Cranial Neuralgias

Carrie Robertson, MD, FAHS Headache p. 665-685 June 2021, Vol.27, No.3 doi: 10.1212/CON.0000000000000962
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KEY POINTS

Neuralgia describes sharp, stabbing, shocklike pain that is often triggered by touching within the sensory dermatome of the affected nerve, whereas neuropathy describes sensory deficit within the nerve distribution, sometimes with persistent neuropathic pain, such as burning, tingling, or prickling.

Classical trigeminal neuralgia is trigeminal neuralgia related to neurovascular compression; nerve atrophy or displacement is required on imaging (not just vascular contact). Secondary trigeminal neuralgia is trigeminal neuralgia related to another cause, such as demyelinating plaque or local mass. Idiopathic trigeminal neuralgia is trigeminal neuralgia without a known cause.

Most patients with trigeminal neuralgia are pain free between attacks, but a subset can develop near-continuous background pain.

Mild sensory changes may be present in trigeminal neuralgia, but true loss of sensation should alert the clinician to look for secondary causes.

Approximately 99% of patients with trigeminal neuralgia report triggers.

Some patients with trigeminal neuralgia may describe a refractory period after severe attacks, during which additional attacks are diminished.

Bilateral trigeminal neuralgia can occur but is uncommon and should raise suspicion for secondary trigeminal neuralgia, such as from multiple sclerosis.

Trigeminal neuralgia associated with pronounced autonomic symptoms should raise clinical suspicion for a trigeminal autonomic cephalalgia.

Unexplained numbness isolated to the chin is a red flag for potential malignancy.

Neurovascular contact of the trigeminal nerve is common even in people without symptoms. Therefore, the severity of compression on imaging may be more relevant, including nerve displacement or atrophy.

A family history of trigeminal neuralgia may be present in up to 11% of patients. Familial cases may have an earlier onset and may be associated with additional neuralgias, such as glossopharyngeal neuralgia or hemifacial spasm.

Patients with multiple sclerosis may have both a demyelinating plaque and neurovascular compression near the trigeminal nerve root entry zone, causing neuralgia through a “double crush” mechanism.

Postherpetic neuralgia should be considered in patients presenting with trigeminal neuralgia who have a history of erythema or rash in the affected area at the onset of pain.

Because of overlap from cervical cutaneous branches over the jawline, the most reliable area to test the mandibular (V3) division is over the chin.

If the patient’s pain is predominantly in V2 and V3 and without cutaneous triggers, a dental evaluation should be considered.

Carbamazepine is considered first-line treatment for trigeminal neuralgia.

For urgent treatment of refractory trigeminal neuralgia, IV fosphenytoin, IV lidocaine, or peripheral blocks can be considered.

A patient with trigeminal neuralgia that is refractory to medical therapy should be referred to a neurosurgeon. If neurovascular compression is present on imaging, microvascular decompression is typically considered first. If not, a neuroablative procedure (with injury to the nerve) is typically considered first.

Recurrence of trigeminal neuralgia after microvascular decompression may be because of a new or previously missed vessel, compression with the synthetic material used in decompression, or arachnoid adhesions.

Repeat microvascular decompression has a lower chance of pain relief and higher risk of complications.

The best dosing and location of radiosurgery (where to aim along the trigeminal root) for trigeminal neuralgia is still being studied.

Pain relief from radiosurgery may start 2 weeks to 2 months after treatment, whereas decreased sensation may start an average of 6 to 36 months after treatment.

Trigeminal neuropathy following a neuroablative procedure for trigeminal neuralgia is called painful posttraumatic trigeminal neuropathy.

By convention, the term postherpetic neuralgia is used for either neuralgic or neuropathic facial pain starting in an area with active herpes zoster rash and persisting for more than 3 months.

Brain MRI is not adequate for numb chin syndrome as it may not visualize the mandible and may miss a malignancy located there.

Stabbing ear pain may be referred along six nerves with overlapping dermatomes: the auriculotemporal nerve, lesser occipital nerve, great auricular nerve, nervus intermedius, glossopharyngeal nerve, and vagus nerve.

Brain MRI is not adequate for unexplained ear pain, as it cannot visualize many structures that radiate pain to the ear, such as the throat, cervical vessels, and thyroid.

Glossopharyngeal neuralgia is provoked by swallowing, yawning, or coughing.

Patients with lightheadedness, palpitations, or syncope with their glossopharyngeal neuralgia pain may require ambulatory ECG monitoring to look for an associated bradyarrhythmia.

Similar to trigeminal neuralgia, glossopharyngeal neuralgia may be related to neurovascular compression or other lesions along the nerve path.

Either microvascular decompression or sectioning of the glossopharyngeal nerve (and sometimes vagus nerve rootlets) is considered a reasonable first-line treatment for medically refractory glossopharyngeal neuralgia.

Nervus intermedius neuralgia may present with stabbing pain deep in the ear triggered by cold wind or using a cotton swab in the ear canal.

Nervus intermedius neuralgia may develop in the setting of classic Bell’s palsy or Ramsay Hunt syndrome (herpes zoster affecting the ear and facial nerve).

Occipital neuralgia is typically described as shooting or stabbing pain that starts at the posterior skull base and radiates either to the vertex (greater occipital nerve) or over the ear toward the temple (lesser occipital nerve).

If loss of sensation is present with occipital neuralgia, a secondary cause of pain should be considered.

PURPOSE OF REVIEW This article discusses the differential diagnosis, evaluation, and management of trigeminal neuralgia and reviews other neuralgias of the head and neck, including those that contribute to neuralgic ear pain.

RECENT FINDINGS Most cases of trigeminal neuralgia are related to vascular compression, a demyelinating plaque, or a compressive mass affecting the trigeminal nerve. However, recent studies have shown that up to 11% of patients have a family history of trigeminal neuralgia, suggesting that some patients may have a genetic predisposition to demyelination or nerve hyperexcitability. In these patients, trigeminal neuralgia may occur at a younger age, on both sides of the face, or in combination with other neuralgias.

