Trigeminal neuralgia (TN), also known as tic douloureux, is a distinctive facial pain syndrome that may become recurrent and chronic. It is characterized by unilateral pain following the sensory distribution of cranial nerve V (typically radiating to the maxillary or mandibular area in 35% of affected patients) and is often accompanied by a brief facial spasm or tic. See the image below.
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Microscopic demonstration of demyelination in primary trigeminal neuralgia. A tortuous axon is surrounded by abnormally discontinuous myelin. (Electro....
Signs and symptoms
TN presents as attacks of stabbing unilateral facial pain, most often on the right side of the face. The number of attacks may vary from less than 1 per day to 12 or more per hour and up to hundreds per day.
Triggers of pain attacks include the following:
Chewing, talking, or smiling
Drinking cold or hot fluids
Touching, shaving, brushing teeth, blowing the nose
Encountering cold air from an open automobile window
Pain localization is as follows:
Patients can localize their pain precisely
The pain commonly runs along the line dividing either the mandibular and maxillary nerves or the maxillary and ophthalmic portions of the nerve
In 60% of cases, the pain shoots from the corner of the mouth to the angle of the jaw
In 30%, pain jolts from the upper lip or canine teeth to the eye and eyebrow, sparing the orbit itself
In less than 5% of cases, pain involves the ophthalmic branch of the facial nerve
The pain has the following qualities:
Characteristically severe, paroxysmal, and lancinating
Commences with a sensation of electrical shocks in the affected area
Crescendos in less than 20 seconds to an excruciating discomfort felt deep in the face, often contorting the patient's expression
Begins to fade within seconds, only to give way to a burning ache lasting seconds to minutes
Pain fully abates between attacks, even when they are severe and frequent
Attacks may provoke patients to grimace, wince, or make an aversive head movement, as if trying to escape the pain, thus producing an obvious movement, or tic; hence the term "tic douloureux"
Other diagnostic clues are as follows:
Patients carefully avoid rubbing the face or shaving a trigger area, in contrast to other facial pain syndromes, in which they massage the face or apply heat or ice
Many patients try to hold their face still while talking, to avoid precipitating an attack
In contrast to migrainous pain, attacks of TN rarely occur during sleep
See Clinical Presentation for more detail.
Diagnosis
No laboratory, electrophysiologic, or radiologic testing is routinely indicated for the diagnosis of TN, as patients with a characteristic history and normal neurologic examination may be treated without further workup.
Strict criteria for TN as defined by the International Headache Society (IHS) are as follows[1] :
A – Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting 1 or more divisions of the trigeminal nerve and fulfilling criteria B and C
B – Pain has at least 1 of the following characteristics: (1) intense, sharp, superficial or stabbing; or (2) precipitated from trigger areas or by trigger factors
C – Attacks stereotyped in the individual patient
D – No clinically evident neurologic deficit
E – Not attributed to another disorder
IHS criteria for symptomatic TN vary slightly from the strict criteria and include the following[1] :
A – Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, with or without persistence of aching between paroxysms, affecting 1 or more divisions of the trigeminal nerve and fulfilling criteria B and C
B – Pain has at least 1 of the following characteristics: (1) intense, sharp, superficial or stabbing; or (2) precipitated from trigger areas or by trigger factors
C – Attacks stereotyped in the individual patient
D – A causative lesion, other than vascular compression, demonstrated by special investigations and/or posterior fossa exploration
A blood count and liver function tests are required if therapy with carbamazepine is contemplated. Oxcarbazepine can cause hyponatremia, so the serum sodium level should be measured after institution of therapy.
Pharmacologic trials should always precede the contemplation of a more invasive approach, as medical therapy alone is adequate treatment for 75% of patients
Single-drug therapy may provide immediate and satisfying relief
Carbamazepine is the best studied drug for TN and the only one with US Food and Drug Administration (FDA) approval for this indication
Because TN may remit spontaneously after 6-12 months, patients may elect to discontinue their medication in the first year following the diagnosis; most must restart medication in the future
Over the years, patients may require a second or third drug to control breakthrough episodes and finally may need surgical intervention
Lamotrigine and baclofen are second-line therapies
Controlled data for adding a second drug when the first fails exist only for the addition of lamotrigine to carbamazepine
Gabapentin has demonstrated effectiveness in TN, especially in patients with multiple sclerosis
Features of surgical treatment include the following:
Three operative strategies now prevail: percutaneous procedures, gamma knife surgery (GSK), and microvascular decompression (MVD)
Ninety percent of patients are pain-free immediately or soon after any of the operations,[2] but the relief is much more long-lasting with microvascular decompression
Percutaneous surgeries make sense for older patients with medically unresponsive trigeminal neuralgia
Younger patients and those expected to do well under general anesthesia should first consider microvascular decompression
Trigeminal neuralgia (TN), also known as tic douloureux, is a common and potentially disabling pain syndrome, the precise pathophysiology of which remains obscure. This condition has been known to drive patients with trigeminal neuralgia to the brink of suicide. Although neurologic examination findings are normal in patients with the idiopathic variety, the most common type of facial pain neuralgia, the clinical history is distinctive. Trigeminal neuralgia is characterized by unilateral pain following the sensory distribution of cranial nerve V—typically radiating to the maxillary (V2) or mandibular (V3) area in 35% of affected patients (see the image below)—often accompanied by a brief facial spasm or tic. Isolated involvement of the ophthalmic division is much less common (2.8%).
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Illustration depicting the trigeminal nerve with its 3 main branches
Typically, the initial response to carbamazepine therapy is diagnostic and successful. Despite obtaining this satisfying early relief with medication, patients may experience breakthrough pain that requires additional drugs and, in some patients, one or more of a variety of surgical interventions.
Historical information
The clinical description of trigeminal neuralgia can be traced back more than 300 years. Aretaeus of Cappadocia, known for one of the earliest descriptions of migraine, is credited with the first indication of trigeminal neuralgia when he described a headache in which "spasms and distortions of the countenance took place." Nicholaus Andre coined the term tic douloureux in 1756.
John Fothergill was the first to give a full and accurate description of this condition in a paper titled "On a Painful Affliction of the Face," which he presented to the medical society of London in 1773. Osler also described trigeminal neuralgia in great and accurate detail in his 1912 book The Principles and Practice of Medicine.[3]
In 1900, in a landmark article, Cushing reported a method of total ablation of the gasserian ganglion to treat trigeminal neuralgia.
The trigeminal nerve is the largest of all the cranial nerves. It exits laterally at the mid-pons level and has 2 divisions—a smaller motor root (portion minor) and a larger sensory root (portion major). The motor root supplies the temporalis, pterygoid, tensor tympani, tensor palati, mylohyoid, and anterior belly of the digastric. The motor root also contains sensory nerve fibers that particularly mediate pain sensation.
The gasserian ganglion is located in the trigeminal fossa (Meckel cave) of the petrous bone in the middle cranial fossa. It contains the first-order general somatic sensory fibers that carry pain, temperature, and touch. The peripheral processes of neurons in the ganglion form the 3 divisions of the trigeminal nerve (ie, ophthalmic, maxillary, and mandibular). The ophthalmic division exits the cranium via the superior orbital fissure; the maxillary and mandibular divisions exit via the foramen rotundum and foramen ovale, respectively.
The proprioceptive afferent fibers travel with the efferent and afferent roots. They are peripheral processes of unipolar neurons located centrally in the mesencephalic nucleus of the trigeminal nerve.
The image below depicts the anatomy of the trigeminal nerve.
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Illustration depicting the trigeminal nerve with its 3 main branches
Because the exact pathophysiology remains controversial, the etiology of trigeminal neuralgia (TN) may be central, peripheral, or both. The trigeminal nerve (cranial nerve V) can cause pain, because its major function is sensory. Usually, no structural lesion is present (85%), although many investigators agree that vascular compression, typically venous or arterial loops at the trigeminal nerve entry into the pons, is critical to the pathogenesis of the idiopathic variety. This compression results in focal trigeminal nerve demyelination. The etiology is labeled idiopathic by default and is then categorized as classic trigeminal neuralgia.
Neuropathic pain is the cardinal sign of injury to the small unmyelinated and thinly myelinated primary afferent fibers that subserve nociception. The pain mechanisms themselves are altered. Microanatomic small and large fiber damage in the nerve, essentially demyelination,[4] commonly observed at its root entry zone (REZ), leads to ephaptic transmission, in which action potentials jump from one fiber to another.[5] A lack of inhibitory inputs from large myelinated nerve fibers plays a role. Additionally, a reentry mechanism causes an amplification of sensory inputs. A clinical correlate, for instance, is the potential for vibration to trigger an attack. However, features also suggest an additional central mechanism (eg, delay between stimulation and pain, refractory period).
Although a questionable family clustering exists, trigeminal neuralgia (TN) is most likely multifactorial.
