Trigeminal Neuralgia

Traditionally referred to as tic douloureux, trigeminal neuralgia is a chronic neuropathic pain disorder characterized by spontaneous and evoked paroxysms of electric shock-like or stabbing pain in one area of ​​the face. Poor quality of life and suicide in severe cases have been attributed to the disease.
A classification of trigeminal neuralgia has been adopted by several professional societies and forms the basis of its definition in the International Classification of Diseases, 11th Revision (ICD-11).

Clinical Features and Diagnosis (video https://youtu.be/MnbNFMcQr2E)
The diagnosis of trigeminal neuralgia is made clinically and is based on three main criteria: pain limited to the territory of one or more segments of the trigeminal nerve; paroxysms of pain that are sudden, intense, and very brief (<1 second to 2 minutes, but usually a few seconds) and described as a “shock” or “electric sensation”; and pain in the trigeminal region of the face or mouth provoked by stimuli that would not normally be expected to cause pain. Triggered paroxysmal pain is specific to trigeminal neuralgia and is reported by 91% to 99% of patients 4-6 , suggesting that it may be a pathognomonic feature of trigeminal neuralgia.

The pain of trigeminal neuralgia most commonly affects the distribution of the second (maxillary) or third (mandibular) division of the trigeminal nerve, with the right side of the face more frequently affected than the left. Bilateral trigeminal neuralgia is rare and should suggest facial neuralgia due to an underlying neurological disorder or a nonneurological disorder affecting the skull. The incidence of trigeminal neuralgia is higher in women than in men and increases with age.

Many forms of facial pain are associated with trigeminal neuralgia, but they are likely to be distinct disorders, sometimes classified under the categories of "atypical facial pain" or "painful trigeminal neuropathy." The posterior third of the scalp, the external ear (excluding the tragus), and the skin overlying the chin and margin are not innervated by the trigeminal nerve and are not areas of pain due to trigeminal neuralgia (Figure 1); pain in these areas suggests an alternative disorder.


Figure 1 Trigeminal Nerve Innervation Zones and Trigger Zone Distribution. Panel A shows the innervation zones of the three trigeminal branches: ophthalmic, maxillary, and mandibular. Panels B and C show the trigger zone distribution in the face and mouth, respectively, based on data from 120 patients with classic trigeminal neuralgia seen at the Neuropathic Pain Center of the Sapienza University in Rome between January 2015 and December 2019 (with a dedicated software that allows trigger zone overlap profile of the extraoral and intraoral regions). The colors represent the number of patients reporting a trigger zone in each region, ranging from 2 patients (grayish lavender, like the top points in Panel B) to 28 patients (orange). The number of trigger zones in the intraoral region is smaller than the number of patients reporting that speaking or chewing is the main trigger maneuver, due to the difficulty patients have in defining a limited trigger zone area in the mouth.

The pain of trigeminal neuralgia can be triggered by the general movements of everyday life, and the triggers are in small sensory areas—for example, the touch of a napkin or towel to the upper lip or even a breeze touching a sensitive facial area. The location of the pain does not always correspond to the location of a sensory trigger. For example, stimuli in and around the lower lip may cause pain in the temple, or sensory triggers on the sides of the nose may cause shock-like pain radiating to the forehead or upper lip. Specific triggering maneuvers for one group of patients are shown in Table 1, while the distribution of trigger areas that cause pain is shown in Figure 1. A few patients report no triggers. The examination for trigeminal neuralgia involves observation of the face while the patient is sitting and completely still. In spontaneous trigeminal neuralgia paroxysms, the doctor may notice a blink or a small mouth movement that the patient is unaware of. Less commonly, during a paroxysmal attack, a strong contraction of the facial muscles, referred to as a “tic convulsion,” may occur. Although some patients report areas of mild hypoesthesia, sensory examination of the face is usually not abnormal in cases of trigeminal neuralgia and is not diagnostic.

