Nervus intermedius neuralgia

INTRODUCTION — Nervus intermedius neuralgia is a rare condition characterized by brief paroxysms of pain felt deeply in the auditory canal. Other terms previously used for this condition include geniculate neuralgia and Hunt neuralgia.

This topic will review the clinical features, diagnosis, and treatment of nervus intermedius neuralgia. Other causes of focal head and facial pain are discussed separately. (See "Overview of craniofacial pain".)

PATHOPHYSIOLOGY — Nervus intermedius neuralgia is a painful condition caused by neuropathic dysfunction restricted to structures innervated by the nervus intermedius. Neuralgia is a form of neuropathic pain that is characterized by paroxysmal, brief (seconds to a few minutes), shock-like or lightning-like pain that follows a peripheral or cranial nerve distribution and can spread to adjacent areas in the course of the attack [1-3].

Anatomy — The nervus intermedius (also called the intermediate nerve of Wrisberg or glossopalatine nerve) is a small branch of the facial nerve (cranial nerve VII) that carries general visceral efferent, special visceral afferent (taste), and general somatic afferent fibers (figure 1) [4]. Nerve fibers from the superior salivary and solitary nuclei in the pons merge to become the nervus intermedius in the subarachnoid space. These fibers then join nerve fibers from the facial nucleus. The cell bodies of the nervus intermedius dwell in the geniculate ganglion. Peripheral axons carry parasympathetic information to the lacrimal and nasopalatine glands, and sensory information is transmitted from portions of the pinna and middle ear, the mastoid process, the eustachian tube, and parts of the tongue [4-6].

Pathogenesis — Although the pain and other clinical features localize to structures supplied by the nervus intermedius, there have not been studies to prove that the neuralgic pain originates in the geniculate ganglion or along the nervus intermedius [5].

Some investigators believe that compression of the nerve by an adjacent blood vessel is an important mechanism [7,8], and relief of pain by vascular decompression of the intermediate nerve provides some support for this hypothesis [7]. However, the role of vascular compression in the pathogenesis of nervus intermedius neuralgia and other neuralgias remains uncertain because otalgia can arise from other cranial nerve afferents in the ear [9,10]. In some surgical reports, section or decompression of a combination of cranial nerves V, VII, VIII, IX, X, and/or XI has been necessary to obtain relief [1,4].

Nervus intermedius neuralgia may also occur in the setting of inflammation at the geniculate ganglion due to herpes zoster infection [11,12]. Neuralgic pain can occur both from inflammation related to the acute infection or from secondary neuronal damage due to fibrosis with membrane hyperexcitability following an infection.

EPIDEMIOLOGY — Nervus intermedius neuralgia is rare, and only limited data from case series and reports are available regarding the incidence, prevalence, and risk factors associated with this condition. In a 2021 review of published reports that included 127 patients with nervus intermedius neuralgia, approximately 66 percent were female [13]. In a systematic review published in 2013, females accounted for 14 of 15 (93 percent) surgical cases of nervus intermedius neuralgia [14].

The median age of symptom onset is 41 to 45 years old, but symptoms have also been reported in young children as well as adults up 89 years old [13,14].

CLINICAL MANIFESTATIONS

Ear pain — Nervus intermedius neuralgia consists of unilateral, severe paroxysmal pain felt within the depths of the ear. Symptoms are typically brief, lasting seconds or a few minutes, and may occur as single paroxysms or as a rapid volley. However, some patients may report constant baseline pain [13]. The pain can be sharp or burning. Symptoms typically involve the auricle but can also radiate from the auditory canal to the parieto-occipital region or to trigeminal sensory zones on the face [11,13,14]. A variable refractory period follows attacks; the duration of the refractory period shortens as the disease progresses.

Triggers — Attacks can be provoked by nonpainful stimulation (allodynia) of trigger points or zones in the posterior wall of the ear canal (figure 2). Pain may also occur spontaneously [13]. The presence of an attack trigger (ie, auditory canal stimulation) was once considered a characteristic feature of nervus intermedius neuralgia. However, a systematic review found that a trigger was described in only 3 of 10 patients with available data [14]. In a review of 48 cases of nervus intermedius neuralgia, the most common triggers were [13]:

●Touch to the ear or external auditory canal – 23 percent

●Air movement or cold temperature – 21 percent

●Jaw movement (eg, eating, talking) – 19 percent

●Noise – 10 percent

●No trigger – 35 percent

Other neurologic symptoms — Altered taste perception, such as a sense of bitter taste, can occur in some individuals, as can disorders of lacrimation or salivation [1,5,11]. Dizziness and vertigo occur in up to approximately 25 percent of patients [13]. Involvement of parasympathetic fibers of the nervus intermedius or other anastomosing cranial nerves may account for these other neurologic symptoms (figure 1). (See 'Anatomy' above.)

