Clinical manifestations

Presentation and course

The ICHD-3 diagnostic criteria broadly categorize trigeminal neuralgia as recurrent, unilateral, brief electric shock-like pains with abrupt onset and termination limited to the distribution of the trigeminal nerve (61). The maxillary (V2) division is the most commonly affected, followed by the mandibular (V3) and then the ophthalmic (V1) (106). Because the maxillary and mandibular branches are most often affected, patients often first present to dentists for evaluation of tooth pain (05). The sharp or electrical paroxysms of pain last seconds to minutes and may occur in rapid succession. Painful attacks may be followed by a brief refractory period. In some cases, patients can have coexisting continuous or near-continuous pain between attacks (61). The pain is often triggered by innocuous stimuli (eg, a simple touch, washing, or shaving the skin) or simple facial movements (such as eating, drinking, smiling, or talking). In some cases, the pain can be triggered by other sensory stimuli, such as bright lights, particular tastes, and loud noises. Over time, the attacks can become more frequent, severe, and disabling. Patients can often have significant psychosocial and functional impairment secondary to the severe disabling lancinating pains.

The ICHD-3 diagnostic criteria (61) for trigeminal neuralgia include paroxysmal attacks of unilateral facial pain occurring in one or more divisions of the trigeminal nerve with no radiation beyond this distribution.

A. Pain has all of the following characteristics:
	1. Lasting from a fraction of a second to 2 minutes
	2. Severe intensity
	3. Electric shock-like, shooting, stabbing, or sharp in quality
B. Precipitated by innocuous stimuli within the affected trigeminal distribution
C. Not better accounted for by another ICHD-3 diagnosis

This definition divides trigeminal neuralgia into three subtypes, as outlined below. A diagnostic category within “pain attributed to a lesion or disease of the trigeminal nerve,” but distinct from trigeminal neuralgia, is painful trigeminal neuropathy due to neural damage, presenting as continuous burning pain or paresthesia.

Classical trigeminal neuralgia

This subcategory fulfills the diagnostic criteria for trigeminal neuralgia when in the context of neurovascular compression with trigeminal nerve root morphological changes demonstrated on MRI and without evidence of other secondary causes (61). This type of compression typically occurs at the nerve root entry or transition zone where the nerve exits the brainstem. Morphological changes may include atrophy, evidence of demyelination, or microvascular changes. This group is further divided based on purely paroxysmal symptoms or the presence of concomitant continuous or near-continuous pain underlying the paroxysms.

It is unusual for classical trigeminal neuralgia to present before 40 years of age, and incidence increases with age (17.5/100000 years in age 60, 25.6/100000 years in age 70) (08). Atypically, it can occur in pediatric patients as young as 1 year of age, but fewer than 10% present under age 40 (08).

Classical trigeminal neuralgia is more prominent in females than males, by a ratio up to 2:1 or 3:1 (36; 69; 81).

About 1% to 2% of cases of trigeminal neuralgia are thought to be familial (08), though it has been reported in up to 5.3% in one population study (69). An autosomal dominant inheritance has been suggested, as there have been families with seven cases (45), two different families with four cases in three generations (63; 111), and one family with four siblings who all developed trigeminal neuralgia between the ages of 24 to 31 years (22).

ICHD3 Diagnostic Criteria For Classical Trigeminal Neuralgia
	(A) Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 trigeminal neuralgia.
	(B) Demonstration on MRI or during surgery of neurovascular compression (not simply contact), with morphological changes in the trigeminal nerve root.
(61)

Secondary trigeminal neuralgia

Like classical trigeminal neuralgia, this subtype meets the criteria for trigeminal neuralgia and may be either paroxysmal or have continuous symptoms (61). However, this form is associated with an identified secondary cause aside from neurovascular compression. The recognized subtypes are those attributed to multiple sclerosis, space-occupying lesions, and other causes. Trigeminal neuralgia attributed to multiple sclerosis is due to a demyelinating plaque within the pons or at the trigeminal root entry, and presentation can be bilateral. Trigeminal neuralgia attributed to a space-occupying lesion in contact with the trigeminal nerve typically occurs with lesions within the cerebellopontine angle, including schwannomas, meningiomas, epidermoid cysts, acoustic neuromas, and cholesteatomas. Other causes of trigeminal neuralgia include skull base deformities, connective tissue diseases, arteriovenous malformation, arteriovenous dural fistula, and genetic disorders (32).

In cases of trigeminal neuralgia caused by multiple sclerosis, the age of onset is younger than classical trigeminal neuralgia (33), and patients with multiple sclerosis have a 20-fold increased risk of developing trigeminal neuralgia than the general population (30). Whereas idiopathic or neurovascular trigeminal neuralgia is almost always (97%) unilateral, when trigeminal neuralgia occurs in multiple sclerosis, it may be bilateral in up to 30% of patients (30). The mechanism of injury in this population is a proposed “double crush” phenomenon, with the formation of a pontine plaque and neurovascular compression both playing a role (42).

Trigeminal neuralgia secondary to multiple sclerosis is more prominent in females than males; one metaanalysis found a prevalence of 2.4% in males to 3.8% in females (64).

ICHD3 Diagnostic Criteria for Secondary Trigeminal Neuralgia
	(A) Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 trigeminal neuralgia, either purely paroxysmal or associated with concomitant continuous or near-continuous pain.
	(B) An underlying disease has been demonstrated that is known to be able to cause, and explain, the neuralgia.
	(C) Not better accounted for by another ICHD-3 diagnosis.
(61)

Idiopathic trigeminal neuralgia

This subtype is distinct from the previous classes in that no identifiable source of nerve injury or compression can be demonstrated on MRI or electrophysiologic testing, but symptoms meet the criteria for trigeminal neuralgia (61). Of note, contact between a blood vessel and the trigeminal nerve without evidence of morphological changes of the nerve root (atrophy, displacement, etc.) is included in this category. This group is further divided based on purely paroxysmal symptoms or the presence of concomitant continuous or near-continuous pain underlying the paroxysms.

