Trigeminal Neuralgia

Etiology

The trigeminal nerve is the largest cranial nerve and is responsible for the sensory supply of the face and the motor and sensory supply to the muscles of mastication. The trigeminal nerve has peripheral sensory components converging at the trigeminal ganglia that relay touch, pain, and temperature information from the ipsilateral face to the contralateral thalamus via the trigeminothalamic tract.[2]

The trigeminal nerve has 3 divisions: ophthalmic (V1), maxillary (V2), and mandibular (V3). The anatomical areas innervated by each division are as follows:

• Ophthalmic (V1): eye, upper eyelid, and forehead
• Maxillary (V2): lower eyelid, cheek, nostril, upper lip, and upper gingivae
• Mandibular (V3): lower lip, lower gingivae, jaw, and the muscles of mastication.

Most cases of trigeminal neuralgia are secondary to compression of the trigeminal nerve root within a few millimeters of its entry into the pons. In 80% to 90% of these cases, the nerve root is compressed by an adjacent artery or a vein; the superior cerebellar artery is implicated in 75% to 80% of these circumstances.[3] Other blood vessels known to compress the trigeminal nerve root and cause trigeminal neuralgia include the petrosal vein and the anterior inferior cerebellar or vertebral arteries. Trigeminal nerve compression may also be secondary to space-occupying lesions such as meningioma, acoustic neuroma, epidermoid cyst, arteriovenous malformation, or saccular aneurysm. Multiple sclerosis is a risk factor for developing trigeminal neuralgia and is the underlying etiology in approximately 2% to 4% of symptomatic patients secondary to demyelination of the trigeminal nerve nucleus.[4]

Epidemiology

Trigeminal neuralgia affects 4 to 13 per 100,000 people annually. Women are more commonly affected than men. The female-to-male prevalence ratio ranges from 1.5 to 1.7 to 1. Most cases of trigeminal neuralgia occur after age 50, but the disease may be seen in the second and third decades of life; trigeminal neuralgia is rarely diagnosed in childhood.[5] The lifetime prevalence of trigeminal neuralgia in population-based studies is estimated at 0.16% to 0.3%.[6]

The development of trigeminal neuralgia in a young person should raise suspicion of multiple sclerosis. The prevalence of trigeminal neuralgia in patients with multiple sclerosis is between 1% and 6.3%. Patients with hypertension have a slightly higher incidence of trigeminal neuralgia than normotensive persons.

Pathophysiology

Most cases of trigeminal neuralgia are due to trigeminal nerve compression and subsequent nerve demyelination in the area of compression. How demyelination leads to the symptoms of trigeminal neuralgia is unknown. It is hypothesized that ectopic impulse generation induced by the demyelinated lesion causes ephaptic transmission, defined as electrical conduction between adjacent neurons through extracellular spaces without using synapses or neurotransmitters.[7] The ephaptic link between fibers involved in pain generation and fibers mediating light touch could account for the precipitation of shock-like pains in the facial trigger zone by light tactile stimulation.

A triggered painful episode followed by a refractory period and a single stimulus leading to painful sensations indicates the possible role of the central pain mechanism in trigeminal neuralgia. Alterations in the sensory and motor cortical gray matter have been described in some patients with trigeminal neuralgia.[8]

Some theories describe demyelination secondary to vascular compression of the nerve root by tortuous or aberrant vessels. Radiologic and pathologic studies have demonstrated the proximity of the trigeminal nerve root to such vessels, especially the superior cerebellar artery.[9] These hypotheses are further strengthened by the relief of symptoms following procedures to separate the offending vessels from the nerve.

The bioresonance hypothesis states that when the vibration frequency of the trigeminal nerve and surrounding structures approach one another, the trigeminal nerve fibers are damaged, leading to abnormal transmission of impulses, resulting in facial pain.[10]

Other conditions, such as infiltrative amyloidosis, bony compression, arteriovenous malformation, and small infarcts in the medulla and pons, have been identified as etiologies of trigeminal neuralgia.