SUMMARY When a patient presents with neuralgic pain, the diagnosis is made by careful history and neurologic examination, with attention to the dermatome involved, the triggers, and the presence of any associated sensory deficit. All patients with new neuralgia or neuropathic facial pain warrant a careful evaluation for a secondary cause. The presence of sensory deficit on bedside examination is particularly concerning for an underlying secondary etiology.

Address correspondence to Dr Carrie Robertson, 200 First St SW, Rochester, MN 55905, [email protected].

RELATIONSHIP DISCLOSURE: Dr Robertson serves on advisory boards for Alder BioPharmaceuticals, Inc; Biohaven Pharmaceuticals; and Impel NeuroPharma, Inc, and receives publishing royalties from UpToDate Inc.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Robertson discusses the unlabeled/investigational use of treatments for trigeminal neuralgia, none of which are US Food and Drug Administration approved for this indication, except for carbamazepine.

INTRODUCTION

Although most headache disorders have been attributed to pathophysiology within the brain, it is well known that irritation of individual nerves in the peripheral nervous system can contribute to head and facial pain as well. This article discusses the differential diagnosis for neuralgic pain in the face and ear, with specific attention to trigeminal neuralgia, glossopharyngeal neuralgia, nervus intermedius neuralgia, and occipital neuralgia.

BACKGROUND ON TERMINOLOGY

When discussing pain involving the cutaneous areas of the head and neck, it is important to distinguish between the terms neuralgia and neuropathy. Neuralgia is a term used to describe a brief paroxysmal, often triggered, lancinating pain within a specific nerve dermatome, sometimes described as sharp, stabbing, or electric shock–like. This is in contrast to neuropathy, in which there may be sensory deficit within the nerve distribution and a persistent pain with neuropathic features, often described as burning, tingling, or prickling, sometimes with a false sense of swelling. If the nerve is also responsible for motor function, weakness may be present in the associated muscles. Both neuralgia and painful neuropathy have been described in branches of multiple cranial nerves (trigeminal, glossopharyngeal, facial, vagus) as well as in terminal branches of the upper cervical nerves (occipital and great auricular).

When a patient experiences what seems to be nerve-related pain in the distribution of one of these nerves, it is important to evaluate for an underlying structural, inflammatory, or infectious process along the length of the nerve. If a secondary cause of neuralgia or neuropathic pain is not clear despite investigation, the neuralgia or neuropathy is termed idiopathic and classified with the nerve affected (eg, idiopathic glossopharyngeal neuralgia).

In some cases, the diagnostic terms may overlap, depending on the underlying pathology. For example, with a secondary neuropathy (such as a tumor infiltrating the glossopharyngeal nerve), a nerve may have components of both sharp paroxysmal stabbing pain and persistent pain. In these cases, the term that best describes the predominant pain type is used.

TRIGEMINAL NEURALGIA

Of all of the cranial nerves, classification of the pain within the trigeminal nerve distribution has been the most complex and often controversial. The International Classification of Headache Disorders, Third Edition (ICHD-3) criteria for trigeminal neuralgia are listed in table 7-1.

With the current classification, if a patient presents with the symptoms listed in the criteria and has signs of neurovascular compression on imaging, including nerve root atrophy or displacement, the term classical trigeminal neuralgia is applied. If the trigeminal neuralgia is due to some other cause, such as a multiple sclerosis plaque or local mass compressing the nerve, the term secondary trigeminal neuralgia is used. If the etiology is unknown, with a normal-appearing MRI and normal electrophysiologic tests, the diagnosis is idiopathic trigeminal neuralgia.

Most patients with trigeminal neuralgia tend to be pain free between these paroxysmal attacks, but a subset of patients can develop continuous or near-continuous background pain between attacks in the same area as the paroxysmal pain. In these cases, the presence of this background pain is clarified at the end of the diagnosis, as in classical trigeminal neuralgia with concomitant continuous pain. As a general rule, loss of sensation should not be present clinically with trigeminal neuralgia, although subclinical sensory deficits may be found on specialized testing. The presence of numbness is more suggestive of a painful trigeminal neuropathy and requires a more detailed investigation for secondary causes.

Clinical Features

Approximately 99% of patients with trigeminal neuralgia report provocation of paroxysmal pain by some type of otherwise innocuous trigger. Triggers tend to include maneuvers that activate the motor or sensory component of the trigeminal nerve, such as chewing/eating, talking, light touch over the face, shaving or applying makeup, brushing teeth, or cold wind on the face (case 7-1). According to one study, cutaneous triggers tend to occur more frequently around the nose and mouth, although anywhere on the face may be described.

CASE 7-1

A 63-year-old woman initially presented with 2 years of electrical shock–like pain that started just in front of her left ear and radiated into her upper teeth and cheek, triggered by lightly touching her face, a cool breeze on her face, chewing, and brushing her teeth. Each attack lasted only seconds, but they frequently occurred in clusters, such as when she was putting on her makeup or eating a meal. She was pain free between the attacks. Her initial neurologic examination was unremarkable, including no evidence of sensory deficit over the face. Carbamazepine was begun and had been helpful initially, but she required escalating doses and was eventually unable to tolerate the doses required for pain relief. A gadolinium-enhanced high-resolution MRI of her brain with thin slices through the posterior fossa showed the superior cerebellar artery compressing and distorting the trigeminal nerve at the root entry zone. Microvascular decompression was performed, with a synthetic pledget placed between the compressing vessel and the trigeminal nerve.

The patient was pain free for the next 11 years, then gradually noticed a return of her neuralgic pain, affecting both V2 and V3. She was subsequently treated with stereotactic radiosurgery to the trigeminal ganglion. Over the next 2 weeks, she noticed gradual numbness, with improvement in her neuralgic pain but new burning, tingling, and itching over the left V1, V2, and V3 region, with weakness of the left masseter and temporalis. She developed corneal keratitis, which was managed by an ophthalmologist. One year after her radiosurgery, the persistent neuropathic pain was still present, requiring gabapentin and opiates for pain relief.

COMMENT

The patient’s initial symptoms were consistent with classical trigeminal neuralgia that improved after microvascular decompression. When her pain returned, she was treated with a neuroablative procedure, leading to a painful posttraumatic trigeminal neuropathy (also known as anesthesia dolorosa).