ICHD3 Diagnostic Criteria for Idiopathic Trigeminal Neuralgia
	(A) Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 trigeminal neuralgia, either purely paroxysmal or associated with concomitant continuous or near-continuous pain.
	(B) Neither 13.1.1.1 classical trigeminal neuralgia nor 13.1.1.2 secondary trigeminal neuralgia has been confirmed by adequate investigation including electrophysiological tests and MRI.
	(C) Not better accounted for another ICHD-3 diagnosis.
(61)

Painful trigeminal neuropathy

This subset of conditions differs from trigeminal neuralgia in that there is evidence of nerve damage. It is characterized by essentially continuous pain in the distribution of the trigeminal nerve, often described as burning, squeezing, or “pins and needles” (61). Clinically detectable sensory changes can be present. There can be a combination of positive (hyperalgesia, allodynia) and negative (hypoaesthesia, hypoalgesia) symptoms. Superimposed paroxysmal pain may be present but is not the predominant pain type. Mechanical allodynia and cold hyperalgesia are common, fulfilling IASP (International Association for the Study of Pain) criteria for neuropathic pain, with allodynic areas being larger than the punctate trigger zones typical of trigeminal neuralgia. The recognized subtypes are outlined below.

Painful trigeminal neuropathy attributed to herpes zoster. Symptoms of this condition must last less than 3 months and occur in the setting of herpetic eruption in the trigeminal nerve distribution, detectable varicella-zoster virus in CSF via polymerase chain reaction, or polymerase chain reaction DNA-positive assay obtained from the base of the lesion (61). The trigeminal ganglion can be affected, and in a large proportion, only the ophthalmic (V1) division is involved. Pain is usually described as burning, stabbing or shooting, tingling, or aching, and cutaneous allodynia may be present.

ICHD3 Diagnostic Criteria for Painful Trigeminal Neuropathy Attributed to Herpes Zoster
	(A) Unilateral facial pain in the distribution(s) of a trigeminal nerve branch or branches, lasting fewer than 3 months.
	(B) One or more of the following:
		(1) Herpetic eruption has occurred in the same trigeminal distribution.
		(2) Varicella zoster virus (VZV) has been detected in the CSF by polymerase chain reaction (PCR).
		(3) Direct immunofluorescence assay for VZV antigen or PCR assay for VZV DNA is positive in cells obtained from the base of lesions.
	(C) Not better accounted for by another ICHD-3 diagnosis.
(61)

Trigeminal post-herpetic neuralgia. This condition is not a true neuralgia but is actually a neuropathy or neuronopathy (61). The symptoms must persist or be recurrent for at least 3 months, occur in the distribution of the previously affected trigeminal nerve, and be in temporal association with the zoster outbreak. Pain often starts during the rash outbreak, but pain onset can be delayed until the rash begins to heal. The ophthalmic branch of the trigeminal nerve is involved in up to 80% of postherpetic neuralgia, which can lead to eye involvement. There tends to be significant allodynia. It is more likely to occur in the elderly after acute herpes zoster infection.

ICHD3 Diagnostic Criteria for Trigeminal Postherpetic Neuralgia
	(A) Unilateral facial pain in the distribution(s) of a trigeminal nerve branch or branches, persisting or recurring for more than 3 months and fulfilling criterion C.
	(B) Herpes zoster has affected the same trigeminal nerve branch or branches.
	(C) Pain developed in temporal relation to the herpes zoster infection.
	(D) Not better accounted for by another ICHD-3 diagnosis.
(61)

Painful post-traumatic trigeminal neuropathy. This condition is characterized by symptoms in the setting of an identifiable traumatic event and the development of symptoms within 6 months of the event (61). The inciting event can be due to mechanical, chemical, thermal, or radiation-related trauma. Radiation-related injury is specifically associated with a delayed onset of symptoms, often more than 3 months after the inciting injury. This subtype may be iatrogenic following trigeminal neuralgia treatment via a neuroablative procedure aimed at the trigeminal ganglion or nerve root; it may coexist with or replace pre-existing trigeminal neuralgia pain.

ICHD3 Diagnostic Criteria for Painful Post-Traumatic Trigeminal Neuropathy
	(A) Facial or oral pain in the distribution(s) of one or both trigeminal nerves and fulfilling criterion C.
	(B) History of an identifiable traumatic event to the trigeminal nerve(s), with clinically evident positive (hyperalgesia, allodynia) or negative (hypesthesia, hypalgesia) signs of trigeminal nerve dysfunction.
	(C) Evidence of causation demonstrated by both of the following:
		(1) Pain is localized to the distribution(s) of the trigeminal nerve(s) affected by the traumatic event.
		(2) Pain has developed fewer than 6 months after the traumatic event.
	(D) Not better accounted for by another ICHD-3 diagnosis.
(61)

Painful trigeminal neuropathy attributed to another disorder. This condition is characterized by unilateral or bilateral pain in the setting of a disorder known to cause painful trigeminal neuropathy with signs of trigeminal nerve dysfunction (61). As with secondary trigeminal neuralgia, the symptoms of this condition can be attributed to multiple sclerosis, space-occupying lesion, or systemic disease, but the symptoms must also include continuous pain and associated sensory deficits. Pain due to connective tissue disease or hereditary disorders is often bilateral but may initially be asymmetric and paroxysmal.

ICHD3 Diagnostic Criteria for Painful Trigeminal Neuropathy Attributed to Another Disorder
	(A) Unilateral or bilateral facial pain in the distribution(s) of one or both trigeminal nerves and fulfilling criterion C.
	(B) A disorder other than those described above but known to be able to cause painful trigeminal neuropathy with clinically evident positive (hyperalgesia, allodynia) or negative (hypaesthesia, hypalgesia) signs of trigeminal nerve dysfunction and affecting one or both trigeminal nerves, has been diagnosed.
	(C) Evidence of causation demonstrated by both of the following:
		(1) Pain is localized to the distribution(s) of the trigeminal nerve(s) affected by the disorder.
		(2) Pain developed after onset of the disorder or led to its discovery.
	(D) Not better accounted for by another ICHD-3 diagnosis.
(61)

Idiopathic painful trigeminal neuropathy. This form of the condition has all the characteristics of trigeminal neuropathy outlined above, but a causative etiology has not yet been determined (61).

ICHD3 Diagnostic Criteria for Idiopathic Painful Trigeminal Neuropathy
	(A) Unilateral or bilateral facial pain in the distribution(s) of one or both trigeminal nerves and fulfilling criterion B.
	(B) Clinically evident positive (hyperalgesia, allodynia) or negative (hypaesthesia, hypalgesia) signs of trigeminal nerve dysfunction.
	(C) No cause has been identified.
	(D) Not better accounted for by another ICHD-3 diagnosis.
(61)

The Barrow Neurological Institute Pain Scale and the Visual Analog Scale are two patient-reported tools used to rate trigeminal neuralgia pain and report outcomes in treatment trials.