Most cases of trigeminal neuralgia are idiopathic, but compression of the trigeminal roots by tumors or vascular anomalies may cause similar pain, as discussed in Pathophysiology. In one study, 64% of the compressing vessels were identified as an artery, most commonly the superior cerebellar (81%).[6] Venous compression was identified in 36% of cases.[6]
Trigeminal neuralgia is divided into 2 categories, classic and symptomatic. The classic form, considered idiopathic, actually includes the cases that are due to a normal artery present in contact with the nerve, such as the superior cerebellar artery or even a primitive trigeminal artery.
Symptomatic forms can have multiple origins. Aneurysms, tumors, chronic meningeal inflammation, or other lesions may irritate trigeminal nerve roots along the pons causing symptomatic trigeminal neuralgia. An abnormal vascular course of the superior cerebellar artery is often cited as the cause. Uncommonly, an area of demyelination from multiple sclerosis may be the precipitant (see the following image); lesions in the pons at the root entry zone of the trigeminal fibers have been demonstrated. These lesions may cause a similar pain syndrome as in trigeminal neuralgia.
View Image
Microscopic demonstration of demyelination in primary trigeminal neuralgia. A tortuous axon is surrounded by abnormally discontinuous myelin. (Electro....
Tumor-related causes of trigeminal neuralgia (most commonly in the cerebello-pontine angle) include acoustic neurinoma, chordoma at the level of the clivus, pontine glioma or glioblastoma,[7] epidermoid, metastases, and lymphoma. Trigeminal neuralgia may result from paraneoplastic etiologies.
Vascular causes include a pontine infarct and arteriovenous malformation or aneurysm in the vicinity.
Inflammatory causes include multiple sclerosis (common), sarcoidosis, and Lyme disease neuropathy.
Infrequently, adjacent dental fillings composed of dissimilar metals may trigger attacks,[8] and one atypical case followed tongue piercing. Another case report of trigeminal neuralgia was reported in a patient with spontaneous intracranial hypotension; both conditions resolved following surgical treatment of a cervical root sleeve dural defect.[9]
In 1968, Penman reported the US prevalence of trigeminal neuralgia (TN) as approximately 107 men and 200 women per 1 million people.[10] By 1993, Mauskop noted approximately 40,000 patients have this condition at any particular time,[11] with an incidence of 4-5 cases per 100,000. More recent estimates suggest the prevalence is approximately 1.5 cases per 10,000 population, with an incidence of approximately 15,000 cases per year.
Rushton and Olafson reported that approximately 1% of patients with multiple sclerosis (MS) develop trigeminal neuralgia,[12] whereas Jensen et al noted that 2% of patients with trigeminal neuralgia have multiple sclerosis.[13] Patients with both conditions often have bilateral trigeminal neuralgia.
No geographic tendency or racial differences have been found for trigeminal neuralgia. However, females are affected up to twice as often as males (range, 3:2 to 2:1). In addition, in 90% of patients, the disease begins after age 40 years, with a typical onset of 60-70 years (middle and later life). Patients who present with the disease when aged 20-40 years are more likely to suffer from a demyelinating lesion in the pons secondary to multiple sclerosis; younger patients also tend to have symptomatic or secondary trigeminal neuralgia . There have also been occasional reports of pediatric cases of trigeminal neuralgia.
Another risk factor for this syndrome is hypertension.
After an initial attack, trigeminal neuralgia (TN) may remit for months or even years. Thereafter the attacks may become more frequent, more easily triggered, disabling, and may require long-term medication. Thus, the disease course is typically one of clusters of attacks that wax and wane in frequency. Exacerbations most commonly occur in the fall and spring.
Among the best clinical predictors of a symptomatic form are sensory deficits upon examination and a bilateral distribution of symptoms (but the absence thereof is not a negative predictor). Young age is a moderate predictor, but a fair degree of overlap exists. Lack of therapeutic response and V1 distribution are poor predictors.
Although trigeminal neuralgia is not associated with a shortened life, the morbidity associated with the chronic and recurrent facial pain can be considerable if the condition is not controlled adequately. This condition may evolve into a chronic pain syndrome, and patients may suffer from depression and related loss of daily functioning. Individuals may choose to limit activities that precipitate pain, such as chewing, possibly losing weight in extreme circumstances. In addition, the severity of the pain may lead to suicide.
Complications
The chief complication in trigeminal neuralgia is the adverse effects and toxicity experienced routinely with long-term use of anticonvulsant agents. Another complication is the waning efficacy over several years of these drugs in controlling neuralgia, necessitating the addition of a second anticonvulsant, which may cause more drug-related adverse reactions.
Failure to diagnose a brainstem tumor and bone marrow aplasia as an idiosyncratic adverse effect of carbamazepine are common pitfalls to avoid.
Standard care must be applied to invasive procedures, which are most subject to potential claims. Percutaneous neurosurgical procedures and microvascular decompression procedures pose risks of long-term complications. Perioperative risks also exist. See Trigeminal Neuralgia Surgery. Moreover, patients may have to wait for weeks or months after the operation for relief, and some find relief only for 1-2 years and then must weigh the option of a second operation.
Some patients permanently lose sensation over a portion of the face or mouth. Occasionally, patients may suffer jaw weakness and/or corneal anesthesia. Corneal ulceration can result because of trophic disturbances from nerve deafferentation.
After any invasive treatments, reactivation of a herpes simplex infection is not uncommon.
The worst complication is anesthesia dolorosa, an intractable facial dysesthesia, which may be more disabling than the original trigeminal neuralgia. This dysesthesia may be caused by procedures and, sometimes, surgery.
Patients benefit from an explanation of the natural history of the disorder, including the possibility that the syndrome may remit spontaneously for months or even years before they need to consider long-term anticonvulsant medications. For this reason, some may elect to taper off their medication after the initial attack subsides; thus, they should be educated about the importance of being compliant with their medication regimen.
Patients also must be educated about the potential risks of anticonvulsant medications, such as sedation and ataxia, particularly in elderly patients, which may make driving or operating machinery hazardous. These drugs may also pose risks to the liver and the hematologic system. Document the discussion with the patient about these potential risks.
No specific preventative therapy exists. Patients may have a premonitory atypical pain for months; therefore, appropriate recognition of this pre–trigeminal neuralgia syndrome may lead to earlier and more efficient treatment.
Patients should avoid maneuvers that trigger pain. Once the diagnosis is established, advise them that dental extractions do not afford relief, even if pain radiates into the gums.
In patients wishing to undergo a procedure, they should be aware of potential adverse effects, as well as report any altered sensation in the face, especially after a procedure. They should be informed about the potential for anesthesia dolorosa.
Other resources
Some patients may wish to consult the resources below.
NINDS Trigeminal Neuralgia Information Page (updated: February 18, 2011)
NIH Neurological Institute
PO Box 5801
Bethesda, MD 20824
Phone: (800) 352-9424 or (301) 496-5751
TTY (for people using adaptive equipment): (301) 468-5981
E-mail: http://www.ninds.nih.gov/contact_us.htm
Web site: http://www.ninds.nih.gov/disorders/trigeminal_neuralgia/trigeminal_neuralgia.htm
TNA Facial Pain Association (formerly: Trigeminal Neuralgia Association)
408 W University Ave
Suite 602
Gainesville, FL 32601
Phone: (800) 923-3608 or (352) 384-3600
E-mail: info@fpa-support.org
Website: http://www.endthepain.org
An interactive questionnaire developed by the Oregon Health & Science University Department of Neurological Surgery allows patients to self-diagnose facial pain based on a brief series of questions. The "Trigeminal Neuralgia - Diagnostic Questionnaire" may be found at: https://neurosurgery.ohsu.edu/tgn.php (accessed April 7, 2011). An artificial intelligence method (neural network modeling) provides immediate feedback to the patient regarding the diagnosis and patient education resources.[14]
For patient education information, see Brain & Nervous System Center, as well Trigeminal Neuralgia (Facial Nerve Pain), Tic Douloureux, and Pain Medications.
Trigeminal neuralgia (TN) presents as a stabbing unilateral facial pain that is triggered by chewing or similar activities or by touching affected areas on the face. The disorder affects the right side of the face 5 times more frequently than the left.
According to Fromm et al, some patients may present with pretrigeminal neuralgia syndrome for a period of weeks or even years before developing the customary symptoms of trigeminal neuralgia.[15] They complain of an unrelenting sinus pain or toothache lasting for hours, triggered by moving the jaw or drinking fluids. Not surprisingly, they first seek dental care. Some find benefit from baclofen or carbamazepine.
Pain localization
Patients can localize their pain precisely. The pain is not confined exclusively to 1 of the 3 divisions of the trigeminal nerve but more commonly runs along the line dividing either the mandibular and maxillary nerves or the mandibular and ophthalmic portions of the nerve. Of affected patients, 60% complain of lancinating pain shooting from the corner of the mouth to the angle of the jaw; 30% experience jolts of pain from the upper lip or canine teeth to the eye and eyebrow, sparing the orbit itself—this distribution falls between the division of the first and second portions of the nerve. According to Patten, less than 5% of patients experience ophthalmic branch involvement.[16]
Pain quality
The pain quality is characteristically severe, paroxysmal, and lancinating. It commences with a sensation of electrical shocks in an affected area, then quickly crescendos in less than 20 seconds to an excruciating discomfort felt deep in the face, often contorting the patient's expression. The pain then begins to fade within seconds, only to give way to a burning ache lasting seconds to minutes. During attacks, patients may grimace, wince, or make an aversive head movement, as if trying to escape the pain, thus producing an obvious movement, or tic; hence the term "tic douloureux."