DIAGNOSIS — Nervus intermedius neuralgia should be considered in patients with transient episodes of isolated ear pain. The diagnosis of nervus intermedius neuralgia is made in patients with characteristic ear pain after excluding other neurologic and otolaryngologic causes [4].

Diagnostic criteria — The diagnosis of nervus intermedius neuralgia, according to the International Classification of Headache Disorders, 3^rd edition (ICHD-3), requires fulfilling all of the following criteria [11]:

●Paroxysmal attacks of unilateral pain in the distribution of nervus intermedius

●Pain has all of the following characteristics:

•Lasting from a few seconds to minutes

•Severe in intensity

•Shooting, stabbing, or sharp in quality

•Precipitated by stimulation of a trigger area in the posterior wall of the auditory canal and/or periauricular region

●Not better accounted for by another ICHD-3 diagnosis

Although the ICHD-3 diagnostic criteria mandate the presence of a trigger area to produce brief pain in the auditory canal, a trigger is not always present, and, for some patients, the pain may occasionally be constant [13,15]. (See 'Clinical manifestations' above.)

Differential diagnosis — The differential diagnosis for nervus intermedius neuralgia includes other conditions that cause otalgia. These conditions may be broadly divided into otologic and neuralgic (referred) causes.

●Otologic conditions – Conditions that cause swelling or injury to the ear may present with ear pain, similar to nervus intermedius neuralgia. These include local infections (eg, otitis media or otitis externa), trauma, and neoplasm [15]. Otologic conditions may be identified by findings on physical examination, otoscopic evaluation, or imaging. (See "Acute otitis media in adults" and "External otitis: Pathogenesis, clinical features, and diagnosis" and "Evaluation and management of middle ear trauma" and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Clinical presentation'.)

●Neuralgic conditions – Nerves that can cause pain at the ear include branches of cranial nerves V, VII, IX, and X, and upper cervical nerve roots (C2 through C3) via the great auricular and lesser occipital nerves (figure 2) [15]. Pathology affecting any of these neural structures can potentially refer pain to the ear. Such conditions include:

•Glossopharyngeal neuralgia – Glossopharyngeal neuralgia is the main disorder in the differential diagnosis of nervus intermedius neuralgia due to adjacent areas of cutaneous innervation. Glossopharyngeal neuralgia typically presents with brief episodes of triggered pain in the ear that also involves the throat, base of the tongue, and angle of the jaw. However, some patients who fulfill diagnostic criteria for nervus intermedius neuralgia [11] may have a variant of glossopharyngeal neuralgia with pain paroxysms initially restricted to the ear [14]. In such cases, the discriminating pharyngeal pain of glossopharyngeal neuralgia may not occur until years later [1]. (See "Overview of craniofacial pain", section on 'Glossopharyngeal neuralgia'.)

•Ramsay Hunt syndrome – The classic triad of symptoms in Ramsay Hunt syndrome (herpes zoster oticus) is unilateral ear pain, ipsilateral facial paralysis, and vesicles in the auditory canal or auricle. Some patients also develop tinnitus, vertigo, or other cranial nerve symptoms due to spread of inflammation to nearby ganglia and cranial nerves. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Ramsay Hunt syndrome (herpes zoster oticus)'.)

•Trigeminal neuralgia – Trigeminal neuralgia can present with brief paroxysms of facial pain, including the ear, that may be triggered by external stimuli, similar to nervus intermedius neuralgia. However, the distribution of pain in trigeminal neuralgia typically involves broader areas of the face, corresponding to one or more major branches of the trigeminal nerve [16,17]. (See "Trigeminal neuralgia".)

•Occipital neuralgia – Occipital neuralgia pain may present with ear pain due to involvement of the lateral aspect of the lesser occipital nerves but typically also includes occipital pain and tenderness, aching, or paresthesias at the nuchal ridge [18]. (See "Occipital neuralgia".)

•Central neuropathic facial pain – Cerebral and cervical spine conditions that cause dysfunction along somatosensory tracts may lead to pain-producing, hypersensitized pathways. Structural lesions from stroke or demyelinative lesions, such as from multiple sclerosis, can result in neuropathic pain, including at the auricle. C1 myelitis, for example, has been reported to give rise to neuralgic otalgia [19]. Pain may be constant or intermittent. Central neuropathic pain may be distinguished by the onset of symptoms after a cerebral or spinal insult that produces a sensory deficit; the pain subsequently develops in the area corresponding to chronic sensory deficit but may extend to adjacent areas. (See "Central neuropathic facial pain".)