Barrow Neurological Institute Pain Scale
	Evaluation of pain relief – BNI Pain Intensity Score
		I. No pain, no medication I. Occasional pain, not requiring medication III. Some pain, adequately controlled with medication IV. Some pain, not adequately controlled with medication V. Severe pain or no pain relief
	Evaluation of facial numbness – BNI Facial Numbness Score
		I. No facial numbness II. Mild facial numbness, not bothersome III. Facial numbness, somewhat bothersome IV. Facial numbness, very bothersome
(27)

Clinical vignette

A 70-year-old female presented to the neurology clinic for evaluation of facial pain. She reported pain in her left upper teeth starting 1 year ago, leading to tooth extraction with worsening pain. Over 3 months, the pain spread to involve her left cheek and chin. She had occasional pain in her left temple and would get mild redness in her left eye during these episodes. Pain was described as “someone taking a pen and running it through her face” and “electrical jolts.” She had difficulty chewing on that side, and she had difficulty with her speech. Brain MRI demonstrated neurovascular conflict from the left superior cerebellar artery with evidence of trigeminal nerve hyperintensity. She was started on carbamazepine 200 mg twice daily with 25% improvement but did not tolerate higher doses. Lamotrigine was added with minimal additional benefit. She underwent trigeminal microvascular decompression with complete pain relief lasting 2 years off medication but then had recurrence of symptoms. She underwent GammaKnife radiosurgery with 50% pain relief. With the re-addition of carbamazepine 200 mg twice daily, she achieved significant, though incomplete, pain relief.

Biological basis

Etiology and pathogenesis

Trigeminal neuralgia is a rare condition. The prevalence is estimated to be 0.03% to 0.3%, similar to multiple sclerosis and Parkinson disease (36; 58; 47). Incidence is estimated to be 4.3 to 8 per 100,000 (70). One observational study in central Sweden reported an incidence of 5.5 cases per 100,000 person-years (112). It is more prevalent in women and in people over 60 years of age (110; 36). Epidemiological studies suggest incidence increases with age, from 16.3 for patients in their 40s compared to 30.6 for patients older than 80 years (121).

The etiology of classical trigeminal neuralgia is attributed to demyelination of the trigeminal afferent pathway in the dorsal root entry zone, which is thought to lead to discharges of the nerve spontaneously or in response to a normally innocuous afferent stimulus (28). Neurovascular compression, typically by a redundant or tortuous loop of the superior cerebellar artery, is thought to cause that demyelination (30). A space-occupying lesion can compress the trigeminal nerve root and produce similar symptomatology. MRI may reveal neurovascular contact of the trigeminal nerve root, but this can also be seen in asymptomatic patients, so it is not diagnostic (32). To convincingly be diagnosed with classical trigeminal neuralgia, there should be evidence of nerve atrophy or displacement, which has a specificity of 97% (100% if at the root entry zone) (33). It is important to note that the presence of nerve compression does not mean trigeminal neuralgia symptoms will occur, as one study found that 92 of 100 asymptomatic cases reviewed were found to have a vessel compressing the trigeminal nerve (96; 33). Demyelination due to multiple sclerosis can lead to trigeminal neuralgia symptoms, and trigeminal neuralgia has a higher incidence in patients with multiple sclerosis.

More recent studies of patients with trigeminal neuralgia and animal models have revealed molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve, similar to those seen in other compressive nerve injuries (28). Schmidt-Lanterman incisures have been noted in trigeminal nerve root biopsies from patients with trigeminal neuralgia, reflecting a pathological increase in metabolic demand for myelin sheath growth and maintenance, seen in chronic nerve compression (38). These compression-related structural changes lead to downstream effects, including dysregulation of voltage-gated sodium (Nav) channels (51) and upregulation of Nav1.3 (an embryotic channel type normally suppressed in adults and seen overexpressed in several neuropathic pain conditions) and other Nav channels (109; 132; 79; 28). Electrophysiological recording of Nav1.3 (tested in the setting of traumatic spinal cord injury) showed persistent sodium and ramp current after stimulation, suggesting the cause of increased response to normally innocuous stimuli (77; 28). Another sodium channel, Nav1.7, that has fast inactivation and slow recovery, making it resistant to repetitive action potentials, is found to be downregulated in chronic compressive injuries (109; 132; 79). Persistent downregulation of myelin-associated glycoprotein is seen with chronic compression injury, which limits the ability of Schwann cells to inhibit axonal growth and may lead to the axonal sprouting seen in trigeminal neuralgia (60; 59; 28).

Functional changes in the trigeminal nerve neurons have also been noted, secondary to the structural changes reviewed above. Recording of trigeminal nerve roots in classical trigeminal neuralgia models shows ectopically generated action potentials and prolonged after-discharges in the demyelinated neurons (25; 24; 97; 98). The “ignition hypothesis” was presented in 2002 by Devor and colleagues, who proposed that demyelination and hyperexcitability of the trigeminal neurons decrease the triggering threshold for activating sensory afferents (39).

Central sensitization, a process in which the nociceptive system becomes hyperexcitable, has been implicated in several chronic pain conditions (129). One series of electrophysiological records in patients with trigeminal neuralgia showed augmentation of the pain-related evoked potentials (91). Pain attacks in trigeminal neuralgia patients have been correlated with increased activity in brain areas associated with pain sensation, including the trigeminal nuclei, thalamus, and somatosensory cortex, but areas involved in pain modulation, emotion, and memory are involved as well (which has been seen in other chronic pain conditions) (86; 136).

Differential diagnosis

Confusing conditions

Dental pain. Dental pain can present in a similar anatomical distribution as trigeminal neuralgia, especially in the early presentation of trigeminal neuralgia. One must exclude dental pain secondary to a structural cause or infection. Most dental pain is acute, and most often, it is unilateral and located within the mouth. A cracked tooth usually presents as shooting pain when biting hard food, whereas dental caries or pulpitis pain often lasts minutes to hours, triggered by cold, heat, or sweetness (126). A lighted examination of the teeth, the attached gingiva, and the soft tissues of the oral mucosa typically elucidate a cause in these cases, such as a cracked tooth or a periodontal abscess. Diseases of the oral mucosa are painful and will be associated with a lesion, such as lichen planus, herpes zoster, herpes simplex, or recurrent oral ulceration.