Pain chronicity and frequency
This condition is an exception to the rule that nerve injuries typically produce symptoms of constant pain and allodynia. If the pain is particularly frequent, patients may be difficult to examine during the height of an attack. The number of attacks may vary from less than 1 per day, to a 12 or more per hour, up to hundreds per day. Outbursts fully abate between attacks, even when they are severe and frequent.
Pain triggers and zones
A valuable clue to the diagnosis is the triggering of the pain with certain activities. Patients carefully avoid rubbing the face or shaving a trigger area, in contrast to other facial pain syndromes, in which they massage the face or apply heat or ice. Also, many patients try to hold their face still while talking to avoid precipitating an attack. According to Sands, trigger zones, or areas of increased sensitivity, are present in one half of patients and often lie near the nose or mouth.[17] Chewing, talking, smiling, or drinking cold or hot fluids may initiate the pain of trigeminal neuralgia. Touching, shaving, brushing teeth, blowing the nose, or encountering cold air from an open automobile window may also elicit pain.
In contrast to migrainous pain, persons with this condition rarely suffer attacks during sleep, which is another key point in the history.
Concomitant multiple sclerosis
Patients with multiple sclerosis (MS) and trigeminal neuralgia have similar complaints to those with the idiopathic variety, except that these individuals present at a much younger age (often < 40 y). Some present with atypical facial pain, without trigger zones, and without the lancinating brief paroxysms of discomfort. Atypical facial pain is characterized by persistent pain in the facial region and can be further divided into pain with demonstrable organic disease and conditions in which no pathology can be found. As previously noted, trigeminal neuralgia is not unusual in multiple sclerosis, but it is rarely the first manifestation. Typically, it occurs in the advanced stages of multiple sclerosis.
Physical examination will usually eliminate alternative diagnoses. However, remember that patients report pain following stimulation of a trigger point; thus, some patients may limit their examination for fear of stimulating these points. For example, male patients may present with an area of the face, the trigger zone, that is unshaven and unkempt.
The diagnosis of idiopathic trigeminal neuralgia (TN) is tenable only if no physical findings of fifth nerve dysfunction or are present. Neurologic examination findings are normal, and facial sensation, masseter bulk and strength, and corneal reflexes should be intact. Thus, no sensory loss is found unless checked immediately after a burst of pain; any permanent area of numbness excludes the diagnosis. Loss of the corneal reflex also excludes the diagnosis of idiopathic trigeminal neuralgia, unless a previous trigeminal nerve section procedure has been performed. Any jaw or facial weakness or swallowing difficulties suggests another etiology.
In patients with multiple sclerosis (MS) or a structural lesion and trigeminal neuralgia, sensory loss often is found on examination.
Although hypesthesia or dysesthesia in the face may be observed transitorily in classic trigeminal neuralgia, these symptoms should be considered part of the symptomatic forms. Paramount, however, is that the absence of these findings does not preclude the presence of an underlying cause; that is, it does not exclude a symptomatic form of trigeminal neuralgia.
A lack of clear definitions for facial pain has hampered the understanding of trigeminal neuralgia (TN), as the condition has no clear natural history and no long-term follow-up study of the progression of the disorder has been published. Below, 2 classifications for classic trigeminal neuralgia are presented.
International Headache Society criteria
Strict criteria for trigeminal neuralgia as defined by the International Headache Society (IHS) (International Classification of Headache Disorders, 2nd ed) in 2004 are as follows[1] :
A - Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting 1 or more divisions of the trigeminal nerve and fulfilling criteria B and C
B - Pain has at least 1 of the following characteristics: (1) intense, sharp, superficial or stabbing; or (2) precipitated from trigger areas or by trigger factors
C - Attacks stereotyped in the individual patient
D - No clinically evident neurologic deficit
E - Not attributed to another disorder
The criteria for symptomatic trigeminal neuralgia vary slightly from the strict criteria above and include the following[1] :
A - Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, with or without persistence of aching between paroxysms, affecting 1 or more divisions of the trigeminal nerve and fulfilling criteria B and C
B - Pain has at least 1 of the following characteristics: (1) intense, sharp, superficial or stabbing; or (2) precipitated from trigger areas or by trigger factors
C - Attacks stereotyped in the individual patient
D - A causative lesion, other than vascular compression, demonstrated by special investigations and/or posterior fossa exploration
Proposed classification scheme by Eller et al
In an attempt to rationalize the language of facial pain, in 2005, Eller et al introduced a new classification scheme that divides facial pain into several distinct categories[18] :
Trigeminal neuralgia type 1 (TN1): The classic form of trigeminal neuralgia in which episodic lancinating pain predominates
Trigeminal neuralgia type 2 (TN2): The atypical form of trigeminal neuralgia in which more constant pains (aching, throbbing, burning) predominate
Trigeminal neuropathic pain (TNP): Pain that results from incidental or accidental injury to the trigeminal nerve or the brain pathways of the trigeminal system
Trigeminal deafferentation pain (TDP): Pain that results from intentional injury to the system in an attempt to treat trigeminal neuralgia (Numbness of the face is a constant part of this syndrome, which has also been referred to as anesthesia dolorosa or one of its variants.)
Postherpetic neuralgia (PHN): Chronic facial pain that results from an outbreak of herpes zoster (shingles), usually in the ophthalmic division (V1) of the trigeminal nerve on the face and usually in elderly patients
Geniculate neuralgia (GeN): Pain typified as episodic and lancinating, felt deep in the ear
Glossopharyngeal neuralgia (GPN): Pain typified in the tonsillar area or throat, usually triggered by talking or swallowing
No laboratory, electrophysiologic, or radiologic testing is routinely indicated for the diagnosis of trigeminal neuralgia (TN), as patients with characteristic history and normal neurologic examination may be treated without further workup.
The diagnosis of facial pain is almost entirely based on the patient's history. In most cases of facial pain, no specific laboratory tests are needed. A blood count and liver function tests are required if therapy with carbamazepine is contemplated. Oxcarbazepine can cause hyponatremia, so the serum sodium should be tested after institution of therapy.
Although rarely indicated, appropriate blood work for rheumatic diseases, such as scleroderma (trigeminal neuropathy is reported in up to 5% of patients with this collagen vascular disease) and systemic lupus erythematosus (SLE), should be undertaken in patients with atypical features of facial pain and a systemic presentation of collagen vascular disease. Appropriate blood work includes a sedimentation rate (ESR), antinuclear antibody titer (ANA), double-stranded DNA, anti-Sm antibody, lupus erythematosus cell preparation, and complete blood cell (CBC) count to look for hematologic abnormalities (eg, hemolytic anemia, leukopenia, thrombocytopenia). Particularly in the case of scleroderma, creatinine kinase and aldolase levels may be elevated with muscle involvement. Antibody titers to SCL-86 and SCL-70 may also be present.
In cases with suspected metastatic carcinomatosis, cerebrospinal fluid analysis may confirm the diagnosis. When surgical procedures are contemplated, appropriate and routine preoperative laboratory tests are in order.
In patients older than 60 years, the clinician may first choose to assess the response to a therapeutic trial of medication before considering imaging. A clear relief of pain with carbamazepine or another anticonvulsant confirms the diagnosis of idiopathic trigeminal neuralgia.
Imaging studies are indicated, because distinguishing between classic and symptomatic forms of trigeminal neuralgia is not always clear. Approximately 15% of patients with trigeminal neuralgia (any form) have abnormalities on neuroimaging (computed tomography [CT] scanning and/or magnetic resonance imaging [MRI]). The most common findings are cerebello-pontine angle tumors and multiple sclerosis.
Brain magnetic resonance imaging (MRI) with and without contrast helps to distinguish secondary causes of trigeminal neuralgia (TN) from the idiopathic form. This study is imaging modality of choice and indicated in patients presenting with trigeminal neuralgia when younger than 60 years, principally to exclude tumor. For example, MRI can reveal multiple sclerosis plaques and pontine gliomas.[22] Perform an MRI if atypical features are present. See the image below.
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Magnetic resonance image (MRI) with high resolution on the pons demonstrating the trigeminal nerve root. In this case, the patient with trigeminal neu....
Some physicians recommend elective MRI for all patients to exclude an uncommon mass lesion or aberrant vessel compressing the nerve roots. However, in a published practice parameter, the American Academy of Neurology stated that because of inconsistency of studies, there was insufficient evidence to support or refute the usefulness of MRI or a specific MRI technique to identify vascular anomalies.[23] The recommendation was that, for patients with trigeminal neuralgia, routine imaging may be considered to identify symptomatic trigeminal neuralgia, and this was graded as a level C or possibly effective action.[23]
Magnetic resonance angiography (MRA) can be useful in locating a vascular compression; however, the sensitivity remains low.