Although each individual episode of paroxysmal pain is brief, episodes may recur as a series of attacks, especially if the trigger is still present (eg, the patient is still eating or brushing their teeth). Most of these series of attacks last less than an hour. After severe paroxysmal pain attacks, some patients describe a refractory period, during which additional attacks either cannot be elicited or attack severity is diminished. Patients may also experience unpredictable remissions of their pain attacks lasting weeks, months, or even years.

Trigeminal neuralgia tends to affect the right trigeminal nerve slightly more than the left and involve the V2 (maxillary) and V3 (mandibular) divisions more than the V1 (ophthalmic) division. However, a small subset of patients (<5%) may present with neuralgia isolated to the V1 division. Bilateral trigeminal neuralgia is uncommon and should raise clinical concern for secondary trigeminal neuralgia, such as from multiple sclerosis.

Mild autonomic symptoms, including conjunctival injection or tearing, may be present with some attacks and may be seen more frequently in patients with involvement of V1. However, if autonomic symptoms are pronounced or frequent, it should raise clinical suspicion for a trigeminal autonomic cephalalgia such as short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) or short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). table 7-2 lists conditions in the differential diagnosis for trigeminal neuralgia.

Most patients with trigeminal neuralgia will have normal sensation on bedside examination, although careful examination in one study demonstrated mild reduction to sensation in 18% of patients with paroxysmal pain and 30% of patients with concomitant persistent pain. In the absence of a history of a surgical or destructive treatment for trigeminal neuralgia, pronounced hypoesthesia or anesthesia should raise the possibility of an alternative diagnosis of painful trigeminal neuropathy and is concerning for a secondary etiology. For example, numbness in the mental nerve distribution, or numb chin syndrome, is a red flag for a neoplastic etiology.

Pathophysiology

The complete underlying mechanism behind trigeminal neuralgia is not clear. By definition, patients with classical trigeminal neuralgia have evidence of vascular compression of the trigeminal nerve, typically by the superior cerebellar artery, but neurovascular conflict involving other vessels (anterior inferior cerebellar artery, trigeminal vein, superior petrosal vein) has been described. An area along the trigeminal nerve root within a few millimeters from where it enters the pons, called the root entry zone, is thought to be particularly vulnerable to injury. In this area, the content of myelin transitions from the oligodendroglia of the central nervous system to the Schwann cells of the peripheral nervous system.

In patients with classical trigeminal neuralgia, it is theorized that the neurovascular compression may contribute to focal demyelination with subsequent trigeminal nerve hyperexcitability. In support of this premise, pathologic specimens have demonstrated focal demyelination along the trigeminal root in the area of compression. It is theorized that in the region of compression, ectopic impulses arise from the demyelinated axons and the close apposition of groups of demyelinated axons facilitates ephaptic cross talk between fibers mediating light touch and those mediating pain. When pain significantly outlasts the trigger, it may be because of injury-induced changes at the trigeminal ganglia, creating ectopic pacemakers with self-sustained firing. It is thought that during a burst of firing, calcium-activated potassium channels open, allowing potassium ions to flow out of these channels. It is only after enough potassium exits the neuron to cause membrane hyperpolarization that the firing stops. If the hyperpolarization is significant enough, it will prohibit additional firing, leading to the clinically described refractory period.

Some patients may have a genetic predisposition to demyelination or nerve hyperexcitability, contributing to earlier or more frequent compressive neuralgia. In these patients, trigeminal neuralgia may occur at a younger age, on both sides of the face, or in combination with other neuralgias.

The theory that compression of the trigeminal nerve at the root entry zone can contribute to symptoms of trigeminal neuralgia is supported by the fact that most patients show improvement in symptoms following microvascular decompression. However, this does not explain the subset of trigeminal neuralgia patients without evidence of compression on imaging or posterior fossa exploration. It is also noteworthy that neurovascular compression can occur without symptoms. In one study examining 3T MRI of 200 trigeminal nerves in 100 asymptomatic individuals, 175 (87.5%) of the nerves showed neurovascular compression. The authors did not grade the neurovascular contact, however, and others have argued that severe compression with displacement or atrophy is rare in asymptomatic individuals.

Epidemiology

Trigeminal neuralgia is a rare condition, with a prevalence of 0.03% to 0.3% and an annual incidence of 4 per 100,000 to 13 per 100,000 people. It is more common in women, with a ratio of approximately 1.5:1 to 1.7:1. The average age of onset is older than 50 years. However, trigeminal neuralgia can occur at any age, including in children. Patients with secondary and idiopathic trigeminal neuralgia tend to present at a younger age than patients with neurovascular compression.

Trigeminal neuralgia is typically sporadic, although a positive family history may be present in up to 11% of patients. In reported familial cases, both autosomal dominant and autosomal recessive inheritance patterns have been described. Some of the reported familial trigeminal neuralgia cases have been in the setting of hereditary peripheral neuropathy, such as Charcot-Marie-Tooth disease, raising the possibility that patients’ abnormal myelin might have contributed to an underlying vulnerability to nerve compression. Other cases may show a genetic predisposition to peripheral nerve hyperexcitability, with mutations similar to other disorders of neuropathic pain. For example, a gain-of-function mutation in NaV1.6 has been described in one patient with classical trigeminal neuralgia, and more recently, whole-exome sequencing of familial cases demonstrated multiple genetic variants in ion channels, including sodium channels, potassium channels, chloride channels, calcium channels, and transient receptor potential (TRP) channels. It has been suggested that familial cases may have an earlier onset and may be associated with additional neuralgias, such as glossopharyngeal neuralgia or hemifacial spasm.