Acute maxillary rhinosinusitis. The obstruction of sinus ostia causes sinusitis, and maxillary sinusitis is the most common (43). Acute maxillary rhinosinusitis can present with pain in a similar distribution to early trigeminal neuralgia. This is often secondary to an infection (viral, bacterial, or fungal) and can also occur secondary to a dental infection or a dental extraction procedure. Other presenting symptoms include purulent nasal secretions and discharge, cough, abnormal transillumination, and tenderness to palpation over the sinuses (43), unlike trigeminal neuralgia, in which mild autonomic symptoms may be seen. Pain is typically described as dull, heavy, or throbbing and located over the cheeks and upper teeth. Pain, in this case, would resolve after sinusitis treatment.

Sphenoid sinus disease. Disease of the sphenoid sinus can cause symptoms due to its close proximity to a number of structures, including cranial nerves (II, III, IV, V1, V2, and VI), the internal carotid artery, carotid sinus, pituitary gland, sphenopalatine ganglion, sphenopalatine artery, pterygoid canal, and dura mater (130). This can include infections, inflammation, tumors, and other conditions, including CSF leak, meningocele, and vascular lesions. It can present with headache, cranial nerve deficits, vision loss, diplopia, and pain or numbness in the distribution of the trigeminal nerve. It is diagnosed with imaging (CT or MRI) and endoscopic examination (49).

Temporomandibular joint disorders. Temporomandibular disorders must be excluded as these can result in acute or chronic facial pain. Chronic temporomandibular disorders are often associated with biological, social, environmental, emotional, and cognitive triggers (53). In the acute setting, temporomandibular disorders can occur after dental treatment or trauma. Pain occurs in the temporomandibular joint and surrounding muscles and ligaments, and it can radiate to the ear, temple, and neck. It is described as intermittent dull and achy pain, which can be acutely worsened by jaw movements. There can be pain-free periods as well. Patients have associated limited jaw opening, crepitus, clicking of the jaw, or muscle pain involving the neck and muscles of mastication. On physical examination, there can be reproducible tenderness to palpation of the temporomandibular joint. The symptoms can improve with a soft diet, analgesics, muscle relaxants, gabapentin, and benzodiazepines. Refractory cases may require surgical evaluation.

Salivary duct blockage. Blockage of the salivary ducts, such as by tumors, stones, or infections (including mumps, bacteria, actinomyces, and other mycobacteria), can also elicit pain at the site of the obstructed gland (92). The pain is intermittent and characteristically occurs just before eating, when saliva would be excreted (127). The involved salivary gland may have associated tenderness and swelling, and xerostomia may be present. Examination requires observing the glands and the mouth and palpating the affected glands, as a stone may be palpable. Pain occurs due to gland swelling, which can be acute or chronic. Imaging, including ultrasound and CT, may be helpful to identify the extent of infection and evaluate anatomy. Treatment includes treating underlying infections, tumor removal, and use of sialagogues. In some cases, referral to an oral or maxillofacial surgeon is required for further management.

Trigeminal autonomic cephalgias. Trigeminal autonomic cephalgias are a group of disorders characterized by unilateral pain with lateralized, ipsilateral cranial parasympathetic autonomic features (61). Two trigeminal autonomic cephalgias, both subcategories of short-lasting unilateral neuralgiform headache attacks, are characterized by short episodes of pain that may be mistaken for trigeminal neuralgia: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). These can be episodic (attacks occurring in periods lasting 7 days to 1 year, separated by pain-free periods of at least 3 months) or chronic (attacks occurring for more than 1 year without remission or with pain-free periods lasting fewer than 3 months). Attacks can last 1 to 600 seconds, occurring as single or a series of stabs, and can occur in a saw-tooth pattern. Other trigeminal autonomic cephalgias include cluster headaches, in which attacks can last 15 to 180 minutes, and paroxysmal hemicrania, in which attacks can last 2 to 30 minutes. Parasympathetic autonomic symptoms are prominent in trigeminal autonomic cephalgias and can include conjunctival injection and lacrimation, nasal congestion and rhinorrhea, eyelid edema, forehead and facial sweating, miosis, and ptosis. By comparison, trigeminal neuralgia may have no or only mild cranial autonomic symptoms like lacrimation without conjunctival injection (93). Unlike trigeminal neuralgia, pain episodes in SUNCT and SUNA can be triggered without a refractory period. Pain attacks are typically distributed in the V1 > V2 distributions (61). SUNCT/SUNA and trigeminal neuralgia can be difficult to differentiate and may even overlap, requiring both diagnoses.

Migraine. Migraine is a primary headache disorder attributed to nerve dysfunction leading to involvement of the trigeminovascular system through the release of calcitonin gene-related peptides. There are four phases, including prodrome, aura (which may or may not be present), migraine attack (headache phase), and postdrome. Migraine attacks consist of unilateral headache, described as throbbing pain, with associated nausea, photophobia, phonophobia, and worsening with activity. Attacks last 4 to 72 hours. Facial pain is rare in migraine but, when present, typically occurs in the V2 or V3 distribution (104). One cohort study from Taiwan concluded that migraine could be a risk factor for the development of trigeminal neuralgia as there was a higher incidence of trigeminal neuralgia in the migraine cohort than the control cohort (78).

Glossopharyngeal neuralgia. Glossopharyngeal neuralgia causes pain in the distribution of the ninth trigeminal nerve (angle of jaw, ear, tonsillar fossa, base of tongue). Given the location of the pain, trigeminal neuralgia, involving especially the mandibular branch, can be confused with glossopharyngeal neuralgia. Most often, glossopharyngeal neuralgia is idiopathic, but it can be secondarily caused by vascular compression, demyelination, inflammatory and autoimmune disease (eg, Sjogren disease), intraoral and peritonsillar infections, space-occupying lesions, Eagle syndrome (styloid process elongation or stylohyoid ligament ossification), and oropharyngeal cancers (108). Like trigeminal neuralgia, pain with glossopharyngeal neuralgia is sharp, stabbing, or electrical shock-like and lasts seconds to minutes, with abrupt onset and resolution. Swallowing can provoke the pain (103). Glossopharyngeal neuralgia can be associated with vagal symptoms like coughing, hoarseness, bradycardia, and even syncope (61).

Nervus intermedius neuralgia. Nervus intermedia neuralgia causes deep ear pain in the distribution of the nervus intermedius (also known as the geniculate nerve), which is a tiny branch off the facial nerve (99). In the literature, nervus intermedius neuralgia has quite variable radiation that can overlap with the distribution of the trigeminal, glossopharyngeal, and occipital nerves; concurrent neuralgias have even been reported. The pain should be severe, sharp, shooting, or stabbing, lasting seconds to minutes with a periauricular or external ear canal trigger area (61).