Subforms of Trigeminal Neuralgia

The International Classification of Headache Disorders, Third Edition (ICHD-3) identifies the following subforms of trigeminal neuralgia:

Classical trigeminal neuralgia: may be purely paroxysmal or with concomitant continuous pain and includes cases attributable to vascular compression of the trigeminal nerve or its root.

Secondary trigeminal neuralgia: may be attributable to multiple sclerosis, a space-occupying lesion, or other causes.

Idiopathic trigeminal neuralgia: is idiopathic and may be purely paroxysmal or with concomitant continuous pain.[1]

Histopathology

Demyelination is the presumptive primary pathophysiologic etiology of trigeminal neuralgia. Schwann cells, a type of glial cell, form the myelin sheath around peripheral nerves and secrete neurotrophic factors that promote axon regeneration. Studies have demonstrated that in patients with trigeminal neuralgia, activated Schwann cells degrade damaged myelin and secrete neurotrophic factors to help regenerate and remyelinate damaged axons; this process may serve as a therapeutic target in the future.[11] 

History and Physical

Trigeminal neuralgia is sometimes classified as type 1 or type 2.[5] Type 1 and type 2 trigeminal neuralgia may coexist in the same patient. Type 1 is predominately paroxysmal, and type 2 is a constant pain with or without paroxysmal episodes.[5] Paroxysmal pain is usually worst at or near its onset. Facial muscle spasms may be seen; hence, the historical name of the disease of tic douloureux.

Most patients with paroxysmal pain describe the pain as an electric or shock-like pain lasting from one to several seconds. Pain in TN is typically unilateral; right-sided symptoms are reportedly more common than left-sided symptoms for reasons unknown.[11] The pain is occasionally bilateral but very rarely co-occurs on both sides of the face.[12] The pain episodes seldom occur during sleep.

The V2 and V3 divisions of the trigeminal nerve are usually involved in the pain distribution.[1] When the V1 subdivision is involved, mild autonomic symptoms like lacrimation, rhinorrhea, and conjunctival injection can be seen. However, isolated V1 division involvement is rare and is seen in less than 5% of patients with trigeminal neuralgia.[13] 

Pain trigger zones may be present in the distribution of the affected nerve, usually near the midline and most often in the nasal and perioral regions. The pain of trigeminal neuralgia can be triggered or replicated by lightly touching these zones.[14] Patients with trigeminal neuralgia frequently know these trigger zones and avoid stimulating them. While not all patients with trigeminal neuralgia have trigger zones, their presence is nearly pathognomonic for the disease. Other reported triggers of trigeminal neuralgia paroxysms include tooth brushing, shaving, face washing, smoking, chewing, talking, grimacing, or exposure to cold air.[13] Younger patients with the signs or symptoms of trigeminal neuralgia should be questioned regarding the common symptomatology of multiple sclerosis, including neurological symptoms such as focal weakness, paresthesias, vision changes, dizziness, and ataxia. 

The physical examination of patients with trigeminal neuralgia does not regularly reveal a focal neurologic deficit. A detailed physical examination of the head, neck, eyes, ears, teeth, mouth, and temporomandibular joint is required to exclude other causes of facial pain. A sensory loss in a trigeminal nerve distribution, the loss of the corneal reflex, or weakness in facial muscles should prompt the consideration of secondary trigeminal neuralgia. A detailed oral examination is necessary to distinguish dental causes of pain from trigeminal neuralgia. Trigger zones, when present, are highly suggestive of trigeminal neuralgia.

Evaluation

Trigeminal neuralgia is usually suspected through historical and physical examination findings. Patients with a clinical diagnosis of trigeminal neuralgia should undergo neuroimaging with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) whenever possible. MRI is preferable to computed tomography.