Causes of Secondary Trigeminal Neuralgia

Red flags for a secondary cause of trigeminal neuralgia include bilateral trigeminal neuralgia, pronounced sensory changes, and a younger age at onset. The most common causes of secondary trigeminal neuralgia include multiple sclerosis or a tumor at the cerebellopontine angle. In one series of patients with both trigeminal neuralgia and multiple sclerosis, the diagnosis of trigeminal neuralgia preceded the diagnosis of multiple sclerosis in about 10% of patients by an average of 5 years. Although patients with multiple sclerosis often have a demyelinating plaque near the trigeminal nerve root entry zone, they can have neurovascular compression ipsilateral to these plaques as well. It is theorized that in these cases, a “double crush” mechanism may be present, in which both the neurovascular compression and the demyelinating plaque contribute to trigeminal neuralgia. Less common causes of secondary trigeminal neuralgia include arteriovenous malformations, epidermoid cysts, aneurysms, small infarcts in the pons or medulla, and bony compression of the nerve such as from an osteoma or osteogenesis imperfecta. In patients without evidence of neurovascular compression or an obvious secondary cause of trigeminal neuralgia, arachnoid thickening and adhesion with the trigeminal nerve and surrounding structures has been proposed as an alternative etiology.

Differential Diagnosis and Evaluation

A number of different causes of facial pain can potentially be confused with trigeminal neuralgia (table 7-2). Prominent autonomic symptoms, such as conjunctival injection, periorbital edema, tearing, or rhinorrhea, should raise suspicion for a trigeminal autonomic cephalalgia such as SUNCT. If the pain is predominantly triggered by eating/chewing, hot/cold foods, or brushing teeth (without cutaneous triggers), a dental etiology should be considered. Often the pain remains intraoral in patients with dental pathology, but rarely a local associated abscess or cellulitis can cause pain that seems to radiate through the affected jaw or ear. If the patient has any history of erythema or rash in the affected painful area at the onset of pain, postherpetic neuralgia should be considered. If the pain is persistent or neuropathic in nature with associated sensory deficit, trigeminal neuropathy should be considered. If the pain is outside the area of the trigeminal nerve, it may be neuralgia related to a different nerve, such as glossopharyngeal neuralgia or nervus intermedius neuralgia, as discussed below.

During a thorough neurologic examination for focal deficits, including testing of all 12 cranial nerves, the clinician should test for sensory loss in all three trigeminal nerve divisions (V1, V2, and V3). Because of overlap from cervical nerve branches over the jaw and lower cheek, the most reliable area to test V3 is over the chin. Masseter and temporalis muscles should be tested for symmetry of muscle bulk and strength.

MRI of the brain, ideally with IV contrast and high-resolution thin cuts through the posterior fossa, is the preferred imaging if no contraindications are present. Three-dimensional time-of-flight magnetic resonance angiogram (MRA) can add additional visualization of arteries. Although not required for diagnosis, trigeminal reflex testing can be particularly useful for evaluating trigeminal nerve impairment in patients with secondary trigeminal neuralgia, with a reported sensitivity and specificity close to 90%. ECG and laboratory testing, including complete blood cell count and electrolytes with kidney and liver function, should be performed to guide medication options. Erythrocyte sedimentation rate should be added if giant cell arteritis is a possibility. A dental evaluation is usually recommended if pain involves predominantly V2 and V3.

Medical Treatment

The initial treatment for trigeminal neuralgia is generally pharmacologic, and either carbamazepine (200 mg/d to 1200 mg/d) or oxcarbazepine (300 mg/d to 1800 mg/d) is generally considered first line. These anticonvulsants block sodium channels, contributing to stabilization of the membrane and likely suppressing the ectopic hyperexcitability of the trigeminal nerve root and ganglion. Carbamazepine has the best evidence as a long-term treatment for trigeminal neuralgia, but a significant number of patients have difficulty tolerating the side effects, which include dizziness, hyponatremia, drowsiness, cognitive symptoms, rash, ataxia, liver damage, and bone marrow suppression; carbamazepine may also potentially interact with a number of other drugs. Oxcarbazepine is reportedly better tolerated and has fewer potential drug interactions but may have a higher risk of causing hyponatremia. In one study, side effects eventually led to withdrawal of medication in 27% of patients on carbamazepine and 18% of patients on oxcarbazepine. Alternatives to carbamazepine and oxcarbazepine with weak evidence include lamotrigine, gabapentin, or onabotulinumtoxinA injections, followed by eslicarbazepine acetate, baclofen, topiramate, valproate, levetiracetam, and phenytoin. Studies are also investigating a new voltage- and use-dependent Nav1.7 channel blocker called vixotrigine for trigeminal neuralgia.

RESCUE TREATMENT

Patients with an acute exacerbation of trigeminal neuralgia that is refractory to medication may present to an urgent care setting. Depending on the clinic and the time of day, a surgeon or specialized proceduralist may not be available for immediate invasive procedures. Pain may be so severe that patients are unable to eat or drink and may require in-hospital treatment. In these cases, IV fosphenytoin or possibly even IV lidocaine (5 mg/kg over 60 minutes) combined with rehydration may be required. Either of these therapies should be delivered under specialist supervision with cardiac monitoring. Another option may be subcutaneous or nasal sumatriptan, which has been reported as possibly effective in small series of patients with refractory trigeminal neuralgia. Acute pain relief might also be achieved with peripheral blocks (bupivacaine with lidocaine) of the most affected trigeminal nerve branches, such as the supraorbital, infraorbital, auriculotemporal, or mental nerve. Requiring slightly more experience, ultrasound-guided trigeminal nerve block via the pterygopalatine fossa has been shown to provide pain relief in a small series.

Surgical and Procedural Management

If a patient with trigeminal neuralgia tries one of the sodium channel blockers and has either insufficient pain relief or intolerable side effects, the patient should be referred for a neurosurgical consultation. If the patient has evidence of neurovascular compression on imaging and no contraindications to surgery, microvascular decompression is considered first line. In patients without neurovascular decompression visible on imaging, typically a neuroablative procedure is considered first. Neuroablative procedures include stereotactic radiosurgery or percutaneous procedures (eg, balloon compression, glycerol injection, or radiofrequency thermocoagulation). The goal of these procedures is to injure the trigeminal nerve enough that the pain is reduced. Partial sensory rhizotomy, internal neurolysis, and peripheral stimulation of trigeminal branches are alternative procedural options for patients with refractory trigeminal neuralgia or patients without neurovascular compression.