Persistent idiopathic facial pain. Persistent idiopathic facial pain is a disorder characterized by daily recurrent non-neuralgiform facial or tooth pain that varies in intensity through the day and has no associated neurologic deficits. Pain lasts for more than 2 hours per day for over 3 months. Pain onset is often associated with surgical or other dental or otolaryngologic procedures, but many patients cannot recall the sequence of events leading to pain onset. Pain is described as dull, aching, or nagging. Pain is usually initially unilateral but can become bilateral (138). Pain is persistent and daily and does not follow a dermatomal pattern. It can be triggered by stress or emotion with associated sharp exacerbations (15).

Tolosa Hunt syndrome. Tolosa Hunt syndrome is a condition of granulomatous inflammation of the cavernous sinus, superior orbital fissure, or orbit seen on MRI or biopsy, leading to paresis of one or more of the ipsilateral third, fourth, and or sixth cranial nerves (61). Symptoms include orbital or periorbital pain, diplopia, and ptosis (71). The optic and trigeminal nerves can be involved. Diagnosis is made using MRI or biopsy, and inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) may be elevated. Treatment is with high-dose intravenous steroids.

Paratrigeminal oculosympathetic syndrome. Paratrigeminal oculosympathetic syndrome (also known as Raeder syndrome) involves the trigeminal and oculosympathetic nerves, leading to ipsilateral pain, sensory loss, miosis, or ptosis with intact sweating (no anhidrosis) (55). It is caused by lesions in the middle cranial fossa, where the internal carotid artery lies, and the internal carotid nerve, containing postganglionic sympathetic nerve fibers, runs alongside the artery before dividing to form the carotid plexus.

Burning mouth syndrome. Burning mouth syndrome is defined by the International Classification of Orofacial Pain, first edition, as intraoral burning or dysesthesia recurring daily for more than 2 hours per day for more than 3 months, without any identifiable causative lesions, with or without somatosensory changes (07). Associated symptoms include subjective xerostomia, dysgeusia, bitter or metallic taste, sialorrhea, foreign body sensation, subjective change in color or tongue morphology, tingling, and itching (02). Patients can have extraoral symptoms, including ophthalmodynia, tinnitus, dizziness, abdominal pain, fibromyalgia, chronic fatigue syndrome, vulvodynia, and low back pain (85). Treatment includes symptomatic treatment with neuropathic pain medication (gabapentin, tricyclic antidepressants, cannabinoids), antidepressants, and lifestyle modification.

Table 1. A Comparison of Trigeminal Neuralgia and Other Similarly Presenting Conditions

Etiology	Pain Sensation	Pain Distribution	Pain Duration	Associated Symptoms
Trigeminal neuralgia	Electric shock-like, shooting, stabbing, or sharp	Trigeminal nerve distribution (V2> V3> V1)	Seconds to 2 minutes ± concomitant continuous pain	No or mild autonomic symptoms (eg, lacrimation)
Painful trigeminal neuropathy	Burning	Trigeminal nerve distribution	Paroxysmal or constant	Numbness or tingling, itching, allodynia
Dental pain	Acute, sharp	Around the affected tooth, may have radiation	Continuous with short triggered exacerbations	Presence of cracked tooth, dental abscess
Acute maxillary rhinosinusitis	Dull, achy, throbbing	Cheeks, upper teeth	Continuous	Fever, anosmia, purulent discharge
Sphenoid sinus disease	Dependent on the structures involved	Holocephalic, face, trigeminal nerve distribution if nerves involved	Continuous	Cranial nerve deficits, vision loss, diplopia, pain or numbness in trigeminal nerve distribution
Temporomandibular joint disorders	Dull, aching, muscle tightness	Temporomandibular joint, angle of mandible, radiation to ear, temple, neck	Minutes to hours	Jaw-clenching, teeth grinding
Salivary duct blockage	Dull, aching	Site of blocked duct	Minutes	Xerostomia, gland swelling
Trigeminal autonomic cephalgias (SUNCT, SUNA)	Sharp	V1>V2	1 to 600 seconds	Parasympathetic autonomic symptoms
Migraine	Classically throbbing,	Classically unilateral head or neck	4 to 72 hours	Nausea, vomiting, photophobia, phonophobia, aura
Glossopharyngeal neuralgia	Electric shock-like, shooting, stabbing, or sharp	Angle of jaw, ear, tonsillar fossa, base of tongue	Seconds to 2 minutes	Vagal symptoms
Nervus intermedius neuralgia	Shooting, stabbing, or sharp	Deep ear	Seconds to minutes
Persistent idiopathic facial pain	Dull, aching, nagging	Unilateral or bilateral, deep, no specific distribution	Hours occurring daily	No neurologic deficits
Tolosa Hunt syndrome	Dull aching pain	Periorbital	Minutes, occurring with eye movement	Periorbital pain, diplopia, ptosis
Paratrigeminal oculosympathetic syndrome	Neuralgiform or numbness	Trigeminal nerve distribution		Ipsilateral miosis and ptosis, intact sweating
Burning mouth syndrome	Burning pain	Intraoral	Daily for longer than 2 hours	Dysgeusia, sialorrhea, foreign body sensation, mood disorders

Associated or underlying disorders

Classical trigeminal neuralgia. Classical trigeminal neuralgia is caused most often by neurovascular compression, typically by a redundant or tortuous loop of the superior cerebellar artery. Other arteries that can be involved include the anterior inferior cerebellar artery, the posterior inferior cerebellar artery, vertebral artery, basilar artery, labyrinthine artery, and other unspecified small arteries. (11; 30). Veins can also compress the trigeminal nerve, including the superior petrosal vein and its tributaries: transverse pontine, pontotrigeminal, cerebellopontine fissure, and middle cerebellar peduncle (118).

Secondary trigeminal neuralgia.

Multiple sclerosis
Intracranial mass lesion

Painful trigeminal neuropathy.