•Auricular neuralgias – Other rare cranial neuralgias that primarily affect the ear include great auricular neuralgia and auriculotemporal neuralgia. These may be idiopathic or due to secondary (structural) causes. The location of pain may be used to distinguish these conditions from nervus intermedius neuralgia (figure 2). Great auricular neuralgia causes pain at the ear, ipsilateral jaw, and neck, correlating with the sensory distribution of the great auricular nerve. The auriculotemporal nerve is a terminal nerve branch of the mandibular (V3) nerve that can cause pain in the tragus, parotid gland, and temporal region of the head. (See "Overview of craniofacial pain", section on 'Auricular neuralgias'.)

•Red ear syndrome – Red ear syndrome is a rare condition characterized by transient, burning ear pain as well as redness. Symptoms may be restricted to the auricle or can involve the face as well. Symptoms may persist for several minutes, up to an hour. (See "Overview of craniofacial pain", section on 'Red ear syndrome'.)

Evaluation — The diagnosis of nervus intermedius neuralgia requires an evaluation to exclude other causes of symptoms. This includes a clinical examination to evaluate for otologic conditions as well as diagnostic imaging to exclude alternative causes and to identify any structural sources of pain such as vascular compression of the nerve.

●Clinical examination – A general clinical examination to evaluate for systemic infection should include a direct inspection of the auditory canal and tympanic membrane as well as referral to an otolaryngologist to evaluate for other otologic causes of ear pain.

●Diagnostic imaging – For patients with symptoms of nervus intermedius neuralgia, we recommend a contrast-enhanced magnetic resonance imaging (MRI) of the brain with dedicated brainstem sequences (such as the fast imaging employing steady-state acquisition [FIESTA] protocol) and a magnetic resonance angiogram (MRA) of the head to evaluate for vascular compression or other underlying structural conditions. Computed tomography (CT) and computed tomography angiography (CTA) of the head are alternative imaging options for patients unable to obtain MRI and MRA. Brain imaging is useful to identify entities such as stroke, demyelinating lesions, or a tumor at the cerebellopontine angle. MRA or CTA is useful show an ectatic blood vessel compressing the nervus intermedius. However, the sensitivity and specificity of imaging studies for identifying a secondary cause of ear pain is unknown for patients with suspected nervus intermedius neuralgia and a normal neurologic examination.

Urgent imaging is warranted for patients with nervus intermedius neuralgia symptoms accompanied by neurologic deficits. Additional imaging may be performed when clinical features are atypical, such as patients with progressive symptoms or those with neurologic deficits, and initial brain MRI and MRA are nondiagnostic [15]. Options include MRI of the cervical spine, face, temporomandibular joint, or soft tissue of the neck or CT of the temporal bones.

●Other testing – Laboratory testing to assess for systemic infection or herpes zoster is reserved for patients with suggestive clinical features such as fever or vesicles in the auditory canal.

TREATMENT

Pharmacotherapy — Medications are first-line treatment and are effective for many patients with nervus intermedius neuralgia. The rarity of nervus intermedius neuralgia has precluded accumulation of high-quality data to guide therapy [4,5]. Pharmacologic treatment for nervus intermedius neuralgia is based largely on efficacy of treatments used for other cranial neuralgias, mainly trigeminal neuralgia. (See "Trigeminal neuralgia", section on 'Medical treatment'.)

Initial treatment — We suggest carbamazepine extended release for the initial treatment of most patients with nervus intermedius neuralgia, based on efficacy for trigeminal neuralgia. Our typical starting dose of carbamazepine extended release is 100 mg twice daily. The daily dose can be increased by 200 mg up to every 2 to 3 days as tolerated and as needed for pain relief, typically up to 1200 mg daily in two divided doses.

Adverse effects of carbamazepine include drowsiness, dizziness, nausea, and vomiting; slow titration may minimize these effects. Carbamazepine-induced leukopenia is a potential adverse effect but is usually benign. The Stevens-Johnson syndrome and toxic epidermal necrolysis are additional rare complications, particularly during the first eight weeks of therapy. They are significantly more common (estimated incidence of 5 percent) among patients with the HLA-B*1502 allele. This allele occurs almost exclusively in patients of Asian ancestry, including South Asian Indians. Screening for this allele is recommended in patients with Asian ancestry prior to starting carbamazepine. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA polymorphism and pharmacogenetics'.)