Newer special techniques such as high-resolution, 3-dimensional (3-D) MRA (eg, posteroinferior cerebellar artery compresses the trigeminal root) and 3-D spoiled gradient-recalled imaging have been under study, but thus far no consensus to recommend them has been reached.[24] Overall, however, magnetic resonance studies on neurovascular conflicts have shown great variability in outcomes and techniques, with sensitivities as low as 52% and specificity as low as 29%. Therefore, this type of imaging still cannot be recommended as reliable.
Computed tomography (CT) scanning provides poor resolution in the posterior fossa. CT angiography is likewise a consideration, but a lack of large, randomized studies precludes a formal recommendation to routinely perform this test.
Clinical neurophysiology testing with a blink reflex study may be helpful to demonstrate a lesion of the trigeminus in which a bilateral delay occurs in response to the stimulation on the pathologic side.[25] The blink reflex can clearly help distinguish between the symptomatic form of trigeminal neuralgia and the idiopathic form of trigeminal neuralgia. The sensitivity of this test across studies has been reported as 59-100%, and the specificity has been noted as 93-100%.
Although not a diagnostic test, histology reveals focal demyelination as the ultimate lesion in both secondary and idiopathic cases of trigeminal neuralgia. In some instances (eg, tumor) of secondary cases of trigeminal neuralgia, the underlying lesion can be assessed by histology. The most frequent anatomic location is the root entry zone (REZ).
Trigeminal neuralgia is treated on an outpatient basis, unless neurosurgical intervention is required. Management of this condition must be tailored individually, based on the patient's age and general condition. In the case of symptomatic trigeminal neuralgia, adequate treatment is that of its cause, the details of which are out of the scope of this article.
Because most patients incur trigeminal neuralgia when older than 60 years, medical management is the logical initial therapy. Medical therapy is often sufficient and effective, allowing surgical consideration only if pharmacologic treatment fails. Medical therapy alone is adequate treatment for 75% of patients.
Patients may find immediate and satisfying relief with one medication, typically carbamazepine. However, because this disorder may remit spontaneously after 6-12 months, patients may elect to discontinue their medication in the first year following the diagnosis. Most must restart medication in the future. Furthermore, over the years, they may require a second or third drug to control breakthrough episodes and finally may need surgical intervention.
Simpler, less invasive procedures are well tolerated but usually provide only short-term relief. At this point, further and perhaps more invasive operations may be required, and with these procedures the risk of the disabling adverse effect of anesthesia dolorosa increases.
Thus, treatment can be subdivided into pharmacologic therapy, percutaneous procedures, surgery, and radiation therapy. Adequate pharmacologic trials should always precede the contemplation of a more invasive approach.
Transcranial magnetic stimulation appears promising, but results are still scarce.[26]
Adjunct Treatments
Adjunct treatments such as mechanical, electrical, and thermal stimuli sometimes modify pain with fewer adverse effects than medication. Self-adhesive bandages may also be used.
Depression is often seen in patients with trigeminal neuralgia; thus, this underlying depression should be adequately treated. Tricyclic antidepressants (eg, amitriptyline, nortriptyline), as well as sodium valproate or pregabalin, have not been well studied. Amitriptyline (Elavil) can be tried, but the success rate is low.
Antiepileptic drugs (AEDs) work well for trigeminal neuralgia (TN) and have been known to do so since a study was completed with phenytoin (PHE) in 1942 (Bergouignan) and another with carbamazepine (CBZ) in 1962 (Blom).[27] With 3 placebo-controlled crossover studies validating its efficacy in trigeminal neuralgia, providing relief by roughly 75% versus only 25% in the placebo arms (Killian, Nicol, Campbell), carbamazepine is the best studied drug for this disorder and the only one with US Food and Drug Administration (FDA) approval in this setting.
Since the carbamazepine studies, however, newer second- and third-generation AEDs have expanded the choice of AED in trigeminal neuralgia, having demonstrated their efficacy in a variety of neuropathic pain syndromes, including trigeminal neuralgia, as well as in painful diabetic polyneuropathy and postherpetic neuralgia.
Other anticonvulsant agents possibly useful in the treatment of this disorder include sodium valproate and clonazepam (Klonopin). Clonazepam has moderate efficacy but is not recommended because of a low level of evidence and its adverse effects (eg, sedation) and dependence. The National Institutes of Health (NIH) currently is sponsoring studies of topiramate.
Also see Antiepileptic Drugs.
Cost
Because patients with trigeminal neuralgia will be using medications for years, perhaps decades, their cost is relevant. Generic carbamazepine is the cheapest; costs vary widely for the other agents, depending on the source, but approach a 4-fold increase for generic gabapentin (GBP), 8-fold for lamotrigine (LTG), 10-fold for topiramate (TPM), and 20-fold for oxcarbazepine (OCB) in moderate daily doses.
To justify these hugely higher costs, providers can point to the promise of improved tolerability of the new agents, often a determining factor in a person with multiple sclerosis or with advanced age. Some drugs do not affect serious idiosyncratic hepatic and hematopoietic reactions, eliminating the burden and cost of routine laboratory monitoring. Some agents offer more linear pharmacokinetics and fewer drug-drug interactions, facilitating combination therapy. Some pose less long-term risk for osteoporosis. Furthermore, some drugs do not autoinduce their metabolism, simplifying dose titration and adjustment.
Efficacy
Most of the literature on medications for trigeminal neuralgia consists of case series, uncontrolled studies with less than a dozen subjects, or small randomized clinical trials, so the apparent efficacy of the drugs requires confirmation through well-designed, large, phase III trials. The controlled data published for lamotrigine and baclofen (BCF) is promising but derives from studies with only 14 and 10 subjects, respectively.
No controlled data exist for the use of phenytoin, clonazepam, sodium valproate, oxcarbazepine, gabapentin, or mexiletine in trigeminal neuralgia; similarly, no controlled data exist for the common practice of adding a second drug when the first fails, except for the addition of lamotrigine to carbamazepine. No head-to-head comparison studies of these agents exists, and only one surgery versus medication study has been published, limited to refractory trigeminal neuralgia, a small (n = 15) trial. Only one Cochran review of medications for trigeminal neuralgia exists, and it looks only at carbamazepine, the traditional favorite. Confusion arises over outcome measures, as some researchers accept only complete relief of pain, whereas others accept partial relief.
Dosing
Serum levels of the anticonvulsants in ranges appropriate for epilepsy may be necessary, at least to control the initial symptoms of trigeminal neuralgia; a much smaller maintenance dosage may be adequate thereafter. Because this disorder may remit spontaneously after 6-12 months, patients may elect to discontinue medication, only to restart it when the pain recurs. Once a patient experiences breakthrough pain on a single agent, a second and even third additional medication may be required to restore relief, at which point, many seek a surgical solution. Resistance develops anywhere from 2 months to 10 years after treatment begins with the most studied and successful drug, carbamazepine.
Risks
According to Dalessio, medications work by interrupting the temporal summation of afferent impulses that precipitate the attack.[28]
Anticonvulsant medications pose risks of sedation and ataxia, particularly in elderly patients, which may make driving or operating machinery hazardous. They also may pose risks to the liver and the hematologic system. Thus, documentation of patient education about these potential risks is important.
Patients also need to understand that medications for trigeminal neuralgia are only palliative and often are of limited and temporary value. They also must be informed thoroughly of the risks involved with neurosurgical interventions, including anesthesia dolorosa.
Carbamazepine and oxcarbazepine are considered first-line therapy in trigeminal neuralgia (TN).[29, 30] Lamotrigine and baclofen are second-line therapy. Other treatments are third line and the evidence for their efficacy is scant.
Carbamazepine acts by inhibiting the neuronal sodium channel activity, thereby reducing the excitability of neurons. A 100-mg tablet may produce significant and complete relief within 2 hours, and for this reason, it is a suitable agent for initial trial, although the effective dose ranges from 600-1200 mg/d, with serum concentrations between 40-100 mcg/mL. Indeed, serum levels of carbamazepine (but not necessarily phenytoin) in ranges appropriate for epilepsy may be necessary, at least to control initial symptoms, although a much smaller maintenance dosage may be adequate thereafter.
So predictable and powerful is the relief that if the patient does not respond at least partially to carbamazepine, reconsider the diagnosis of idiopathic trigeminal neuralgia.
Once a patient experiences breakthrough pain on a single agent, a second and even third additional medication may be required to restore relief. If this dosage does not relieve the discomfort adequately, administer a higher dose.
Many adverse central nervous system (CNS) effects (eg, vertigo, sedation, ataxia, diplopia) are associated with carbamazepine, which may make it difficult to use in elderly patients. The dose may be tapered once pain is controlled, since remission may occur.
Oxcarbazepine (Trileptal) has not been studied as extensively as carbamazepine, but efficacy outcomes are similar. Better tolerability can be considered an advantage over carbamazepine.[31]
Gabapentin has demonstrated effectiveness in trigeminal neuralgia (TN), especially in patients with multiple sclerosis (MS). In an early study, Sist et al reported 2 patients with trigeminal neuralgia whose condition had a response to gabapentin,[32] 1 of whom was previously unresponsive to carbamazepine.