Acute Herpes zoster infection
Post-herpetic neuralgia
Post-traumatic trigeminal neuropathy (anesthesia dolorosa)

Diagnostic workup

Trigeminal neuralgia is diagnosed based on typical history and clinical features. Neurologic examination is normal; allodynia and hyper- or hypoalgesia in the trigeminal nerve distribution ipsilateral to the facial pain may be present in patients with painful trigeminal neuropathy. Physical examination should evaluate for intraoral etiologies like a cracked tooth or blocked salivary gland, temporomandibular joint function, rashes in the distribution of pain, and cranial autonomic symptoms. Although there are no specific laboratory or diagnostic tests to confirm the diagnosis, MRI with thin cuts through the trigeminal nerve is highly recommended to look for potential structural causes, such as neurovascular conflict, cerebellopontine angle meningiomas, schwannomas, pontine gliomas, arteriovenous malformation, saccular aneurysms, or multiple sclerosis plaques. In rare cases, trigeminal neuralgia has been associated with a pontine lesion (119). Steady-state free precession sequences (such as constructive interference steady state [CISS] from Siemens, and fast imaging employing steady-state acquisition [FIESTA] from GE Healthcare) are helpful as they can help to distinguish soft tissue from CSF, resulting in better imaging of the trigeminal nerve and adjacent vessels (65; 21). These investigations may identify a cause in up to 15% of patients. MRA of the head can further evaluate vascular etiologies and is helpful in surgical treatment planning for microvascular decompression (115). Preoperative magnetic resonance tomographic angiography has been suggested as useful in patient selection and outcome prediction for microvascular decompression surgery (125).

If there is a contraindication to MRI, trigeminal reflexes or evoked potentials can be considered (13). Evoked potentials, quantitative sensory testing, and electrophysiological studies can also help detect symptomatic trigeminal neuralgia, but more research is needed before these studies can be routinely recommended.

Management

Treatment for trigeminal neuralgia is multidisciplinary and can include medication and surgery.

Pharmacotherapy

	• First-line pharmacotherapy includes carbamazepine (200 to 1800 mg per day) and oxcarbazepine (300 to 2700 mg per day)
	• Second-line pharmacotherapy includes lamotrigine, gabapentin, pregabalin, baclofen, phenytoin, and botulinum toxin type A. These can be used in place of first-line therapies if not tolerated or as add-on therapy.

First-line treatment for trigeminal neuralgia is with pharmacotherapy. The antiseizure medication carbamazepine is considered the gold standard of treatment, and it is the only FDA-approved therapy for trigeminal neuralgia (124). Oxcarbazepine has been found to have similar efficacy (57). There are limited randomized controlled trials regarding the use of these medications in trigeminal neuralgia, but they are considered effective by clinicians and are recommended for use in United States and European guidelines (57; 13). The clinical utility of these medications may be limited by their side effect profile. Carbamazepine can cause drowsiness, rash, liver damage, ataxia, and potential drug interactions. Oxcarbazepine may have fewer side effects. They have been found to be less tolerated in females (18).

Carbamazepine has Level A evidence (48). The starting dose is 200 to 400 mg, and an increase up to 200 to 1800 mg per day is recommended (57; 13; 14). Dosing is split over two to four doses per day. It is recommended to start at a low dose and increase gradually to help minimize adverse effects and improve patient tolerability of the medication. Testing for HLA B1502 allele is also recommended in patients of Asian descent as there is an increased risk with this allele of developing Stevens-Johnson syndrome or toxic epidermal necrosis. This has been attributed to the Han Chinese population, but the allele is frequently seen in many other Asian populations (48).

Oxcarbazepine is a structural analog to carbamazepine and shares a similar mechanism of action (voltage-gated sodium channel blockade), but it is metabolized differently (01). There is Level B evidence for use in trigeminal neuralgia (57; Administration 2016; 13). A starting dosage of 300 to 600 mg increased up to 300 to 2700 mg per day is recommended (14). Dosing is split over two to four doses per day.

Second-line or add-on pharmacotherapy for trigeminal neuralgia includes lamotrigine, baclofen, gabapentin, pregabalin, phenytoin, and botulinum toxin A. These can be used in place of carbamazepine or oxcarbazepine if poorly tolerated, or they can be used in addition to them if symptom control is inadequate (57; 14).

Lamotrigine has Level C evidence for use in trigeminal neuralgia (57). A starting dose of 25 mg daily, up to a maximum dose of 100 to 400 mg total daily dose is recommended. Dosing is split over two doses per day (14).

Baclofen has Level C evidence for use in trigeminal neuralgia (57). A starting dose of 10 mg up to a maximum dose of 15 to 70 mg per day is recommended. Dosing is split over three doses per day (14).

Gabapentin has low-quality evidence for use in trigeminal neuralgia but can be considered as second-line or add-on therapy (57). A starting dose of 300 mg up to a maximum of 600 to 3600 mg daily is recommended. Dosing is split over three doses per day (14).

Pregabalin and phenytoin have some efficacy in trigeminal neuralgia seen in clinical experience, but evidence is limited (14).

Botulinum toxin type A has been shown to have efficacy in trigeminal neuralgia. One systematic review found that doses ranging from 25 to 100 U were effective in reducing pain severity and frequency by 50%. As overall evidence is weak, it is recommended as an add-on therapy (14).

In addition to these traditional pharmacologic agents, there are other medications being studied for the treatment of trigeminal neuralgia. A novel agent, vixotrigine, is being prepared for a phase III trial in treating trigeminal neuralgia. This agent is a selective Nav1.7 sodium channel blocker and has been shown in a phase II randomization withdrawal study to decrease both pain severity and the number of paroxysms that occurred (73). A case series with six patients looked at the use of erenumab for patients with trigeminal neuralgia and concurrent migraine, with five reporting trigeminal neuralgia benefit (68). A phase II/III randomized controlled trial is underway for basimglurant, a metabotropic glutamate receptor 5 (mGluR5) inhibitor, as a treatment for trigeminal neuralgia (An Efficacy and Safety Study of Basimglurant in Patients With Trigeminal Neuralgia).

Surgical management

	• Microvascular decompression is the gold standard.
	• Stereotactic radiosurgery (eg, Gamma Knife radiosurgery) is a noninvasive treatment modality that is less effective than microvascular decompression but has lower complication rates.
	• Percutaneous treatments include balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation, which can be less invasive but also less effective

For long-term cases refractory to pharmacotherapy and in which there is a clear structural abnormality on neuro-imaging, more aggressive interventional techniques are warranted. Microvascular decompression is considered the gold standard for classical trigeminal neuralgia; other options include Gamma Knife and CyberKnife radiosurgery and percutaneous techniques, including balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation (29).

Microvascular decompression. Microvascular decompression is performed to alleviate abnormal compression of the trigeminal nerve by a blood vessel. There is no true nerve destruction with this modality. Patients tend to recover more quickly and have longer periods between relapses with this technique compared to other surgical interventions. The procedure is safe and effective, with initial pain relief as high as 98% (102). One review series found that 70% of patients were pain-free at 10 years (11). For patients with recurrent symptoms, repeat microvascular decompression can be an effective option (67).