MICROVASCULAR DECOMPRESSION

Microvascular decompression involves a retromastoid craniotomy and posterior fossa exploration to identify both the affected trigeminal nerve and the compressive vessel. The vessel is then relocated away from the nerve, with most surgeons using a piece of synthetic material to create a barrier between the vessel and the nerve (figure 7-1). Compared with other treatments for classical trigeminal neuralgia, microvascular decompression is reported to have the greatest probability of pain relief, with 68% to 88% of patients reporting pain freedom at 1 to 2 years postoperatively and approximately 64% of patients still pain free 10 years after surgery. Factors that may increase the risk of pain recurrence include female sex, symptoms lasting longer than 8 years, venous compression rather than arterial compression, the presence of arachnoiditis, the lack of immediate postoperative pain relief, and the presence of persistent pain between attacks.

Patients with more severe neurovascular compression on imaging (especially with distortion of the nerve or atrophy) seem to have a better outcome after microvascular decompression, possibly because it increases the likelihood that the neurovascular contact was not simply an incidental imaging finding.

Side effects of microvascular decompression include CSF leak (1.5%), ipsilateral hearing loss (1.2%), facial palsy (0.9%), severe facial numbness (1.6%), aseptic meningitis (16.8%), trochlear or abducens palsy (1.1%), brainstem infarct (0.1%), and death (0.2%).

When patients have recurrence of trigeminal neuralgia after microvascular decompression, sometimes a repeat posterior fossa exploration is performed. This exploration may identify a new or previously missed compressing vessel, compression with the synthetic material used in decompression, a foreign body inflammatory giant cell granulomatous reaction around the synthetic material (eg, “Teflon granuloma”), or formation of arachnoid adhesions/arachnoiditis. Repeat microvascular decompression has a lower chance of pain relief and a higher risk of complications but may be an option in select patients.

STEREOTACTIC RADIOSURGERY

Stereotactic radiosurgery involves aiming a carefully targeted external beam of radiation to part of the trigeminal nerve root during a single session, with a goal of inducing focal axonal degeneration. Techniques vary slightly, with a variety of technologies (eg, Gamma Knife, CyberKnife) used. Lower doses of radiation are felt to have very little impact on the trigeminal nerve structure and higher doses can potentially cause necrosis of neurons. Because the targeting is precise, the radiation can be directed anywhere along the nerve root, with some surgeons favoring targeting the root entry zone close to the brainstem (sometimes overlapping with the brainstem) and others favoring just proximal to the trigeminal ganglion or the ganglion itself. One large systematic review found that both targets had similar efficacy initially, but the more anterior retrogasserian target was slightly better tolerated. Of the approximately 85% of patients with trigeminal neuralgia who achieve pain relief with stereotactic radiosurgery, most start feeling the relief within 2 weeks to 2 months (general consensus is the maximum interval for pain relief is 180 days). By 4 to 5 years after surgery, about 33% to 56% of patients remain pain free. Decreased sensation is common and may develop an average of 6 to 36 months after radiation. Sensory loss is only severe or bothersome in about 3% of patients; however, select patients may experience corneal numbness with neurotrophic keratopathy, dysesthesia, anesthesia dolorosa (painful numbness), and associated weakness of masticatory muscles.

PERCUTANEOUS LESIONING OF THE TRIGEMINAL NERVE

Percutaneous ablative procedures are performed under fluoroscopic guidance and involve passing a long cannula into the cheek and through the foramen ovale, then lesioning the trigeminal nerve branches or ganglion. Radiofrequency thermocoagulation involves destruction of nerve fibers with heat, and patients are typically required to be awake briefly in the middle of the procedure to make sure the sensation of paresthesia matches the painful area. With chemical destruction (ie, glycerol rhizotomy) or mechanical destruction of nerve fibers (ie, balloon compression), patients are typically anesthetized the entire time. Initial pain relief rates with percutaneous procedures are high (>90% of patients), but the relief falls to 53% to 69% by 3 years. About 20% of patients will have severe numbness, and, similar to other neuroablative procedures, some patients may experience additional complications, such as anesthesia dolorosa, exposure keratitis (damage to the cornea due to dryness), troublesome dysesthesia, and weakness of the masticatory muscles.

PARTIAL SENSORY RHIZOTOMY OR INTERNAL NEUROLYSIS

Partial sensory rhizotomy involves surgical section of the sensory root of the trigeminal nerve; it has a reported clinical response in 70% to 88% of patients. As in other destructive procedures, an increased risk exists of numbness, exposure keratitis, and difficulty with chewing. Internal neurolysis consists of dissecting sensory and motor roots of the trigeminal nerve into 5 to 10 fasciculi from the root entry zone to the Meckel cave. In one series, improvement in pain was reported in 77% of patients at 1 year and in 72% at 5 years postoperative.

PAINFUL TRIGEMINAL NEUROPATHY

Trigeminal neuropathy typically manifests as numbness in one or more branches of the trigeminal nerve, sometimes associated with paresthesia or continuous or near-continuous neuropathic pain (ie, burning, prickling, itching, or pins-and-needles sensation). Patients may have superimposed brief paroxysms of pain resembling neuralgia, but they are not the predominant type of pain. Similarly, large areas of mechanical allodynia or hyperalgesia may be present within the painful territory, but they are different than the small trigger zones in trigeminal neuralgia.

Like other neuropathies, trigeminal neuropathy can be secondary to injury from a multitude of traumatic, metabolic, inflammatory, neoplastic, or infectious causes. Sometimes local trauma may affect only one branch of a nerve, such as following a dental procedure, salivary gland biopsy, or face-lift (eg, mental neuropathy, inferior alveolar neuropathy, infraorbital neuropathy). Other times, painful posttraumatic trigeminal neuropathy may involve the entire nerve with injury to the nerve root or ganglion, such as after neuroablative procedures for trigeminal neuralgia, surgical trauma, or avulsion injuries.