In another study, Khan reported complete relief of secondary trigeminal neuralgia in 6 of 7 patients with multiple sclerosis who received gabapentin doses of 900-2400 mg/d.[33] The patients previously had not responded to a variety of drugs. Once on gabapentin, 2 subjects were able to discontinue all other pain medications, and the remaining 5 could stop all but one other pain medication.[33] All patients maintained the response at 1 year of therapy with minimal adverse effects. In a similar, uncontrolled, small study of patients with multiple sclerosis, Solaro et al reported that 5 of 6 individuals found complete and sustained relief with gabapentin.[34]
To date, the efficacy of gabapentin and lamotrigine versus placebo or their efficacy in patients whose pain is refractory to carbamazepine has not been established. In paclitaxel-induced neuropathic pain, lamotrigine appears to be a promising drug. The difference in responses shown by different antiepileptic drugs depends on the etiology of the underlying mechanisms in neuropathic pain.[35] As stated by Carrazana and Schachter, of these 2 agents, gabapentin has advantages, which include faster titration, no known drug interactions, and no known idiosyncratic skin reaction.[36]
Lamotrigine (Lamictal) has been proven more effective than placebo in trigeminal neuralgia (TN). This agent provided impressive and sustained relief in A small, open-label, prospective study,[37] in which all 5 patients with symptomatic trigeminal neuralgia associated with multiple sclerosis (MS) and 11 of 15 patients with idiopathic disease gained complete relief. This was maintained during a follow-up period of 3-8 months. Drug levels closely predicted pain relief, although the dosage required for adequate relief varied widely from 100 to 400 mg/d.[37]
The dosage should be increased slowly for better tolerance (eg, 25-mg daily dose each week; up to 250 mg twice a day).[38]
Phenytoin, although not approved by the US Food and Drug Administration (FDA) for idiopathic trigeminal neuralgia (TN) and believed to be less effective than carbamazepine, is probably effective for some patients with this disorder.[39]
Phenytoin has the same mechanism of action as carbamazepine and poses a similar risk panel, except for the risk of aplastic anemia. Of those patients who fail to attain relief with carbamazepine alone, an additional 8-20% of patients may have an adequate response if phenytoin is added to the treatment regimen.
According to a small study by Braham, phenytoin produced complete relief of pain in 30-40% of 43 patients and partial relief in an additional 30-40% at 300-600 mg/d.[40] Blom stated that doses of 300 mg/d were less effective, although doses of 400-600 mg caused more adverse effects.[27]
No correlation has been found between blood levels of phenytoin and therapeutic effect. Loeser recommended that the dose can be increased until relief is obtained or undesirable adverse effects appear (eg, dizziness, ataxia, diplopia, nystagmus, nausea).[39]
Raskin reported relief of intolerable pain with 250 mg of intravenous phenytoin over 5 minutes, allowing relief for hours to 3 days, sufficient for an adequate history and reexamination.[41]
In 2006, He et al reported that the evidence from randomized controlled trials was insufficient to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia (TN).[42]
Baclofen therapy
Baclofen may be effective in patients with trigeminal neuralgia.[43, 44] Tizanidine was investigated in a few trials but did not show significant benefit. Commonly, baclofen is added to anticonvulsants when breakthrough symptoms occur.
In an early small, uncontrolled study, Fromm et al demonstrated baclofen to be useful.[15] Of the 14 patients with idiopathic trigeminal neuralgia resistant to carbamazepine, 10 found relief with 60-80 mg/d of baclofen.[15] The starting dosage is 10 mg/d, which can be increased, if needed, to 60-80 mg/d administered 3-4 times per day (it has a short half-life of 3-4 h).[15] According to Parekh et al and Raskin, the dose of carbamazepine then may be reduced to 500 mg/d to maintain a putative synergistic effect.[41, 45]
In another study, Fromm and Terrence suggested that L-baclofen represents a significant improvement over racemic baclofen in the treatment of trigeminal neuralgia.[46]
Other agents
The National Institutes of Health (NIH) is also investigating the use of dextromethorphan in doses much higher than those used in over-the-counter cough preparations. A randomized, double-blind, cross-over trial compared 6 weeks of oral dextromethorphan with active placebo (low-dose lorazepam) in 19 patients, stratified into 3 groups: 11 with facial pain and possible trigeminal neuropathy, 5 with anesthesia dolorosa, and 3 with idiopathic trigeminal neuralgia.[47] Dosage was titrated in each patient to the highest level reached without disrupting normal activities.
Dextromethorphan shows little or no analgesic efficacy in pain due to possible trigeminal neuropathy and anesthesia dolorosa. Additional trials are necessary to conclusively evaluate the efficacy of NMDA-receptor antagonists in trigeminal neuralgia.
Botulinum toxin was shown to be successful for at least 90 days in a single case report in a patient with trigeminal neuralgia in whom carbamazepine and rhizolysis had previously failed.[48]
Trials of newer N- methyl-D-aspartate receptor blockers have not been done. A nonsteroidal anti-inflammatory agent (NSAID), misoprostol, has shown modest efficacy in a small prospective open study in patients with multiple sclerosis (MS).[49]
Over time, the drugs used for the treatment of trigeminal neuralgia (TN) often lose effectiveness as patients experience breakthrough pain. For patients in whom medical therapy has failed, surgery is a viable and effective option. According to Dalessio, 25-50% of patients eventually stop responding to drug therapy and require some form of alternative treatment.[28] The clinician then may consider referral to a surgeon for one of the procedures discussed below. Among patients who develop trigeminal neuralgia when younger than 60 years, surgery is the definitive treatment.
Many operations have been offered to patients in recent decades. Local ablation of the peripheral nerve and wide sectioning of the sensory roots largely have been abandoned. In the past, alcohol or phenol injection was given to the affected nerve, with the goal to destroy selective pain fibers. Although it was an easy procedure, the success rate is low, in part because of a low selectivity of effect on the fiber type with this substance; recurrence rates are around 50% at 1 year. Rhizotomy or tractotomy was recommended if pharmacologic treatment was unsuccessful.
In a review of surgical options by Tatli et al, which mostly included microvascular decompression and radiofrequency thermorhizotomy, each surgical technique for treatment of trigeminal neuralgia had merits and limitations.[50] The investigators also found that microvascular decompression provides the highest rate of long-term patient satisfaction with the lowest rate of pain recurrence.[50]
Neurosurgery is generally more helpful in those patients with paroxysmal rather than constant pain and in patients whose pain follows the anatomic distribution of one or more trigeminal distributions rather than being spread diffusely. The various operations often fail after 1 or several years of initial relief. This requires a repeat procedure, often with improved but still incomplete results. Thus, many patients eventually restart pain medication after surgery.
Surgery appears to be less effective for trigeminal neuralgia secondary to multiple sclerosis (MS).
For more information, see the following:
Trigeminal Neuralgia Surgery
International RadioSurgery Association Stereotactic radiosurgery for patients with intractable typical trigeminal neuralgia who have failed medical management. Harrisburg, Pa: IRSA; 2009. Harrisburg, Pa: IRSA; 2009. (Radiosurgery practice guideline report; no. 1-03). Available at: http://guideline.gov/content.aspx?id=14309. Accessed April 8, 2011.[51]
Gronseth G, Cruccu G, Alksne J, et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008 Oct 7;71(15):1183-90. Available at: http://www.neurology.org/content/71/15/1183.long. Accessed April 8, 2011.[23]
Current techniques
The success rate varies according to the experience of the surgeon or the anesthesiologist, and, therefore, surgical correction should be performed only by experienced surgeons. Surgical therapy can be divided into procedures on the nerve or gasserian ganglion (external or percutaneous, usually performed by pain management specialists) and on the nerve root (open skull surgery called microvascular decompression and performed by neurosurgeons, and gamma-knife radiation performed by radiation therapists).
Three operative strategies now prevail: percutaneous procedures, gamma knife surgery (GSK), and microvascular decompression (MVD). Ninety percent of patients are pain-free immediately or soon after any of the operations,[2] although the relief is much more long-lasting with microvascular decompression. Percutaneous surgeries make sense for older patients with medically unresponsive trigeminal neuralgia. Younger patients and those expected to do well under general anesthesia should first consider microvascular decompression—presently, this is the most cost-effective surgery although it is also more invasive.
Pain-free intervals after percutaneous procedures (percutaneous retrogasserian glycerol rhizotomy [PRGR] and percutaneous balloon microcompression [PBM]) last 1.5-2 years, 3-4 years after another (percutaneous radiofrequency trigeminal gangliolysis [PRTG]), and 15 years commonly after microvascular decompression.[52] Those in whom the first percutaneous procedure fails may undergo a repeat procedure, which usually provides relief.
More recently, however, posterior fossa exploration has frequently revealed some structural cause for neuralgia (despite normal findings on computed tomography [CT] scans, magnetic resonance images [MRI], or arteriograms), such as an anomalous artery or vein impinging on the trigeminal nerve root. In such cases, simple decompression and separation of the anomalous vessel from the nerve root produces lasting relief of symptoms.