Alternative treatment options — For patients who do not tolerate or respond to carbamazepine, we suggest either oxcarbazepine or baclofen [13].

●Oxcarbazepine is started at 150 mg twice daily. The daily dose can be increased if needed for pain relief by up to 300 mg each week as tolerated up to 1800 mg daily in divided doses.

●Baclofen is started at 5 mg three times daily. The total daily dose can be increased as tolerated and needed for pain relief by 15 to 30 mg every three days, up to a daily dose of 80 mg daily in divided doses.

Other options that may provide benefit include gabapentin, pregabalin, phenytoin, and tricyclic antidepressants (eg, amitriptyline) [13].

Surgery for refractory symptoms — Neurosurgery is considered as a last resort when pharmacotherapy fails or when adverse effects of medications significantly reduce quality of life. However, there are limited data to guide operative techniques [20]. The opinion of an experienced neurosurgeon, familiar with the detailed anatomy of the nervus intermedius and its variants and with intraoperative anatomic findings, should be obtained to choose the most appropriate intervention [20].

●Excision – Surgical treatment for refractory nervus intermedius neuralgia frequently involves excision of the nervus intermedius and geniculate ganglion [21], with or without exploration and/or section of cranial nerves V, IX, and X [22]. Sectioning of the nervus intermedius alone is often ineffective [23,24]. One series of 64 patients who had excision of the nervus intermedius and geniculate ganglion reported "excellent" results in 63 patients, but outcomes were not objectively defined in this report [21]. Complications included a temporary partial facial paralysis in 11 patients (17 percent). In addition, permanent ipsilateral xerophthalmia is an expected outcome due to sectioning of the greater petrosal nerve as part of the surgical approach to the geniculate ganglion.

●Microvascular decompression – Decompression of cranial nerves V, IX, and X, with or without section of the nervus intermedius, is another option [6,25,26]. In a series of 10 patients with nervus intermedius neuralgia treated with microvascular decompression who had long-term (>12 months) follow-up, an "excellent" outcome was reported for three patients and partial relief for six [27].

PROGNOSIS — Limited data are available regarding the prognosis of nervus intermedius neuralgia. Chronic symptoms that persist for years have been reported in observational studies of patients undergoing surgical treatment for refractory nervus intermedius neuralgia [28].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain".)

SUMMARY AND RECOMMENDATIONS

●Definition – Nervus intermedius neuralgia is a rare disorder characterized by pain felt deeply in the auditory canal. The median age of symptom onset is 41 to 45 years old, and females are predominantly affected. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical features – The symptoms of nervus intermedius neuralgia consist of episodes of severe paroxysmal ear pain felt in the depths of the ear (figure 2). Symptoms are typically brief, lasting seconds or a few minutes. Pain may occur spontaneously or may be associated with a trigger zone in the posterior wall of the ear canal. Altered taste perception, such as a sense of bitter taste, can occur in some individuals, as can disorders of lacrimation or salivation. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of nervus intermedius neuralgia is made in patients with characteristic ear pain after excluding other neurologic and otolaryngologic causes. (See 'Diagnosis' above.)

•Differential diagnosis – The differential diagnosis for nervus intermedius neuralgia includes other conditions that cause otalgia. Otologic causes include local infections (eg, otitis media or otitis externa), trauma, and neoplasm. Neuralgic causes include glossopharyngeal neuralgia, Ramsay Hunt syndrome, trigeminal neuralgia, occipital neuralgia, central neuropathic facial pain syndrome, auricular neuralgias, and red ear syndrome. (See 'Differential diagnosis' above.)

•Neuroimaging – For patients with suspected nervus intermedius neuralgia, we recommend a contrast-enhanced brain MRI with dedicated brainstem sequences to rule out a structural lesion or vascular compression. Additional imaging, such as MRI of the cervical spine, face, temporomandibular joint, or soft tissue of the neck or CT of the temporal bones, are performed when clinical features are atypical and initial brain MRI and MRA are nondiagnostic. (See 'Evaluation' above.)

●Treatment – For patients with nervus intermedius neuralgia, we suggest initial treatment with carbamazepine (Grade 2C). Alternatives include oxcarbazepine, baclofen, gabapentin, pregabalin, and phenytoin. (See 'Treatment' above.)

Neurosurgical treatment is reserved for patients with symptoms refractory to pharmacotherapy.