Postherpetic Neuralgia

Acute herpes zoster (shingles) can cause a painful trigeminal neuropathy involving pain in the distribution of one or more trigeminal branches, with herpetic vesicles in the same distribution as pain. In rare cases in which no rash is present (zoster sine herpete), the diagnosis can be confirmed with a positive varicella-zoster virus polymerase chain reaction (PCR) in the CSF. After the rash has healed, some patients may be left with continued debilitating neuropathic pain in the affected area. If this pain lasts more than 3 months, it is diagnosed as postherpetic neuralgia. Postherpetic neuralgia is more common in older adults, and it is often quite difficult to treat. First-line treatment includes tricyclic antidepressants (eg, amitriptyline or nortriptyline), antiepileptic drugs (eg, gabapentin or pregabalin), or topical medicines (eg, lidocaine or capsaicin). Multiple medicines may be required to achieve pain relief, and some patients require long-term pain management with a specialized pain physician. Botulinum toxin A shows promise as a treatment for postherpetic neuralgia, but larger randomized trials are still needed.

Numb Chin Syndrome

In the absence of a temporally associated dental procedure, numbness with or without neuropathic pain isolated to the chin and lip on one side (ie, numb chin syndrome) can be an ominous sign. This is because neuropathy isolated to the mental or inferior alveolar nerve may be the presenting symptom of an orofacial or systemic malignancy. The neuropathy may be due to direct invasion of the nerve or mandible, such as from squamous cell carcinoma, leptomeningeal metastases, or mandibular metastases of distant neoplasms. In one systematic review of 136 patients with malignancy-related numb chin syndrome, breast cancer was the most commonly associated malignancy, followed by lymphoma, prostate cancer, and leukemia.

It is common for patients presenting to neurologists with facial numbness to be evaluated for trigeminal neuropathy with a gadolinium-enhanced MRI of the brain, and in cases of numb chin syndrome, this may help with evaluation for demyelinating or leptomeningeal disease. However, a typical brain MRI may not extend inferiorly enough to view the mandible and may therefore miss a focal mass or osseous lesion. In cases of numb chin syndrome, additional facial MRI with gadolinium and special attention to the inferior alveolar canal may be helpful. If suspicion is high for neoplasm, a CT of the chest, abdomen, and pelvis; fludeoxyglucose positron emission tomography (FDG-PET)/CT; or CSF testing for malignant cells may also be helpful.

NEURALGIC EAR PAIN

Patients presenting with ear pain should be evaluated by an otolaryngologist for underlying ear pathology. If the evaluation is negative, the pain may be referred to the ear from surrounding structures, such as the throat, teeth, parotid gland, lateral neck including vessels, or upper cervical roots. Neuralgic pain can be referred along six different nerves that innervate the ear, often with overlapping dermatomes (figure 7-2). Local structural irritation or trauma of these nerves, infection, inflammation, or neoplasm could contribute to pain within the nerve territories (table 7-3). The first test after evaluation by an otolaryngologist is often a brain MRI with gadolinium, because it can visualize the internal auditory canal and the root entry zones of the cranial nerves. However, an MRI of the brain cannot visualize many of the structures that refer pain to the ear, so patients with neuralgic ear pain of unclear etiology may also require an MRI of the face and soft tissues of the neck with gadolinium. To remember the various structures that can cause stabbing pain in the ear, the mnemonic ENT may be helpful:

  • Ear pathology (intrinsic to the ear)
  • Neuralgia of one of the nerves to the ear (cranial nerves V, VII, IX, X; lesser occipital nerve; and great auricular nerve)
  • Throat, tonsils, tongue, thyroid, trachea, teeth, temporomandibular joint, and tunnels for vessels (jugular foramen and carotid sheath)

GLOSSOPHARYNGEAL NEURALGIA

Glossopharyngeal neuralgia is described as unilateral paroxysmal electrical shock–like pain affecting the posterior tongue, pharynx, tonsillar fossa, deep in the ear, and/or beneath the angle of the jaw. It is typically provoked by swallowing, yawning, coughing, or sometimes talking. Attacks last 2 seconds to 2 minutes on average. Given that it is quite rare (with an estimated incidence of 0.2 per 100,000 to 0.7 per 100,000) and the fact that it can co-occur with other neuralgias, such as trigeminal neuralgia, diagnosis is often complicated.

Approximately 2% of patients have associated symptoms of syncope with their pain. Some have hypothesized that this is related to irritation of the afferent branches of the glossopharyngeal nerve, whereas others feel this is more likely spillover of impulses from the glossopharyngeal nerve via the tractus solitarius to the dorsal motor nucleus of the vagus nerve. Bradycardia, hypotension, seizures, and even cardiac arrest have been described with excessive vagal involvement during an attack of glossopharyngeal neuralgia (ie, vagoglossopharyngeal neuralgia). For this reason, patients with lightheadedness, palpitations, or syncope with their pain may require ambulatory ECG monitoring to look for associated bradyarrhythmia.

Similar to trigeminal neuralgia, glossopharyngeal neuralgia may be caused by neurovascular compression of the glossopharyngeal-vagal complex, typically by the posterior inferior cerebellar artery or less commonly by the anterior inferior cerebellar artery or vertebral artery. Secondary causes can be related to compression, irritation, or infiltration of the nerve anywhere along the glossopharyngeal pathway, such as from demyelinating lesions; laryngeal, oropharyngeal, or skull base tumors (case 7-2); inflammation or infection (ie, parapharyngeal abscess); carotid sheath trauma; or elongated/calcified styloid processes (referred to as Eagle syndrome). Pharmacologic treatment is similar to treatment of trigeminal neuralgia and includes carbamazepine, oxcarbazepine, or other membrane-stabilizing agents. A topical anesthetic on the pharynx/tonsillar pillars or injected anesthetic as an extraoral glossopharyngeal nerve block can be helpful diagnostically and provide temporary pain relief.

CASE 7-2

A 73-year-old woman presented for a neurologic consultation with a 7-month history of sharp, electrical shock–like shooting pain in her left throat and deep into her left ear. The pain was triggered by swallowing and yawning. Talking, chewing, and touching her face did not affect the pain. She could not recall any rash in her throat or ear. The back of her throat felt very sensitive, and this tenderness, along with the triggered sharp pains, had been so severe that she had not been able to eat much. Because of this, she had lost 3.6 kg (8 lb) in the previous 4 months. An MRI of the brain with gadolinium 4 months into her symptoms showed no pathology along the glossopharyngeal nerve root entry zone. Erythrocyte sedimentation rate had been normal. At a local clinic, an otolaryngologist had performed a topical lidocaine block over the pharyngeal region. This provided significant relief, and she was able to swallow pain free until it wore off. Carbamazepine and gabapentin at low doses had not helped with her pain, and she had been unable to tolerate higher doses.