In elderly patients with limited life expectancy, radiofrequency rhizotomy is sometimes preferred, as it is easy to perform, has few complications, and provides symptomatic relief for a period.
Costs
The cost per quality adjusted pain-free year was $6,342 for glycerol rhizotomy, $8,174 for microvascular decompression, and $8,269 for stereotactic radiosurgery, according to Pollock and Ecker.[53] In 2005, approximately 8000 patients with trigeminal neuralgia underwent surgery in the United States, at an estimated cost exceeding $100 million.
Timing
The timing for surgery is debatable, and no randomized study has addressed this question. However, the earlier a surgical technique is applied, it seems the better the outcome. At least 2 medication trials should be performed and carefully evaluated before more invasive techniques are instituted.[50]
Risks
Surgery exposes the patient to operative risks and the risk of permanent, residual facial numbness and dysesthesias. The primary complications of surgery include permanent anesthesia over the face or the troubling dysesthetic syndrome of anesthesia dolorosa—often disabling, is occasionally worse than the original trigeminal neuralgia, and is often untreatable. For this reason, procedures with the best long-term success and the least risk of a residual facial dysesthetic syndrome are the most promising.
Many patients require pain medication even after surgery.
Jannetta pioneered microvascular decompression (MVD). This procedure is commonly performed in younger, healthier patients, especially those with pain isolated to the ophthalmic division or in all 3 divisions of the trigeminal nerve and in those with secondary trigeminal neuralgia (TN). It is now the most common surgery performed for trigeminal neuralgia and general anesthesia is required.
Microvascular decompression consists of opening a keyhole in the mastoid area and freeing the trigeminal nerve from the compression/pulsating artery; then, a piece of Teflon is placed between them. Large series have been published, and the initial efficacy is greater than 80%. Recurrence rates are among the lowest (20% at 1 year, 25% at 5 years) compared with other invasive treatments.[54, 53] Usually, it requires the demonstration of true contact and compression by the artery on the nerve, but series are published that show an almost equally effective result without any demonstrated abnormality on imaging or even frank compression shown preoperatively. A 2015 systematic review and meta-analysis found that MVD had a significantly higher rate of initial pain-free outcomes (BNI grade 1) and a significantly lower pain-free recurrence rate when compared with GKS.[55]
See a surgical image below.
View Image
Microvascular decompression (Jannetta procedure) used to treat trigeminal neuralgia. The anteroinferior cerebellar artery and the trigeminal nerve are....
Patients spend 4-10 days in the hospital and another week convalescing at home. Thus, recovery is more prolonged than with percutaneous procedures. In addition, mortality for this more invasive procedure approaches 0.5%. Serious morbidity includes dizziness, temporary facial palsy, cerebrospinal fluid leaks, meningitis, cerebellar stroke, and hearing loss, which may occur in 1-5% of cases.
Percutaneous procedures usually can be performed on an outpatient basis under local or brief general anesthesia at acceptable or minimal risk of morbidity. For these reasons, they commonly are performed in debilitated persons or those older than 65 years.
Zakrzweska and Thomas described 3 types of procedures: percutaneous radiofrequency trigeminal gangliolysis (PRTG), percutaneous retrogasserian glycerol rhizotomy (PRGR), and percutaneous balloon microcompression (PBM).[56] Patients are left with minor, local, residual facial numbness after PRTG; may occasionally lose sensation after PRGR; and rarely do so after PBM. In each procedure, the surgeon introduces a trocar or needle lateral to the corner of the mouth and, under fluoroscopic guidance, into the ipsilateral foramen ovale. The ganglion is lysed at this location.
Percutaneous procedures and surgery yield the best results when applied early in the course of trigeminal neuralgia. Even if medical treatment comes first, trials, when they are adequately completed and the agent is deemed ineffective, should be followed promptly by the next trial in order not to delay and decrease the efficacy of more invasive treatments.
Percutaneous radiofrequency rhizotomy and percutaneous microcompression with balloon inflation are relatively inexpensive and accessible techniques, and they are less invasive than surgery, with a lower (long-term) efficacy-to-recurrence ratio. A comparison of the two techniques found them both effective with a median duration of pain relief of 21 months after PRGR and 20 months after PBC.[57] The result is highly dependent on the surgeon's skill. General anesthesia is required.
Also see Trigeminal Neuralgia Surgery.
PRTG, PRGR, and PBM
In PRTG, a radiofrequency heating tip sears the ganglion until the area of facial pain becomes numb. This procedure has gained wide acceptance according to several investigators, because the patient is awake during the procedure, recovers quickly, and goes home the day of the procedure or the next day. However, according to Tan et al, the recurrence rate approaches 25% with PRTG, and occasionally patients suffer complications of jaw weakness and corneal anesthesia.[58]
In PRGR, a spinal needle likewise penetrates the face, this time to the trigeminal cistern, at which point a cisternogram is obtained with water-soluble contrast material. After removing this material, the surgeon instills anhydrous glycerol, asking the patient to remain seated for an additional 2 hours to fully ablate the nerve.
PRGR may be the favored procedure, as it has a higher efficacy rate and a lower recurrence rate than the alcohol injection and includes only a minimal risk of disturbed facial sensitivity postoperatively. In addition, it is easy to perform, and anesthesia is not needed. However, Cappiabianca et al and Taha and Tew, who favor the radiofrequency rhizotomy, argue that PRGR has the highest rate of pain recurrence.[59, 60]
With PBM, the operator inserts a balloon catheter through the foramen ovale into the region of the ganglion and inflates it for 1-10 minutes. As related by Meglio and Cioni, some surgeons report excellent results with PBM, comparable to those with PRTG.[61]
In 1953, Leksell irradiated the trigeminal nerve in 2 patients with good initial success but did not publish this data until 1971.[62] Progress really began when, in the 1990s, surgeons learned to target the nerve precisely with stereotactic magnetic resonance imaging (MRI), determine the proper radiation dose to quickly relieve pain without incurring facial sensory loss, and ascertain the length of nerve to be radiated.[63]
Gamma knife surgery (GKS) has become more widely available since 2000. This surgery is less technically demanding, less operator-dependent, and less invasive than the percutaneous procedures. It is among the newer techniques for treating trigeminal neuralgia and has fewer complications. Gamma knife surgery appears to be about as effective (80% of patients) as the percutaneous procedures but takes weeks to months to bring relief, which may be too long for some patients, and costs slightly more.
This procedure consists of multiple rays (>200) of high-energy photons concentrated with high accuracy on the target (ie, trigeminal nerve root),[64, 65] destroying specific components of the nerve. Of those treated, 60% of patients are immediately free of pain, and more than 75% of patients have greater than 50% relief after 1.5 years. Recurrence rates are around 25 % between 1 and 3 years. The device contains a stable source of radiation (60-Co) that frees this technique from requiring an external source of radioactivity (eg, cyclotron). See the image below.
View Image
Magnetic resonance image (MRI) with high resolution on the pons demonstrating the trigeminal nerve root. In this case, the patient with trigeminal neu....
The pain recurrence rate is low for patients who initially attain complete relief. Gamma knife surgery is generally effective, even in patients in whom previous surgery or medication trials failed.
In one study, most patients already had no relief with either microvascular decompression or glycerol rhizotomy, whereas following gamma knife surgery, at a median follow-up point of 18 months, 60% of patients were pain free, 17% were moderately improved, and 23% were minimally or not improved.[64] The investigators concluded that this technique is minimally invasive, is associated with a low risk (10%) of facial paresthesias or sensory loss, and offers a high rate (86%) of significant, initial pain relief.[64]
New facial numbness or paresthesias develop slowly over the first 12-15 months after gamma knife surgery, reaching bothersome levels in 9-20% of patients.
Neurosurgical consultation is needed when medical treatment does not effectively control episodes of breakthrough facial pain. Pain management specialists may also be consulted for intractable pain.
Longitudinal follow-up care is important because of the chronicity of trigeminal neuralgia, and because many treatments fail to maintain their efficacy (eg, pharmacologic, procedural).
In patients treated with carbamazepine or phenytoin, obtain a blood count during the first few weeks of therapy (ie, monthly for at least 3 mo for carbamazepine, once after 2 wk for phenytoin), every time the dose is adjusted or adverse effects appear, and yearly thereafter. Agranulocytosis and aplastic anemia are extremely rare adverse effects, but suppression of the white blood cell (WBC) count in the range of 2000-3000 103/µL is not uncommon. This mild suppression of the WBC count does not warrant discontinuation of carbamazepine therapy. Hepatic function should also be monitored. Up to 70% of patients receive complete or acceptable partial relief, at least temporarily.
Oxcarbazepine is a newer agent that may have fewer side effects, but it can cause hyponatremia, which should be monitored with serial serum sodium measurements in the first few weeks of therapy.
Patients who experience breakthrough pain may need an increase in the dosage of their medication, if tolerated, or the addition of a second anticonvulsant medication or baclofen. No published data from randomized, prospective, controlled studies are available to guide clinicians regarding multidrug therapy, leaving providers to empiric trials of one agent or another.