Table 1. Maneuvers that Triggered Pain in 120 Patients with Classical Trigeminal Neuralgia

Types and Causes of Trigeminal Neuralgia
Three types of trigeminal neuralgia have been described: classic, secondary, and idiopathic. The most common, the classic type, is caused by intracranial vascular compression of the trigeminal nerve root, as described below. The responsible vessel is usually the superior cerebellar artery, which causes morphologic changes in the trigeminal nerve root. Secondary trigeminal neuralgia, which accounts for approximately 15% of cases, is attributable to a neurologic disorder such as multiple sclerosis or a tumor at the cerebellopontine angle that alters the entry site of the trigeminal nerve or otherwise compresses the nerve. Idiopathic trigeminal neuralgia, which does not cause any apparent nerve damage, accounts for approximately 10% of cases.

The clinical features of classic and secondary trigeminal neuralgia are similar, but patients with secondary trigeminal neuralgia are usually younger, more likely to have facial sensory loss, and more likely to have bilateral pain. Trigeminal neuralgia may be clinically indistinguishable from each other, in which case magnetic resonance imaging (MRI) may be able to diagnose multiple sclerosis and gadolinium-enhanced series may be able to diagnose a cerebellopontine mass. A recent study has shown rare variants in genes encoding voltage-gated ion channels in patients with a family history of classic or idiopathic trigeminal neuralgia, but the frequency and clinical significance of this finding are unknown.

Neurovascular Compression in Classical Trigeminal Neuralgia
Over the past few decades, the classic form of neuralgia was recognized by the work of Peter Jannetta and others, and the potential for treatment through intracranial microvascular surgery has been investigated. The pathophysiology is thought to be compression of the sensory portion of the trigeminal nerve by a small adjacent branch of the basilar artery, most commonly the superior cerebellar artery, near the root entry site in the pons. However, simple contact between the nerve and a vascular structure does not appear to be sufficient to cause or explain the disorder. To attribute the disorder to neurovascular compression, the abnormal vessel must ideally be shown to induce anatomic changes in the trigeminal root, such as distortion or atrophy. The most characteristic finding at surgery is a small, tortuous artery or arterial loop impinging on the medial aspect of the trigeminal root at the entry site, causing lateral dislocation, distortion, flattening, or atrophy of the trigeminal root (Figure 2). Neurovascular compression can be visualized using MRI and three-dimensional reconstruction. Imaging techniques include three-dimensional T2-weighted MRI sequences with detailed examination of the cisternal and cavernous segments of the nerve, three-dimensional TOF magnetic resonance angiography to visualize arteries, and phase-contrast MRI to visualize vessels. The specific imaging features that precisely define morphologic changes in the trigeminal root vary among investigators. However, several studies have suggested that microstructural changes in the nerve at sites of vascular compression can be measured using diffusion tensor imaging and tractography to reveal focal demyelination and edema. Although these sensitive techniques are not used in most centers, imaging diagnosis can be made with more traditional MRI methods. Vascular decompression may reverse these abnormalities at the trigeminal root entry site where the sensory portion of the nerve enters the ventral pons.


Figure 2. Neurovascular Compression

Pathophysiology
At its entry into the pons, the trigeminal nerve loses its Schwann cell myelin sheath (like all peripheral nerves), becoming instead covered by central myelin produced by oligodendroglia. This transition zone is vulnerable to damage and especially to demyelination. Vascular compression is the usual cause of demyelination in the area just before the nerve enters the pons, and multiple sclerosis is the typical cause in the area just after it enters the pons. Demyelination at these sites has been demonstrated in neurophysiological, neuroimaging, and histological studies.
When the myelin sheath becomes thin enough to allow ions to cross the membrane in the underlying axon, the axon is ill-equipped to pump sodium out immediately. The resulting depolarization makes the axon hyperexcitable (discharges that occur after the end of the stimulus) and causes crosstalk between fibers (called ephaptic transmission) and the generation of high-frequency ectopic impulses. Histological evidence suggests that the nerve fibers most involved in demyelination are the A-β fibers (large, non-nociceptive fibers) that are most susceptible to demyelination from mechanical injury or multiple sclerosis. It has been suggested that high-frequency discharges originating at the site of demyelination along A-β primary afferents are redirected to the brain to be perceived by brainstem neurons as paroxysmal pain. Some researchers have suggested that patients with trigeminal neuralgia may have increased excitability or decreased volume of various cortical and subcortical cerebral areas, but such changes probably result from decreased adaptation to chronic stimulation of these areas.