The diagnostic criteria established by the ICHD-3 for trigeminal neuralgia are:

1. Recurrent paroxysms of unilateral facial pain in the distribution of the trigeminal nerve and fulfilling criteria B and C
2. Pain has all the following characteristics:
   • Pain lasting a fraction of a second to about 2 minutes
   • Pain with severe intensity
   • Electric shock-like, sharp, or shooting pain 
3. Innocuous stimuli within the affected nerve distribution precipitate the pain
4. No alternative ICHD-3 diagnosis better explains the symptoms.[1]

Neuroimaging studies may identify etiologies of secondary trigeminal neuralgia and vascular compression in primary cases.[15][16][17] In some machines, a targeted or high-resolution MRI, called FIESTA sequencing, can be performed with or without gadolinium contrast to obtain detailed images of the blood vessels and the brain. FIESTA sequencing permits 1-mm thick coronal imaging sectioning without skips, permitting visualization of the entire course of the trigeminal nerve and any offending vascular compression. Patients less than 40 years of age, those with bilateral symptoms, and those in whom physical examination reveals sensory loss are at a higher risk of secondary trigeminal neuralgia. 

Treatment / Management

Pharmacologic Therapy

First-line therapy

Medical therapy is the preferred initial therapeutic intervention for patients with classic trigeminal neuralgia. The antiepileptics carbamazepine or oxcarbazepine are the preferred initial therapeutic agents; only carbamazepine is approved by the United States Food and Drug Administration (FDA) for treating trigeminal neuralgia. These antiepileptic agents may control pain by binding to voltage-gated sodium channels.[2] Both medications are initiated at a low dose and titrated upward until the pain is controlled. Neither medication provides immediate relief; assessments of therapy must not occur before 2 weeks after initiation.[18] These medications control pain for most people, perhaps 70%, in the early stages of the disease. In some patients, the effectiveness of carbamazepine decreases over time.[2](B3)

Adverse effects of carbamazepine include drowsiness, dizziness, diplopia, and nausea. In patients of Asian ancestry, before starting carbamazepine, testing for the HLA-B*15:02 allele is recommended; this allele is strongly associated with developing toxic epidermal necrolysis or Stevens-Johnson syndrome when taking carbamazepine and structurally related pharmaceuticals.[19] Oxcarbazepine is a newer drug increasingly used as first-line therapy for patients with trigeminal neuralgia who do not respond to or tolerate carbamazepine; oxcarbazepine should also be avoided in those testing positive for the HLA-B*15:02 allele. However, unlike carbamazepine, oxcarbazepine is not metabolized by cytochrome P450 and has fewer potential interactions with other medications. Adverse effects of oxcarbazepine include diplopia and dizziness. Both medications can cause hyponatremia. 

Second-line therapy

Patients who fail initial therapy may benefit from therapy with gabapentin, clonazepam, and other antiepileptics such as lamotrigine, phenytoin, and valproic acid; comprehensive efficacy data is lacking.[18] Lamotrigine has been evaluated prospectively in a randomized trial of heavily pretreated patients with trigeminal neuralgia and demonstrated significant pain relief compared to a placebo.[18] Small studies have demonstrated pain relief with phenytoin and fosphenytoin, but these effects are short-lived, and these medications are considered a bridging therapy. Phenytoin has several problematic adverse effects, including ataxia, dysarthria, nystagmus, gingival enlargement, cardiac arrhythmias, anemia, and teratogenicity.[18] 

Gabapentin was evaluated as first-line therapy for trigeminal neuralgia and despite an efficacy of 60% to 80% was found to be inferior to oxcarbazepine. Gabapentin has been investigated in patients who have failed surgical therapy; a 47% reduction in facial pain was reported. Adverse effects of gabapentin include vertigo, confusion, and sedation.[18] In patients with a poor response to carbamazepine, clonazepam reduced trigeminal neuralgia pain in 70% of participants. Adverse effects of clonazepam include somnolence, ataxia, and dementia with long-term use.

Valproic acid can reduce the frequency of paroxysmal attacks but is teratogenic and may cause hair loss and weight gain; valproic acid carries a black box warning for hepatotoxicity and pancreatitis.[18] Baclofen is a muscle relaxant shown to decrease the intensity and severity of attacks in 74% of patients with trigeminal neuralgia; efficacy may be even higher when combined with other drug therapies, such as carbamazepine.[18]Adverse effects of baclofen include dizziness, sedation, and dyspepsia.