Neurologists caring for younger patients (< 60 y at onset) should consider early neurosurgical consultation, even after a negative magnetic resonance image (MRI) of the brain. Surgical procedures occasionally can afford complete relief, delaying the need for anticonvulsant medications for many years, if not permanently.
Monitoring patients after procedures or open skull surgery helps screen for complications such as corneal abrasions and anesthesia dolorosa.
In 2019, the European Academy of Neurology (EAN) developed guidelines for daily clinical management of patients with trigeminal neuralgia (TN).[66] Recommendations include the following:
all TN patients should undergo MRI
carbamazepine and oxcarbazepine should be used as first-line prophylactic treatments of TN
lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen, and phenytoin may be used either alone or as add-on therapy
patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated
in patients with classical TN, microvascular decompression is recommended as first-line surgery
Carbamazepine remains the criterion standard, but a number of other drugs have been used for a long time and with fair success in trigeminal neuralgia (TN). These agents should be considered successively in case of resistance. Rarely, combination therapy can be provided, but it should remain exceptional for tolerance reasons and because a synergistic effect rarely occurs.[43] Duration of treatment depends on clinical evolution but usually is long term, often lasting years. Topical analgesics have failed in patients with ophthalmologic manifestations of trigeminal neuralgia.[67]
Clinical Context:
Carbamazepine is the criterion standard in the medical management of trigeminal neuralgia. A 100-mg tablet may produce significant and complete relief within 2 hours, and, for this reason, a 100 mg twice a day (bid) prescription is suitable to start. If this initial dose fails, one may push the dose to 1200 mg daily (qd), as the patient will tolerate, for initial relief; maintenance doses generally are lower, 100-800 mg daily bid. If using the extended-release caplet, begin with 200 mg qd and increase as needed to a maximum dose of 1200 mg/d bid. Titrating slowly improves tolerance.
So immediate, predictable, and powerful is the relief that if the patient does not respond at least partially to carbamazepine, one should reconsider the diagnosis of idiopathic trigeminal neuralgia. Note, however, that 15% of patients do not benefit from carbamazepine, forcing trials of other medications.
Clinical Context:
Small, uncontrolled studies have indicated possible effectiveness of gabapentin in patients whose pain has become refractory to carbamazepine. This agent is often better tolerated than carbamazepine by elderly patients. No placebo-controlled studies have been published, but several open trials have reported an improvement on this drug.
As for other indications, an adequate dosage seems to vary greatly, and a trial should include raising the dose (eg, 3600 mg/d) as long as no efficacy is yet encountered, before stopping it.
Clinical Context:
Lamotrigine provided sustained relief in 2 small prospective studies. In an open-label design by Lunardi et al, all 5 patients with symptomatic trigeminal neuralgia associated with multiple sclerosis (MS) and 10 of 15 patients with idiopathic disease gained complete relief when followed for 3-8 months.[37] Doses varied widely from 100-400 mg/d.
In a double-blind, placebo-controlled, crossover study, Zakrzewska et al found 400 mg of lamotrigine relieved the pain in 7 of 13 patients with trigeminal neuralgia compared with only 1 of 14 on placebo.[38]
The adverse event to prevent is a rash, sometimes severe and life threatening, mostly if titration is too rapid.
Clinical Context:
Phenytoin has a similar mechanism of action to carbamazepine but is probably less effective. Phenytoin may provide relief as an add-on drug when carbamazepine monotherapy wanes, as commonly happens after 1 or several years. This drug has several common adverse effects, which are often troublesome in older patients, and drug levels do not always correlate with efficacy.
Clinical Context:
This therapy is experimental. In a pilot study of 3 patients enrolled in a National Institutes of Health (NIH)–sponsored trial, investigators could not confirm the benefits of topiramate.[65] However, it may be a reasonable second-line agent.
Zvartau-Hind et al reported success in an uncontrolled, open-label trial of 200-300 mg daily in 6 patients with multiple sclerosis (MS), prescribed as monotherapy (in 5 of the 6 individuals) over a 6-month interval.[66] All 6 patients reported complete relief and appeared to tolerate the drug well. Solaro et al found 150-300 mg total daily doses relieved all trigeminal neuralgia pains in a case series of 4 patients, 2 with multiple sclerosis, 1 with idiopathic trigeminal neuralgia, and 1 with previous arteriovascular malformation resection, when followed for 6 months. Carbamazepine and gabapentin had previously failed in all patients.
Clinical Context:
Oxcarbazepine is a close cousin of carbamazepine and presumably works on similar mechanisms. This agent offers a better tolerance and is easier to manage. Studies are limited, as opposed to the large body of high-level evidence with carbamazepine.
Daily maintenance doses of oxcarbazepine 400-2400 mg/d were effective in several small uncontrolled studies.[67] Three small, multicenter, double-blind randomized trials found it as efficacious as carbamazepine in newly diagnosed or refractory trigeminal neuralgia and to be better tolerated.[68]
The recommended starting dose is 300 mg bid. Note that this drug has not yet been approved by the US Food and Drug Administration (FDA) for trigeminal neuralgia.
This drug has not yet been approved by the FDA for trigeminal neuralgia (TN).
Anticonvulsant drugs reduce the excitability of gasserian ganglion neurons, preventing anomalous discharges and related lancinating volleys of pain. Thus, these agents may help control paroxysmal pain by limiting the aberrant transmission of nerve impulses and reducing the firing of nerve potentials in the trigeminal nerve.
Clinical Context:
Baclofen is the only medication in this class with published data to support efficacy. This drug may induce hyperpolarization of afferent terminals and inhibit both monosynaptic and polysynaptic reflexes at the spinal level.
Baclofen is most often used after therapy with carbamazepine has been initiated, and its effects may be synergistic with those of carbamazepine.
Several small, uncontrolled studies in the 1970s and 1980s, including those by Parekh et al and Fromm et al, demonstrated effectiveness of baclofen, particularly when added to an existing regimen of carbamazepine that is not providing adequate pain control. Once baclofen is added to an anticonvulsant, the dosage of the anticonvulsant often can be reduced.
Tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. They have central effects on pain transmission and block the active reuptake of norepinephrine and serotonin.
Clinical Context:
Subcutaneous injections of botulinum toxin have been beneficial in a pilot study of patients with ophthalmologic manifestations of trigeminal neuralgia, but these results await confirmation.
Toxins are a relatively recent experimental approach to management of trigeminal neuralgia and have been mentioned to respond to patient inquiries. These agents are not recommended because of scant evidence of efficacy. The mechanism of action of these agents remains unclear, but they appear to potentially decrease painful afferents.[68]
What is trigeminal neuralgia (TN)?What are the signs and symptoms of trigeminal neuralgia (TN)?How is trigeminal neuralgia (TN) diagnosed?How is trigeminal neuralgia (TN) treated?How is trigeminal neuralgia (TN) characterized?When was trigeminal neuralgia (TN) first described?What is the cranial anatomy relevant to trigeminal neuralgia (TN)?What is the pathophysiology of trigeminal neuralgia (TN)?What causes trigeminal neuralgia (TN)?What is the prevalence of trigeminal neuralgia (TN)?Which patient groups have the highest prevalence of trigeminal neuralgia (TN)?What is the prognosis of trigeminal neuralgia (TN)?What are the possible complications of trigeminal neuralgia (TN)?What is included in patient education about trigeminal neuralgia (TN)?Where are patient education resources about trigeminal neuralgia (TN) found?Which clinical history findings are characteristic of trigeminal neuralgia (TN)?How is pain localized in trigeminal neuralgia (TN)?How is the pain of trigeminal neuralgia (TN) characterized?How frequent are attacks of trigeminal neuralgia (TN)?What may trigger an attack of trigeminal neuralgia (TN)?How does idiopathic trigeminal neuralgia (TN) differ in presentation from multiple sclerosis-associated trigeminal neuralgia (TN)?Which physical findings are characteristic of trigeminal neuralgia (TN)?How is trigeminal neuralgia (TN) classified?What are the IHS diagnostic criteria for trigeminal neuralgia (TN)?What is the Eller classification scheme for trigeminal neuralgia (TN)?How is the differential diagnoses of trigeminal neuralgia (TN) narrowed?How is trigeminal neuralgia (TN) differentiated from migraine and cluster headaches?How is trigeminal neuralgia (TN) differentiated from atypical face pain?How is trigeminal neuralgia (TN) differentiated from glossopharyngeal neuralgia and occipital neuralgia syndromes?How is trigeminal neuralgia (TN) differentiated from paroxysmal hemicrania syndromes?How is secondary trigeminal neuralgia (TN) differentiated from idiopathic trigeminal neuralgia (TN)?How is trigeminal neuropathy differentiated from idiopathic trigeminal neuralgia (TN)?When should multiple sclerosis be included in the differential diagnoses of trigeminal neuralgia (TN)?How is herpetic and postherpetic neuralgia (PHN)differentiated from trigeminal neuralgia (TN)?What