Continuous Painful Trigeminal Neuralgia
Although paroxysmal facial pain is the hallmark of trigeminal neuralgia, 24% to 49% of patients report constant or prolonged pain between paroxysmal attacks. It is defined as a background pain, burning, throbbing, or aching that is consistent with a distribution consistent with paroxysmal pain. Trigeminal neuralgia characterized by this symptom, regardless of the cause, was previously classified as trigeminal neuralgia type 2 or atypical trigeminal neuralgia but is now classified as “trigeminal neuralgia with concomitant constant pain.” The mechanism underlying constant pain is different from that underlying paroxysmal pain, as less relief of constant pain is seen after treatment with sodium channel blockers or microvascular decompression compared with paroxysmal pain. The pathophysiologic link between the two pain entities is unclear. Progressive nerve root damage and central sensitization mechanisms are discussed here. As has been shown in other neuropathic pain conditions, the burning, throbbing, or aching pain is likely due to deterioration of C fibers (unmyelinated sensory axons that slowly conduct impulses). Loss of C fibers in the trigeminal sensory root may cause abnormal spontaneous activity in secondary order neurons in the brainstem as a result of denervation supersensitivity of postsynaptic membranes exposed to neurotransmitters. The previous idea that persistent pain develops as a result of long-standing trigeminal neuralgia is not supported by more recent data.

Secondary Trigeminal Neuralgia
In 15% of patients with typical pain attacks, trigeminal neuralgia is caused by multiple sclerosis or benign tumors of the cerebellopontine angle. The risk of trigeminal neuralgia is increased 20-fold in patients with multiple sclerosis compared with the general population.,7 The prevalence of the disease among patients with multiple sclerosis is 2% to 5%. Trigeminal neuralgia associated with multiple sclerosis is attributed to a demyelinating plaque in the fascicle of the trigeminal nerve that courses through the ventral pons. Occasionally, trigeminal neuralgia occurs as a clinically isolated syndrome in patients with multiple sclerosis; the age at onset of multiple sclerosis in these patients is higher than in those without trigeminal neuralgia. A neuroimaging study has shown an association between neurovascular compression and multiple sclerosis-associated trigeminal neuralgia, suggesting that they may coexist and be additive. The frequency of this dual mechanism is unknown, but it has implications for treatment. Pharmacologic treatment of trigeminal neuralgia pain in patients with multiple sclerosis is challenging because of drug side effects, worsening of multiple sclerosis symptoms such as fatigue and ataxia, and limited efficacy in such patients. Case series suggest that microvascular decompression surgery tends to be less effective in patients with trigeminal neuralgia caused by multiple sclerosis than in patients with classic trigeminal neuralgia. Cerebellopontine angle tumors that compress the trigeminal nerve root and cause trigeminal neuralgia include acoustic neuromas, meningiomas, epidermoid cysts, and cholesteatomas. Interestingly, trigeminal neuromas (which are rare) have not been associated with trigeminal neuralgia. In an analysis of data from four studies of 243 patients with trigeminal neuralgia, tumors were the cause in 20 patients (8%). Compression of the trigeminal nerve by tumors triggers focal demyelination of the trigeminal nerve root, producing the same high-frequency discharges in thinned or stripped axons that occur with vascular compression of the nerve. Infiltrative malignant tumors can also cause axonal degeneration, resulting in hypoesthesia and persistent pain in the facial regions. Trigeminal neuropathies due to trauma and rheumatologic diseases such as systemic lupus erythematosus and scleroderma may present as paroxysmal pain mimicking trigeminal neuralgia, but these associations are rare. In these cases, trigeminal neuropathy may begin with unilateral paroxysmal pain, but soon develops bilateral sensory loss in the facial areas with ongoing pain, a disorder commonly referred to as trigeminal neuritis. Facial trauma, dental procedures, or maxillofacial surgery may damage the trigeminal nerve branches, causing paroxysmal stabbing, electric shock, or burning pain. However, the pain attacks are more prolonged than the paroxysms of trigeminal neuralgia, and most patients also describe ongoing severe pain without sensory trigger zones. Isolated idiopathic trigeminal neuropathy, a benign bilateral, symmetric, purely sensory trigeminal neuropathy, and a more serious progressive disease, facial onset sensory motor neuropathy, may also initially present as unilateral paroxysmal facial pain. Trigeminal reflex testing has been used as a neurophysiologic technique to detect trigeminal nerve damage. This diagnostic test is useful in patients who cannot undergo MRI or to detect demyelination and neuropathies that mimic trigeminal neuralgia.