Newer drugs, such as eslicarbazepine, an active metabolite of oxcarbazepine, have been approved by the FDA. However, further study of its efficacy is needed.[2] Vixotrigine, a Nav1.7 blocker, is currently being investigated in a phase III clinical trial (NCT03070132).[2](B3)

Patients with secondary trigeminal neuralgia may respond well to pharmacotherapy. However, treating the underlying etiologic lesion or disease is recommended when possible.

Surgical Therapy

Surgical intervention is recommended for patients with classic trigeminal neuralgia who have failed maximal medical therapy. Some interventions include microvascular decompression, rhizotomy, and peripheral nerve block. These methods have varying levels of initial efficacy and pain recurrence rates.[18]

Microvascular decompression 

Microvascular decompression is one of the most frequently employed procedures to treat trigeminal neuralgia and benefits patients with compression of the nerve root.[20] Microvascular decompression is performed via craniotomy and posterior fossa exploration to identify and relocate the compressing blood vessel. A soft cushion is placed between the nerve and the offending vessel to allow the nerve to recover and the pain to abate. The procedure is efficacious in greater than 90% of patients; pain recurs in approximately 10%, usually within the 2 years following the procedure.[18] Microvascular decompression is an invasive procedure with the associated complications of partial hearing loss, cerebellar hematoma, cerebrospinal fluid leaks, infarction, and facial weakness. However, microvascular decompression is currently the most effective long-term surgical treatment available to patients with trigeminal neuralgia.[21](B2)

Rhizotomy 

Microvascular ablative procedures include rhizotomy with thermocoagulation, chemical injection, or mechanical balloon compression to damage the trigeminal nerve root and interrupt pain signal transmission. Rhizotomy with thermocoagulation employs heat via an electrode, chemical rhizotomy injects glycerol directly into the trigeminal nerve, and balloon compression mechanically damages nerve fibers. The result of rhizotomy is decreased signal transmission.[22][23] Overall rates of pain relief are 80% to 90% initially; 5-year pain recurrence rates are 53% regardless of rhizotomy method.[18] Complications of rhizotomy include postoperative dysesthesia, corneal numbness, sensory loss in trigeminal nerve distribution, and anesthesia dolorosa, or numbness and spontaneous pain without stimuli.[24] (B2)

Peripheral neurectomy and nerve blockade

Neurectomy can be performed on peripheral branches of the trigeminal nerve, such as the supraorbital, infraorbital, lingual, and alveolar nerves.[25] Neurectomy may be performed via alcohol injection, incision, cryotherapy, or radiofrequency lesioning. Peripheral neurectomy may be preferred in older patients in remote and rural areas where neurosurgical facilities are not readily available.[26] Initial pain relief rates following peripheral neurectomy range from 70% to 90%, but recurrence rates are approximately 20% and may be due to nerve regeneration.[18] However, the evidence regarding these peripheral techniques for trigeminal neuralgia is inconclusive.

Deep brain stimulation

Stimulation of the periaqueductal gray matter, periventricular gray matter, and thalamus may result in pain relief through the endogenous release of opioids.[18] However, long-term data for deep brain stimulation are lacking, and early prospective trials failed to demonstrate efficacy.[27] Despite this, deep brain stimulation is used for salvage therapy in refractory cases of trigeminal neuralgia.(A1)

Botulinum toxin injections 

Botulinum toxin injection may benefit some patients, particularly middle-aged and elderly patients, who are refractory or intolerant to medical therapy.[28] Pain relief rates with botulinum toxin injections range from 70% to 87%, but the procedure is well-tolerated, carries fewer adverse effects, and is less invasive than many surgical options.[28][29][30]

Differential Diagnosis

A comprehensive medical history and physical examination can help when differentiating trigeminal neuralgia from other causes of facial pain. Commonly encountered causes of facial pain include but are not limited to:

• Postherpetic trigeminal neuralgia secondary to acute herpes zoster
• Dental or odontogenic pain
• Short-lasting unilateral neuralgiform headache attacks (SUNA) and
• Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) 
• Trigeminal neuropathy
• Temporomandibular joint syndrome
• Glossopharyngeal neuralgia.

