and 70 to 75% remain so at 10 years. Mortality is 0.2 to 0.5%. Risks include CSF leak, aseptic meningitis, facial numbness, hearing loss and infarction.
• Stereotactic radiosurgery (gamma knife): 70 to 90 Gy to the nerve root entry zone using a 4 mm collimator. Pain relief begins at weeks to months, 70 to 80% initially respond, and recurrence rates rise with time. Facial numbness occurs in about 10 to 30%.
• Percutaneous procedures through the foramen ovale: radiofrequency thermocoagulation (65 to 90 degrees Celsius for 60 to 90 seconds), glycerol rhizolysis, and balloon compression (inflation to about 1.3 atm for 1 to 1.5 minutes). They are useful in frail patients and in multiple sclerosis. Facial numbness, corneal anaesthesia and anaesthesia dolorosa are potential risks.
• Peripheral neurectomy or nerve blocks have limited and short lived benefit.

Long term care

• Once pain free for several months, try slow tapering of the drug over weeks to months, because spontaneous remission occurs.
• Corneal protection and ophthalmology review in V1 involvement with sensory loss.
• Dental review and nutrition support, with screening for depression.
• Treat the primary lesion in secondary disease: tumour resection, MS disease modifying therapy, and AVM management.
• Counsel women of childbearing age on carbamazepine teratogenicity and the need for folic acid 5 mg daily and contraceptive counselling.