Treatment

Medical treatment
In patients with trigeminal neuralgia, regardless of cause, the anticonvulsant agents carbamazepine, approximately 200 to 1200 mg daily, and oxcarbazepine (300 to 1800 mg daily) have been considered first-line treatments for the control of paroxysmal pain. Although these treatments are not supported by data from randomized, controlled trials, clinicians believe that the drugs are highly effective, providing significant pain control in nearly 90% of patients. The treatment effect is suggested to be related to the blockade of voltage-gated sodium channels, stabilization of hyperexcited neuronal membranes, and inhibition of repetitive firing. However, clinical improvement is often compromised by side effects such as dizziness, diplopia, ataxia, and elevated aminotransferase levels, and 23% of patients discontinue the drug. Oxcarbazepine may have fewer side effects and less potential for drug-drug interactions than carbamazepine, but may be discontinued because of excessive central nervous system depression or dose-related hyponatremia. Other, more selective sodium channel blockers are in development. Contraindications to the use of sodium channel blockers include a high degree of cross-reactivity (40 to 80%) with aromatic antiepileptic drugs and cardiac conduction problems and allergic reactions. Carbamazepine and oxcarbazepine reduce the high-frequency discharges characterized by electric shock-like paroxysms, but the effect of these drugs on accompanying persistent pain is usually limited. Gabapentin, pregabalin, and antidepressant agents shown to be effective in the treatment of other neuropathic conditions characterized by persistent pain may be tried as add-on agents in combination with oxycarbazepine or carbamazepine. Clinical experience suggests that gabapentin may have less effect on trigeminal neuralgia than carbamazepine and oxcarbazepine, but if associated with acceptable treatment because of fewer side effects, it may be tried as monotherapy or as an add-on treatment in patients with multiple sclerosis. If a course of medical therapy is ineffective or is associated with unacceptable side effects, surgical decompression of the trigeminal nerve may be considered.