Radiation Oncology

Radiotherapy in Trigeminal Neuralgia

The use of radiotherapy in trigeminal neuralgia may be considered in patients who have failed maximal medical therapy, are poor surgical candidates, or have failed surgical intervention. Radiotherapy is a noninvasive procedure wherein a highly concentrated dose of ionizing radiation is delivered to a precise target at the trigeminal nerve root. The radiation creates a lesion near the nerve root, interrupting the pain signals from transmission to the brain. Lesion formation is slow, and hence, the pain relief offered by this procedure is delayed by several weeks or months. 

Treatment delivery

Single-treatment stereotactic radiosurgery (SRS) is the standard therapeutic approach for patients with trigeminal neuralgia. However, hypofractionated courses have been described in the literature. Several delivery systems have been utilized to treat trigeminal neuralgia, with the outcomes recorded in several case series.[31] Gamma Knife^®, a cobalt-60 source-based system, has been used extensively and has the largest recorded data set regarding outcomes in patients with trigeminal neuralgia.[31] Alternative delivery systems include linear accelerator-based SRS (LINAC) and robotic radiosurgery with CyberKnife^®. The treatment outcomes appear comparable between all 3 systems.[31]

Simulation 

The simulation process varies with the treatment delivery system. In a conventional Gamma Knife^® system, a rigid stereotactic headframe immobilization system is fixed directly to the patient’s skull. However, there are reports of “frameless” stereotactic radiosurgery employing thermoplastic masks.[32][33] LINAC-based SRS and Cyberknife^® typically use a specialized thermoplastic facial mask.  

MRI of the brain is useful when identifying the trigeminal nerve root and is an essential part of treatment planning. T1-weighted imaging with and without contrast enhancement and T2-constructive interference steady state/fast imaging employing steady-state acquisition are most commonly used.[31] MRI images may be fused with the CT simulation to identify the target and at-risk surrounding structures. There are case series using CT-based planning that may apply to patients who cannot obtain an MRI.[34]

Dosing 

Doses range from 70 to 90 Gy delivered in a single session; 70 Gy is considered the minimal effective dose and 90 Gy the maximally effective dose. Efficacy is thought to be similar within that dose range, but the rate of complications tends to increase with dose escalation. The dose is prescribed to the 100% isodose line in Gamma Knife^® cases, while LINAC-based SRS or CyberKnife^® systems are typically prescribed to the 80% to 90% isodose lines.[31]

Although single-fraction treatment is generally standard, there are reports of hypofractionated courses using LINAC-based SRS with a dose of 72 Gy in 6 fractions.[35] However, a retrospective analysis comparing SRS and hypofractionated treatment suggests that while pain relief may be comparable, there is a 3-times higher rate of recurrence with hypofractionated radiotherapy.[35]

Dose constraints 

The proximity of the trigeminal nerve root to other critical structures makes it imperative that dose constraints are closely followed. The critical structures outlined in most cases include the brainstem, spinal cord, optic nerve, optic chiasm, pituitary gland, cochlea, and brain tissue. The brainstem is typically the structure of most concern in these treatments, given the origin of the trigeminal nerve. The American Association of Physicists in Medicine Task Group 101 (AAPM TG-101) provides dose constraints for single-fraction SRS.[36] The risk of brainstem necrosis or cranial neuropathy with doses of less than 12.5 Gy is less than 5% but rapidly increases if the treatment volume exceeds 4 cm³ or the dose exceeds 15 Gy.[37] Normal brain tissue volume receiving 12 Gy should be kept at 5 to 10 cm³ of volume.[37] However, the risk of brain radionecrosis is both dose- and location-dependent. Employing the previously mentioned constraints, the risk of radionecrosis would exceed 20% if located in the basal ganglia but less than 5% in the temporal lobe. Spinal cord maximum dosing should be kept below 13 Gy, which has a less than 1% risk of myelopathy.[37] Other structures, such as the optic nerves, optic chiasm, pituitary, and cochlea, typically receive doses far below their complication threshold but are documented.