are the differential diagnoses for Trigeminal Neuralgia?What is the role of lab testing in the workup of trigeminal neuralgia (TN)?What is the role of MRI in the workup of trigeminal neuralgia (TN)?What is the role of MRA in the workup of trigeminal neuralgia (TN)?What is the role of CT scanning and CT angiography in the workup of trigeminal neuralgia (TN)?What is the role of clinical neurophysiologic testing in the workup of trigeminal neuralgia (TN)?Which histologic findings are characteristics of trigeminal neuralgia (TN)?What is the approach to treatment of trigeminal neuralgia (TN)?How is trigeminal neuralgia (TN) treated initially?What are the treatment options for trigeminal neuralgia (TN)?Which adjunct therapies are used in the treatment of trigeminal neuralgia (TN)?How is depression treated in patients with trigeminal neuralgia (TN)?What is the role of antiepileptic drugs in the treatment of trigeminal neuralgia (TN)?What is the cost of medications for the treatment of trigeminal neuralgia (TN)?What is the efficacy of antiepileptic drugs for the treatment of trigeminal neuralgia (TN)?How are antiepileptic drugs dosed for the treatment of trigeminal neuralgia (TN)?What are the potential risks of antiepileptic drugs for the treatment of trigeminal neuralgia (TN)?What are the first- and second-line medications for the treatment of trigeminal neuralgia (TN)?What is the role of carbamazepine in the treatment of trigeminal neuralgia (TN)?What is the role of oxcarbazepine (Trileptal) in the treatment of trigeminal neuralgia (TN)?What is the role of gabapentin in the treatment of trigeminal neuralgia (TN)?What is the role of lamotrigine (Lamictal) in the treatment of trigeminal neuralgia (TN)?What is the role of phenytoin in the treatment of trigeminal neuralgia (TN)?What is the efficacy of non-antiepileptic drugs in the treatment of trigeminal neuralgia (TN)?What is the role of baclofen in the treatment of trigeminal neuralgia (TN)?What is the role of dextromethorphan in the treatment of trigeminal neuralgia (TN)?What is the role of botulinum toxin in the treatment of trigeminal neuralgia (TN)?What is the role of misoprostol in the treatment of trigeminal neuralgia (TN)?What is the role of surgery in the treatment of trigeminal neuralgia (TN)?What types of surgical interventions are used in the treatment of trigeminal neuralgia (TN)?What is the cost of surgery for trigeminal neuralgia (TN)?What is the timing for surgical intervention to treat trigeminal neuralgia (TN)?What are the risks of surgery for trigeminal neuralgia (TN)?What is the role of microvascular decompression (MVD) in the treatment of trigeminal neuralgia (TN)?What is the role of percutaneous procedures in the treatment of trigeminal neuralgia (TN)?How is PRTG performed for the treatment of trigeminal neuralgia (TN)?How is PRGR performed for the treatment of trigeminal neuralgia (TN)?How is PBM performed for the treatment of trigeminal neuralgia (TN)?What is the role of gamma knife surgery in the treatment of trigeminal neuralgia (TN)?Which specialist consultations are beneficial to patients with trigeminal neuralgia (TN)?What is included in the long-term monitoring of trigeminal neuralgia (TN)?What are the EAN guidelines on trigeminal neuralgia (TN) treatment?What is the role of medications in the treatment of trigeminal neuralgia (TN)?Which medications in the drug class Toxins are used in the treatment of Trigeminal Neuralgia?Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Trigeminal Neuralgia?Which medications in the drug class Skeletal Muscle Relaxants are used in the treatment of Trigeminal Neuralgia?Which medications in the drug class Anticonvulsant Agents are used in the treatment of Trigeminal Neuralgia?
Manish K Singh, MD, Assistant Professor, Department of Neurology, Teaching Faculty for Pain Management and Neurology Residency Program, Hahnemann University Hospital, Drexel College of Medicine; Medical Director, Neurology and Pain Management, Jersey Institute of Neuroscience
Disclosure: Nothing to disclose.
Coauthor(s)
Gordon H Campbell, MSN, FNP-BC, Neuroscience Nurse Practitioner, Neurology Service, Portland Veterans Affairs Medical Center; Primary Faculty, Clinical Instructor, and Guest Lecturer, Family Nursing Department, Oregon Health Sciences University School of Nursing
Disclosure: Nothing to disclose.
Helmi L Lutsep, MD, Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of Medicine; Associate Director, OHSU Stroke Center
Disclosure: Medscape Neurology Editorial Advisory Board for: Stroke Adjudication Committee, CREST2; Physician Advisory Board for Coherex Medical; National Leader and Steering Committee Clinical Trial, Bristol Myers Squibb; Consultant, Abbott Vascular, Inc. .
Siddharth Gautam, MBBS, Resident Physician, Jersey Neuroscience Institute
Disclosure: Nothing to disclose.
Chief Editor
Robert A Egan, MD, NW Neuro-Ophthalmology
Disclosure: Received honoraria from Biogen Idec and Genentech for participation on Advisory Boards.
Acknowledgements
Jane W Chan, MD Professor of Neurology/Neuro-ophthalmology, Department of Medicine, Division of Neurology, University of Nevada School of Medicine
Jane W Chan, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Ophthalmology, American Medical Association, North American Neuro-Ophthalmology Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.
James R Couch, MD, PhD, FACP Professor of Neurology, University of Oklahoma Health Sciences Center
Disclosure: Nothing to disclose.
Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, Weill Cornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine
Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: Alliance for Clinical Education, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council of Emergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Simon K Law, MD, PharmD Associate Professor of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.
Andrew W Lawton, MD Medical Director of Neuro-Ophthalmology Service, Section of Ophthalmology, Baptist Eye Center, Baptist Health Medical Center
Andrew W Lawton, MD is a member of the following medical societies: American Academy of Ophthalmology, Arkansas Medical Society, and Southern Medical Association
Disclosure: Nothing to disclose.
Marc E Lenaerts, MD, FAHS Staff Neurologist, Mercy Medical Group; Associate Clinical Professor of Neurology, Department of Neurology, University of California, Davis, School of Medicine
Marc E Lenaerts, MD, FAHS is a member of the following medical societies: American Academy of Neurology, American Headache Society, and International Headache Society
Disclosure: Nothing to disclose.
Jorge E Mendizabal, MD Consulting Staff, Corpus Christi Neurology
Jorge E Mendizabal, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, National Stroke Association, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.
Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.
Tom Scaletta, MD Chair, Department of Emergency Medicine, Edward Hospital; Past-President, American Academy of Emergency Medicine
Tom Scaletta, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Brian R Younge, MD Professor of Ophthalmology, Mayo Clinic School of Medicine
Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society
[Guideline] International RadioSurgery Association. Stereotactic radiosurgery for patients with intractable typical trigeminal neuralgia who have failed medical management. Harrisburg, Pa: IRSA; 2009. (Radiosurgery practice guideline report; no. 1-03). Available at http://guideline.gov/content.aspx?id=14309. Accessed: April 8, 2011.
Barbor, M. MVD Bests Gamma Knife for Pain in Trigeminal Neuralgia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/852161. October 5, 2015; Accessed: October 22, 2015.
Beydown A, et al. Meta-analysis of comparative trials of oxcarbazepine versus carbamazepine in trigeminal neuralgia. Oxcarbazepine Study Group. Poster presented at the 21st American Pain Society Annual Meeting, Baltimore, Md; Mar 14-17, 2002.
Microscopic demonstration of demyelination in primary trigeminal neuralgia. A tortuous axon is surrounded by abnormally discontinuous myelin. (Electron microscope; 3300×).
Illustration depicting the trigeminal nerve with its 3 main branches
Illustration depicting the trigeminal nerve with its 3 main branches
Microscopic demonstration of demyelination in primary trigeminal neuralgia. A tortuous axon is surrounded by abnormally discontinuous myelin. (Electron microscope; 3300×).
Magnetic resonance image (MRI) with high resolution on the pons demonstrating the trigeminal nerve root. In this case, the patient with trigeminal neuralgia has undergone gamma-knife therapy, and the left-sided treated nerve (arrow) is enhanced by gadolinium.
Microvascular decompression (Jannetta procedure) used to treat trigeminal neuralgia. The anteroinferior cerebellar artery and the trigeminal nerve are in direct contact. Courtesy of PT Dang, CH Luxembourg
Magnetic resonance image (MRI) with high resolution on the pons demonstrating the trigeminal nerve root. In this case, the patient with trigeminal neuralgia has undergone gamma-knife therapy, and the left-sided treated nerve (arrow) is enhanced by gadolinium.
Illustration depicting the trigeminal nerve with its 3 main branches
Microscopic demonstration of demyelination in primary trigeminal neuralgia. A tortuous axon is surrounded by abnormally discontinuous myelin. (Electron microscope; 3300×).
Magnetic resonance image (MRI) with high resolution on the pons demonstrating the trigeminal nerve root. In this case, the patient with trigeminal neuralgia has undergone gamma-knife therapy, and the left-sided treated nerve (arrow) is enhanced by gadolinium.
Microvascular decompression (Jannetta procedure) used to treat trigeminal neuralgia. The anteroinferior cerebellar artery and the trigeminal nerve are in direct contact. Courtesy of PT Dang, CH Luxembourg
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