Local Surgical Procedures

Although surgical procedures are effective in reducing the severity and frequency of attacks of trigeminal neuralgia in appropriately selected patients, such surgery is usually performed only when standard drug doses are inadequate to control symptoms or when side effects prevent continued use.
The first group of surgical interventions, which is rarely used today, involves peripheral blockade of the trigeminal nerve branches at the sites where they emerge from the facial bones, by neurectomy, alcohol injections, or radiofrequency lesions or cryolesions. The aim of these procedures is to create an area of ​​anesthesia that corresponds to the distribution of the injured nerve in the face. However, the benefits of such treatments have not been adequately supported by clinical trials 8 and the procedures often result in anesthesia dolorosa (intense pain in the area of ​​sensory loss). A second group of interventions attempts to percutaneously damage the trigeminal ganglion in Meckel's cave or the ascending branches of the ganglion at the base of the skull by radiofrequency thermocoagulation, chemical damage by glycerol injection, or mechanical compression by balloon inflation. Radiofrequency thermocoagulation preferentially damages small-diameter painful fibers. To prevent corneal deafferentation and the resulting keratitis, the electrode is targeted to avoid damage to the first branch (V1) of the trigeminal nerve. Balloon compression and glycerol injection preferentially damage large myelinated fibers. Pain relief is immediate with these techniques, and the following cases have been reported to have success rates: 68% (range, 55 to 80) with balloon compression (follow-up, 4.2 to 10.7 years), 58% (range, 26 to 82: follow-up, 3.0 to 9.3 years) with radiofrequency thermocoagulation, and 28% (range, 19 to 58) with glycerol rhizolysis (follow-up, 4.5 to 8.0 years). Trigeminal sensory deficits are usually transient with balloon compression and glycerol injection and are more severe and longer-lasting after radiofrequency thermocoagulation. Creating a lesion of the trigeminal root with a gamma knife treatment is a more recently introduced procedure and is supported by several studies. One difficulty with this procedure is the accurate identification of the coordinates of the trigeminal root before entering the pons; here, the radiation beams must be collimated to avoid damaging the pons. In contrast to the immediate pain relief associated with percutaneous lesions of the trigeminal ganglion, the pain-relieving and 33 to 56% reported continued pain relief at 4 to 5 years. 8 Facial numbness was reported in 16% of patients, and anesthesia dolorosa was almost absent. A meta-analysis showed that approximately 34% of patients had no pain relief at 1 year and required repeat procedures. effects of gamma-knife stereotactic radiosurgery take 6 to 8 weeks to develop. Approximately 24 to 71% of patients experience continued pain relief 1 to 2 years after undergoing the procedure.

Microvascular Decompression
Microvascular decompression has become the surgical procedure of choice for most cases of trigeminal neuralgia that no longer respond to drug therapy. The neurosurgeon identifies the vessel compressing the trigeminal nerve root, moves it from below the nerve to above the nerve if necessary (Figure 3), and typically places a small sponge to separate the impinging artery from the nerve root. In approximately 11% of patients, the surgeon finds no neurovascular compression or only a contact without apparent nerve compression. In these cases, the surgeon usually places the separating sponge anyway, although the failure rate is higher than when nerve root distortion is detected. This issue underscores the advantage of using established MRI criteria to identify morphologic changes in the trigeminal root. Despite the lack of high-level evidence-based data,49,50 meta-analyses have suggested that microvascular decompression is the most effective surgical intervention for classic trigeminal neuralgia. At 1 to 2 years after the procedure, 68 to 88% of patients have pain relief, and at 4 to 5 years, this rate is 61 to 80%. The average mortality rate associated with surgery is 0.3%. In our series, this rate is 0%. Cerebrospinal fluid leak occurs in 2.0% of patients, brainstem infarction or hematoma in 0.6%, and meningitis in 0.4%. Loss of sensation in part or all of the facial trigeminal nerve sensory distribution occurs in 2.9% of patients. Although rare (incidence 1.8%), the most bothersome long-term complication may be suggested, there is insufficient evidence to support or refute the efficacy of surgical treatment of trigeminal neuralgia in patients with multiple sclerosis. However, both percutaneous ganglion lesions and gamma-knife lesions have been reported to have good results in patients with multiple sclerosis.

Figure 3 Microvascular Decompression.
In microvascular decompression, after craniotomy, the neurosurgeon incises the dura mater, displaces the cerebellar hemisphere, and uses microscopy to visualize the nerves exiting the ventral pons. The vessel compressing the trigeminal nerve root is identified and moved if necessary, and a small sponge (Teflon) is placed to separate the pulsating artery from the root.

Conclusions
Trigeminal neuralgia is an extremely painful condition that can be difficult to diagnose and treat. Carbamazepine and oxcarbazepine constitute first-line medical therapy. However, many patients have side effects and those with persistent pain are less likely to respond well to treatment. Diagnostic tests, particularly neuroimaging, are useful in determining the cause and identifying patients with trigeminal neuralgia due to major neurologic disease and those in whom small branches of the basilar artery compress the proximal nerve. Application of standardized MRI criteria to identify neurovascular compression may aid in the selection of patients for microvascular decompression.