Target delineation

The target must be defined once the appropriate planning scans have been acquired. The contrast between the darker nerve against the bright cerebrospinal fluid in the pre-pontine cistern on a T2-weighted MRI facilitates accurate identification. There is some variation in anatomic placement along its course in the pre-pontine cistern, varying from 0 to 8 mm.[31] Two-isocenter techniques are also documented in the literature. A prospective, double-blind, randomized trial investigated outcomes of a single- versus double-isocenter technique and found no difference in pain relief but increased complications with the latter.[38] Concentric 8mm/4mm isocenters also failed to improve outcomes.[39]

Although MRI offers superior soft tissue delineation, targeting the trigeminal nerve with CT images only has been attempted with similar rates of postprocedural pain control and complications.[40] This approach may be useful in patients with a contraindication to MRI.[40]

Outcomes

Most data to support the use of SRS for treating trigeminal neuralgia is derived from retrospective case series. The freedom from pain response is approximately 85%, with no significant differences found between treatment delivery systems.[31] However, many of these patients continue to require medical therapy; 53% of patients remain pain-free without the use of medications.[31] Unlike surgery, pain relief following radiotherapy is not immediate and may take weeks to months. The median time to relief ranged from 10 to 90 days for those treated with Gamma Knife^®. The durability of pain relief at 3 years is approximately 60%, and pain control continues to decline to as low as 30% to 45% at 10 years.[31] The consensus on the maximum pain relief time is approximately 6 months. 

Several retrospective comparisons of various surgical interventions and Gamma Knife^® have been performed. A retrospective review comparing patients treated with glycerol rhizotomy versus SRS demonstrated comparable rates of pain control (86% versus 92%) and recurrence (53% versus 42%). However, the time to pain relief was significantly longer with SRS. A single prospective nonrandomized trial comparing Gamma Knife^® SRS to microvascular decompression demonstrated higher rates of initial and durable pain control.[41] Hypofractionated radiation therapy has also been attempted; pain recurrence rates are much higher.[35]

Positive factors influencing initial and later pain relief after treatment are age greater than 70, classic pain presentation, and no previous surgery. Younger patients, prior surgery, multiple sclerosis, and diabetes lead to poorer initial pain response.[31]

Recurrent pain

Given the lower rates of durable pain control with SRS compared to surgical intervention, it is likely many patients experience recurrent symptoms. Retreatment with SRS may be an option, especially if the patient has robust symptom relief. Retreatment dosing is typically 45 to 50 Gy. More than half of patients experience pain relief; more than 20% will develop new neurological dysfunctions such as bite weakness, taste alteration, or numbness.[42]

Complications

The most concerning complications of treatment are late toxicities, which can take several months to develop. Hypesthesia is the most cited complication of this treatment, with a mean rate ranging from 18% to 28% and a mean onset time of 6 to 36 months.[31] There are no differences in complication rates concerning treatment delivery type.[31] Other noted complications include neurotrophic keratopathy, trismus, dysgeusia, decreased corneal reflex, and masticator muscle weakness are found in the case reports for LINAC-based SRS and CyberKnife^® but not for Gamma Knife^®. 

Prognosis

While trigeminal neuralgia is not a life-threatening condition, it can lead to lifelong pain and disability. The course of trigeminal neuralgia is variable; some patients may have episodes lasting weeks or months, followed by pain-free intervals, while others have continuous background facial pain in addition to paroxysmal episodes. Medical therapies may lose effectiveness over time, and while surgical intervention may offer immediate pain relief, recurrence is common.

Complications

The pain associated with trigeminal neuralgia can be chronic and lead to depression in the absence of adequate therapy. Associated facial muscle spasms may cause social withdrawal and isolation. Anticonvulsant therapy, while effective, may have adverse effects. Surgical and salvage therapies also carry risks. Despite multiple therapeutic options, some patients may develop facial numbness, corneal anesthesia, jaw weakness, or the intractable facial dysesthesia known as anesthesia dolorosa.