The most significant complications following microvascular decompression for trigeminal neuralgia are cerebellar swelling or hematoma, arterial or venous infarct of the cerebellum or the brainstem, hearing loss, and CSF leak (102). One study noted a complication rate of 8.2%, with a 0% mortality rate, so it is felt to be safe overall (62).

Microvascular decompression, radiosurgery, and percutaneous techniques are treatment options for patients whose pain has been refractory to medical management. Although microvascular decompression is the gold standard for treatment, not all patients are candidates. Patients with no evidence of neurovascular or venous compression and those who previously had microvascular decompression are not good candidates for microvascular decompression (26).

Radiosurgical techniques--Gamma Knife and CyberKnife. Gamma Knife radiosurgery is a noninvasive outpatient procedure in which a high dose (70 to 90 Gy) of a highly focused beam of gamma radiation is delivered at the trigeminal root entry zone, which over time causes axonal degeneration and necrosis and, thus, interrupts pain signals (105; 03). It has been found to be inferior to microvascular decompression in patient relief and recurrence rate, but it has a lower complication rate (04). The 2008 American Academy of Neurology and European Federation of Neurological Societies review of treatments for trigeminal neuralgia found that 69% of patients were pain-free at 1 year after Gamma Knife radiosurgery, 52% were pain-free at 3 years, and pain relief can be delayed on average up to 1 month (57). Side effects include facial numbness (9% to 37%) and sensory loss or paresthesia (6% to 13%), which may develop with a delay of up to 6 months (03).

CyberKnife is another radiosurgical technique used for trigeminal neuralgia that has been refractory to medications. Unlike Gamma Knife radiosurgery, which uses radioactive cobalt as the source of the gamma radiation and requires the patient to have a rigid frame fixed to their skull, CyberKnife uses a linear accelerator mounted on a robotic arm and x-ray guidance to track and correct for target movement. It can be performed multiple times with success in treating trigeminal neuralgia, but repeated treatments can lead to sensory complications (100). Patients can have long-term benefit from CyberKnife treatment, up to 13 years seen in one review (17).

Percutaneous techniques. Percutaneous techniques include balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation. They have the benefit of short procedure duration, minimal anesthesia risk, and immediate patient feedback, but a large proportion of patients have pain recur long-term. Balloon compression involves inflating a balloon in Meckel’s cave, injuring large pain fibers, and it does not require the patient to be awake and cooperative. Pain control has been reported up to 91% at 6 months and 66% at 3 years. Glycerol rhizotomy has similar pain-free rates, but it has higher complication rates. Radiofrequency thermocoagulation has pain-free rates of 97% initially and 58% at 5 years (29).

Ablative techniques (radiosurgery, percutaneous techniques) are better for those without neurovascular compression or who are poor candidates for microvascular decompression. Contraindications include numbness in the distribution of the trigeminal nerve, as this is more consistent with a diagnosis of trigeminal neuropathic pain or deafferentation pain, not trigeminal neuralgia, as there is an increased risk of iatrogenic post-traumatic painful trigeminal neuropathy (26).

Balloon decompression requires the patients to undergo general anesthesia due to the pain of the procedure (26). Thermal rhizotomy can be used for classical trigeminal neuralgia as well as secondary and idiopathic trigeminal neuralgia (26).

Complications

Although microvascular decompression can lead to improvement in pain, complications can include CSF leak, facial numbness, hearing impairment, infection, hematoma, and rarely, death (41).

Radiosurgery can lead to facial numbness as the radiation dose is increased. There was one case report published of superior cerebellar artery aneurysm rupture after two Gamma Knife treatments (44).

Thermal rhizotomy can lead to diminished corneal reflex, masseter weakness and paralysis, dysesthesia, keratitis, and CSF leak (26).

Neuroablative procedures aimed at the trigeminal ganglion or nerve root can result in neuropathic pain in one or more divisions of the trigeminal nerves and, per ICHD3, is considered post-traumatic (61).

Other management

	• Neuromodulation, including nerve blocks and transcranial magnetic stimulation, is a treatment consideration for symptom relief in trigeminal neuralgia.
	• Future research is needed to better understand the role of neuromodulation in the treatment of trigeminal neuralgia.

Neuromodulation. Neuromodulatory techniques are an ongoing area of interest in trigeminal neuralgia, though available data remain sparse. These include peripheral nerve blocks and transcranial magnetic stimulation.

Peripheral nerve blocks are performed by injecting local anesthetic at the site of nerve branches. Trigeminal nerve blocks can be performed in the face. Sphenopalatine ganglion blocks target the maxillary branch of the trigeminal nerve and autonomic supply to the head and face through administration of lidocaine up the nose to the pterygopalatine fossa, where the sphenopalatine ganglion lies. One study found that peripheral nerve blocks were effective for short-term relief (10). There are case reports in which the use of sphenopalatine ganglion blocks was found to be effective in treating classical and secondary trigeminal neuralgia (82; 89).

Transcranial magnetic stimulation and transcranial direct current stimulation are two additional modalities that have been shown to be beneficial for neuropathic pain. Transcranial magnetic stimulation is a noninvasive technique in which an electromagnetic coil is used to create a magnetic field, stimulating the brain cortex during brief magnetic pulses to changes in cortical excitability (133). It has been studied in several neuropathic pain conditions, but there is insufficient evidence to determine its efficacy in trigeminal neuralgia. Transcranial direct current stimulation has been studied in trigeminal neuralgia, and preliminary evidence shows that it may effectively alleviate trigeminal neuralgia pain (09).

Special considerations

Given the significant psychosocial impact of trigeminal neuralgia, a multifaceted treatment approach involving referrals to psychology or psychiatry and speech or swallow therapies as warranted is highly recommended. Dental care is an important consideration, as many patients with orofacial pain avoid routine maintenance of oral health due to pain concerns (72). The dental team should understand the patient’s pain condition, appointments should be scheduled during times of lowest pain intensity or symptom remission, and procedures should minimize pain stimuli, such as using soft brushes or sponges soaked in chlorhexidine and taking the least invasive approach possible. Local anesthesia can exacerbate pain. Communication between the patient and dental team is important to understand trigger zones and each patient’s specific symptoms (83).

Regarding the treatment of painful trigeminal neuralgia associated with acute herpes zoster infection, the United States has three drugs approved for treatment: acyclovir, valacyclovir, and famciclovir. One meta-analysis showed that acyclovir accelerated pain resolution in patients with herpes zoster, with fewer patients having postherpetic neuralgia at 3 and 6 months (128). Oral treatment with the above medications also reduces ocular complications associated with herpes zoster ophthalmicus from 50% down to 20% or 30%. A consultation with an ophthalmologist or corneal specialist is highly recommended (54).