 Neurologic examination was normal; however the patient had a hard palpable mass along the lateral neck that she said she had started noticing in the past 2 months. A gadolinium-enhanced MRI of the face and soft tissues of the neck showed findings suspicious for a left palatine tonsillar carcinoma, with a pathologic-appearing level 2/3 lymph node consistent with possible lymphatic metastasis.

COMMENT

This patient’s symptoms were consistent with glossopharyngeal neuralgia. In this case, she had secondary glossopharyngeal neuralgia related to a palatine tonsillar carcinoma. It is important to note that a typical MRI of the brain may not provide adequate visualization of the throat. Patients with pain in the throat or deep in the ear may need additional imaging with a gadolinium-enhanced MRI of the face or soft tissues of the neck.

In cases refractory to medical therapy, surgery may be considered, typically either microvascular decompression or direct sectioning of the glossopharyngeal nerve and upper rootlets of the vagus nerve, or both. Both have good short- and long-term success, and both have potential complications, including long-term dysphagia and hoarseness. In patients in whom neurovascular compression is visible on imaging, microvascular decompression may be preferred, although this is more technically difficult than microvascular decompression of the trigeminal nerve. In one systematic review comparing microvascular decompression, nerve section, and stereotactic radiosurgery, the authors concluded that nerve sectioning might provide the most favorable treatment response for pain relief and postoperative outcome. Stereotactic radiosurgery, radiofrequency nerve ablation, balloon compression, and other neuroablative procedures have also been described.

NERVUS INTERMEDIUS NEURALGIA

The nervus intermedius is a branch of the facial nerve that carries parasympathetic fibers to the lacrimal and nasopalatine glands as well as sensory information from the tongue and concha of the ear. Nervus intermedius neuralgia, also known as geniculate neuralgia, is characterized by paroxysmal deep ear pain (sometimes described as being stabbed in the ear with an ice pick), with possible radiation to just behind the ear. Pain can be triggered by light touch (eg, with a cotton swab) or cold wind over the posterior wall of the auditory canal or periauricular region and may be accompanied by a disorder of lacrimation, salivation, or taste.

Nervus intermedius neuralgia may follow infection or inflammation of the facial nerve and may therefore develop during or just after Ramsay Hunt syndrome or Bell’s palsy. When the neuralgic pain is related to varicella-zoster virus, the ICHD-3 recommends using the term painful nervus intermedius neuropathy; if the pain persists longer than 3 months, the term postherpetic neuralgia of nervus intermedius is used. Medical therapy is similar to that used for trigeminal neuralgia, with carbamazepine or other antiepileptic drugs. Rare cases of vascular compression have been described, and both microvascular decompression and sectioning of the nervus intermedius may be considered in cases that do not respond to pharmacologic treatment.

OCCIPITAL NEURALGIA

The greater occipital nerve derives from the dorsal ramus of the C2 spinal nerve emerging at the posterior skull base and ascending to the vertex (figure 7-3). The lesser occipital nerve originates from branches of C2 and C3 in the cervical plexus and wraps around the sternocleidomastoid to innervate the lateral scalp, including the top of the external ear. The third occipital nerve is supplied by the medial branch of the C3 dorsal ramus and provides innervation to the lower occipital scalp and upper medial neck.

Occipital neuralgia refers to paroxysmal shooting or stabbing pain in the posterior scalp in the dermatome of the greater occipital, lesser occipital, or third occipital nerves. Patients may describe the pain as starting in the posterior skull base and radiating toward the vertex (greater occipital nerve) or over the ear toward the temple (lesser occipital nerve). By ICHD-3 criteria, the pain is associated with dysesthesia and/or allodynia apparent during innocuous stimulation of the scalp and is associated with tenderness or a painful trigger point over the emergence of the affected nerve. Also by criteria, the pain is improved temporarily by a local anesthetic block of the affected nerve.

Similar to other neuralgias, the patient should have a neurologic examination that includes looking for a sensory deficit in the distribution of the painful area. Rarely, occipital neuralgia can be secondary to lesions in the upper cervical cord, including cavernous malformations and demyelinating lesions. Neuralgia with associated mild sensory deficit in the occipital nerve dermatomes has been described with occipital nerve schwannomas. Irritation of the upper cervical nerve roots by blood vessels or Chiari malformation may also present with neuralgic pain in the occipital nerve distributions. Given the possibility of secondary etiologies, it may be prudent to consider imaging with an MRI of the brain and cervical spine in patients with new and unexplained occipital neuralgia.

In most patients with occipital neuralgia, physical therapy and treatment with antiepileptic drugs or tricyclic antidepressants is often effective. For flares of pain, nerve blocks can be performed by injecting anesthetic, sometimes combined with a corticosteroid, near the emergence of the occipital nerves at the skull base. This treatment can provide pain relief for a few weeks and in a small subset of patients may last several months. Patients with occipital neuralgia not responding adequately to medical therapies or repeated blocks may benefit from pulsed radiofrequency treatment, neurolysis, onabotulinumtoxinA, or occipital nerve stimulation.

Patients with severe pain refractory to medication or nerve blocks should be reevaluated for alternative diagnoses, such as referred pain from the atlantoaxial or upper zygapophysial joints. Primary headache disorders (eg, migraine) can sometimes be difficult to distinguish from occipital neuralgia, as they may have tenderness over the posterior skull base and may sometimes respond well to occipital nerve blocks.

CONCLUSION

When evaluating a patient with neuralgic pain in the face or head, the diagnosis is made by careful history and examination, with attention to the dermatome involved, the triggers, and any associated sensory deficit. Patients with sensory deficit are particularly concerning for a secondary etiology, although all patients with new facial pain warrant additional evaluation for an underlying cause.