There is limited evidence for the use of intravenous medications for acute exacerbations of trigeminal neuralgia. One study found that intravenous lacosamide and phenytoin effectively reduced pain in acute exacerbations in a cohort of 121 patients. More adverse effects were seen with phenytoin administration, and the group that received lacosamide had lower readmission rates and more sustained pain relief (88). Other considerations include valproic acid, lidocaine, and clonazepam, but more research is needed (107).

Outcomes

The course of trigeminal neuralgia can be variable between patients and etiologies. Episodes can last weeks to months, with pain-free intervals lasting weeks to years. Some patients have a component of persistent pain (80). Recurrence rates can depend on the treatments administered, as highlighted above.

Microvascular decompression is safe and effective, with initial pain relief as high as 98% (102). One review series found that 70% of patients were pain-free at 10 years (11) For patients with recurrent symptoms, repeat microvascular decompression can be an effective option (67). The annual risk of recurrence is approximately 2% in the first 5 years after the procedure and less than 1% after 10 years (76). One retrospective study found that of 400 patients treated with microvascular decompression, pain recurred in 36 patients after 2 years (9%), with higher rates of recurrence in females (9.4%) compared to males (8%); recurrence rate was about 8.6% in the vascular compression group, and the highest recurrence rate in those with pain was seen in the V2 to 3 group (13.4%) compared to V2 (12.5%), V1 (9.1%), V3 (7.5%), V1 to 2-3 (4.4%), V1 to 2 (4.3%), and V1 to 3 (0%) (137).

Pain resolution from radiosurgery can take months to achieve, up to 180 days after treatment (131). Initial rates of pain relief are estimated to be about 53.1% with Gamma Knife and 56.3% with CyberKnife (123). Factors affecting long-term pain relief include radiation dose (with doses less than 80 Gy leading to poorer outcomes), calibration dose rate (less than 2.5 Gy/minute leading to poorer outcomes), and distance between the isocenter and trigeminal nerve emergence (greater than 8 mm leading to poorer outcomes) (12).

Radiosurgery can be repeated after initial treatment and can also be an option for subsequent treatment for symptom recurrence after microvascular decompression, and microvascular decompression is sometimes performed after failure of radiosurgery. One metaanalysis evaluating outcomes of Gamma Knife radiosurgery versus microvascular decompression after failed Gamma Knife radiosurgery found that adequate pain reduction occurred immediately in 83% with repeat Gamma Knife radiosurgery and 88% with microvascular decompression, complete pain reduction in 46% with repeat Gamma Knife radiosurgery and 72% with microvascular decompression; at 1 year, there was adequate pain reduction in 80% after repeat Gamma Knife radiosurgery and 81% with microvascular decompression and complete pain reduction in 47% with repeat Gamma Knife radiosurgery and 44% with microvascular decompression (94). There was no significant difference between the two treatments after failed Gamma Knife radiosurgery, but microvascular decompression gave a higher chance of complete pain reduction. Another review found that repeat Gamma Knife radiosurgery had pain cessation rates up to 88%, but there was new hypesthesia in about 33% of cases reviewed (122). Repeating radiosurgery a third time is a safe option, with one small retrospective review of 17 patients (age 51 to 95 years, 7 males, 10 females) reporting initial pain relief in 47.1% and another 47.1% with partial pain relief, 35.3% reporting sustained relief at an average follow up of 22.9 months, an average time to response of 2.9 months after third Gamma Knife radiosurgery, and none of the patients developing new or worsened sensory disturbances (117).

With repeated radiosurgical procedures, cumulative radiation dose should be taken into consideration. One review found that a single treatment dose of more than 82 Gy was associated with increased treatment response compared to lower doses but had higher rates of treatment-related facial numbness (74). Another review of 28 patients who received multiple treatments with Gamma Knife radiosurgery found the median initial dose was 80 Gy, median retreatment dose was 45 Gy, and median cumulative dose was 125 Gy, with an average of 18.1 months between procedures; a cumulative dose of more than 130 Gy was found to have successful pain control (greater than 50%) but was more likely (greater than 20%) to result in new dysfunction, including numbness, paresthesia, dysesthesia, altered taste, and bite weakness (46).

Contrast enhancement of the trigeminal nerve can be seen after radiosurgery. One study found that when enhancement was present at the time of repeat radiosurgery, there was an association with less satisfactory pain control and higher rates of facial sensory loss, which may warrant consideration for dose reduction and separation of radiosurgical targets (87).

Special considerations

Pregnancy

Treatment of trigeminal neuralgia during pregnancy can be challenging due to the teratogenic effects of the medications used for treatment. Though trigeminal neuralgia is more common in the elderly, it can occur in patients of child bearing age. As previously discussed, the mainstays of trigeminal neuralgia medication treatment include carbamazepine and oxcarbazepine. Carbamazepine is FDA pregnancy category D, with an increased risk of neural tube defects. Oxcarbazepine is FDA pregnancy category C, with adverse effects seen in animal studies. These medications should be discontinued when pregnancy is suspected or planned.

Onabotulinum toxin A has not been studied in pregnancy, but a report from the manufacturer found that in 137 cases reviewed, there was no increased risk of birth defects (NIH: OnabotulinumtoxinA (Botox®) 1994). As the molecule itself is large (150 kD), when administered properly (intramuscularly), it does not enter systemic circulation and, therefore, cannot cross the placenta (116).

Peripheral nerve blocks with lidocaine are considered safe during pregnancy, as it is FDA category B. There are limited data for peripheral nerve blocks in trigeminal neuralgia. One pilot study found that weekly trigeminal nerve blocks were an effective treatment option for those who did not tolerate first-line treatment, though the study was done with blocks performed with bupivacaine, which has not been studied in pregnancy (84). Sphenopalatine ganglion blocks could also be considered, as they have been found to be an effective treatment for tension-type headaches in pregnant patients (56). Topical 5% lidocaine-medicated plaster is another consideration, as it has been found to be effective in trigeminal neuralgia and postherpetic neuralgia (19; 135).

Surgical interventions are also not preferred during pregnancy, so percutaneous interventions are more preferable treatment options. Radiation exposure to the fetus during fluoroscopy is an important consideration, and effects depend on the stage of development. No radiation dose is considered absolutely safe, but up to 100 mGy may be considered an acceptable dose after 15 weeks gestation (113).