When evaluating neuralgic pain in the head and neck, a reasonable first image would be an MRI of the brain with contrast and specific views of the suspected nerve involved. However, this image is limited in scope and may miss pathology along the distal branches of V3 (mental or inferior alveolar nerves) as well as many structures in the neck that can radiate pain to the ear. For this reason, depending on the affected nerve, if the MRI brain is unremarkable, additional imaging with an MRI face or MRI soft tissues of the neck may be necessary. In the case of neuralgic pain in the distribution of the occipital nerves, if concern exists for a secondary etiology, an MRI of the cervical spine might also be considered.

Treatment of neuralgias includes antiepileptic medicines, baclofen, and tricyclic antidepressants. Cases refractory or intolerant to medication may benefit from surgical procedures, such as microvascular decompression, stereotactic radiosurgery, or percutaneous procedures. Occipital neuralgia may respond to injections with local anesthetic, sometimes combined with a corticosteroid.

KEY POINTS

  • Neuralgia describes sharp, stabbing, shocklike pain that is often triggered by touching within the sensory dermatome of the affected nerve, whereas neuropathy describes sensory deficit within the nerve distribution, sometimes with persistent neuropathic pain, such as burning, tingling, or prickling.
  • Classical trigeminal neuralgia is trigeminal neuralgia related to neurovascular compression; nerve atrophy or displacement is required on imaging (not just vascular contact). Secondary trigeminal neuralgia is trigeminal neuralgia related to another cause, such as demyelinating plaque or local mass. Idiopathic trigeminal neuralgia is trigeminal neuralgia without a known cause.
  • Most patients with trigeminal neuralgia are pain free between attacks, but a subset can develop near-continuous background pain.
  • Mild sensory changes may be present in trigeminal neuralgia, but true loss of sensation should alert the clinician to look for secondary causes.
  • Approximately 99% of patients with trigeminal neuralgia report triggers.
  • Some patients with trigeminal neuralgia may describe a refractory period after severe attacks, during which additional attacks are diminished.
  • Bilateral trigeminal neuralgia can occur but is uncommon and should raise suspicion for secondary trigeminal neuralgia, such as from multiple sclerosis.
  • Trigeminal neuralgia associated with pronounced autonomic symptoms should raise clinical suspicion for a trigeminal autonomic cephalalgia.
  • Unexplained numbness isolated to the chin is a red flag for potential malignancy.
  • Neurovascular contact of the trigeminal nerve is common even in people without symptoms. Therefore, the severity of compression on imaging may be more relevant, including nerve displacement or atrophy.
  • A family history of trigeminal neuralgia may be present in up to 11% of patients. Familial cases may have an earlier onset and may be associated with additional neuralgias, such as glossopharyngeal neuralgia or hemifacial spasm.
  • Patients with multiple sclerosis may have both a demyelinating plaque and neurovascular compression near the trigeminal nerve root entry zone, causing neuralgia through a “double crush” mechanism.
  • Postherpetic neuralgia should be considered in patients presenting with trigeminal neuralgia who have a history of erythema or rash in the affected area at the onset of pain.
  • Because of overlap from cervical cutaneous branches over the jawline, the most reliable area to test the mandibular (V3) division is over the chin.
  • If the patient’s pain is predominantly in V2 and V3 and without cutaneous triggers, a dental evaluation should be considered.
  • Carbamazepine is considered first-line treatment for trigeminal neuralgia.
  • For urgent treatment of refractory trigeminal neuralgia, IV fosphenytoin, IV lidocaine, or peripheral blocks can be considered.
  • A patient with trigeminal neuralgia that is refractory to medical therapy should be referred to a neurosurgeon. If neurovascular compression is present on imaging, microvascular decompression is typically considered first. If not, a neuroablative procedure (with injury to the nerve) is typically considered first.
  • Recurrence of trigeminal neuralgia after microvascular decompression may be because of a new or previously missed vessel, compression with the synthetic material used in decompression, or arachnoid adhesions.
  • Repeat microvascular decompression has a lower chance of pain relief and higher risk of complications.
  • The best dosing and location of radiosurgery (where to aim along the trigeminal root) for trigeminal neuralgia is still being studied.
  • Pain relief from radiosurgery may start 2 weeks to 2 months after treatment, whereas decreased sensation may start an average of 6 to 36 months after treatment.
  • Trigeminal neuropathy following a neuroablative procedure for trigeminal neuralgia is called painful posttraumatic trigeminal neuropathy.
  • By convention, the term postherpetic neuralgia is used for either neuralgic or neuropathic facial pain starting in an area with active herpes zoster rash and persisting for more than 3 months.
  • Brain MRI is not adequate for numb chin syndrome as it may not visualize the mandible and may miss a malignancy located there.
  • Stabbing ear pain may be referred along six nerves with overlapping dermatomes: the auriculotemporal nerve, lesser occipital nerve, great auricular nerve, nervus intermedius, glossopharyngeal nerve, and vagus nerve.
  • Brain MRI is not adequate for unexplained ear pain, as it cannot visualize many structures that radiate pain to the ear, such as the throat, cervical vessels, and thyroid.
  • Glossopharyngeal neuralgia is provoked by swallowing, yawning, or coughing.
  • Patients with lightheadedness, palpitations, or syncope with their glossopharyngeal neuralgia pain may require ambulatory ECG monitoring to look for an associated bradyarrhythmia.
  • Similar to trigeminal neuralgia, glossopharyngeal neuralgia may be related to neurovascular compression or other lesions along the nerve path.
  • Either microvascular decompression or sectioning of the glossopharyngeal nerve (and sometimes vagus nerve rootlets) is considered a reasonable first-line treatment for medically refractory glossopharyngeal neuralgia.
  • Nervus intermedius neuralgia may present with stabbing pain deep in the ear triggered by cold wind or using a cotton swab in the ear canal.
  • Nervus intermedius neuralgia may develop in the setting of classic Bell’s palsy or Ramsay Hunt syndrome (herpes zoster affecting the ear and facial nerve).
  • Occipital neuralgia is typically described as shooting or stabbing pain that starts at the posterior skull base and radiates either to the vertex (greater occipital nerve) or over the ear toward the temple (lesser occipital nerve).
  • If loss of sensation is present with occipital neuralgia, a secondary cause of pain should be considered.

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