This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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Orofacial and cephalic pain can arise from a variety of conditions that affect the nerves that supply the head, their roots, and other pain sensitive structures. Trigeminal neuralgia, the prototypical cephalic neuralgia, is characterized by bursts of excruciating facial pain in the distribution of one or more branches of the trigeminal nerve. Chewing, yawning, speaking, and even light touch or a gentle breeze can trigger a single jolt or a flurry. A careful history, physical examination, and diagnostic testing usually reveal underlying or associated conditions. Cranial neuralgias may respond to antiepileptic drugs or various invasive procedures. Pain due to other conditions is best treated by treating the underlying condition.
• Cranial neuralgias may, more frequently than other headache syndromes, be secondary to central nervous system or peripheral pathology, including carotid artery dissection, arterial venous malformations, aneurysmal dilatation with subsequent compression, etc.
• For several cranial neuralgias, the diagnostic workup should include structural imaging with MRI with and without contrast to evaluate for evidence of inflammation or space-taking lesions, vascular imaging consisting of either MRA or CTA to evaluate for neurovascular compression, and frequently a laboratory evaluation checking for signs of inflammation (whether autoimmune or related to infection), potentially including cerebrospinal fluid analysis.
• In as much as secondary causes are found, treating the underlying disorder is considered to be effective in the management of cranial neuralgias. In the absence of a clear secondary cause, we are often left to use treatments proven in other settings for neuropathic pain that may or may not have high quality evidence in this particular genre.
• Because these disorders were classically challenging to diagnose with no objective findings on examination and because they are frequently associated with psychiatric comorbidities such as depression and anxiety, they have often been mischaracterized as being purely psychiatric in nature and may carry stigmata for patients and their families.
• As many of these syndromes tend to be refractory to treatment and may persist for years without spontaneous remission, there is a high degree of associated disability, and many patients undergo multiple unnecessary procedures in an attempt to relieve their pain, which may lead to additional problems henceforth.
Trigeminal neuralgia. The first known description of trigeminal neuralgia, was written in the second century AD by Aretaeus of Cappadocia, a contemporary of Galen. Also known for his descriptions of migraine, he makes reference to a pain in which spasm and distortion of facial expression take place. Jujani, an 11th century Arab physician, mentions in his writings unilateral facial pain causing spasms and anxiety. Interestingly, he suggests that the cause of the pain is “the proximity of the artery to the nerve.” The first full account of trigeminal neuralgia was published in 1773 when John Fothergill presented a paper to the Medical Society of London. He described the classic trigeminal neuralgia, including paroxysms of unilateral facial pain, evoked by eating or speaking or touch, starting and ending abruptly, and associated with anxiety. Some time earlier, Nicolaus André had used the term “tic douloureux” to describe a similar entity. Later observations in the 18th and 19th centuries by Pujol, Chapman, and Tiffany helped to differentiate trigeminal neuralgia from other common facial pains.
In the early 20th century, Oppenheim alluded to an association between multiple sclerosis and trigeminal neuralgia.
Modern neurosurgical treatment can be traced back to 1925 when the concept of vascular decompression was introduced; however, it was at least 50 years later that microvascular decompression gained wide‐spread acceptance as a treatment method. Gardner and Miklos promoted the theory and modified the technique further in the 1950s and 1960s. It was not until the large case series published in 1970s by Jannetta that a major shift in neurosurgical practice began to appear. Neuroablative procedures kept evolving throughout the century, with attempts to balance the adverse effects of neural injury with sufficient pain control.
Pharmacotherapy had little success in this condition until Bergouignan’s discovery in 1942 that phenytoin was effective in preventing pain paroxysms. Soon, following the introduction of carbamazepine for treatment of epilepsy, controlled trials were published showing its superiority over placebo in trigeminal neuralgia. Since then, anticonvulsants have remained the mainstay of pharmacological treatment (119).
Glossopharyngeal neuralgia. The first description of glossopharyngeal neuralgia is credited to Theodore H Weisenburg in 1910. His patient presented with the classical symptoms of lancinating pain in the ear and neck, which on autopsy 6 years later were identified as secondary to an underlying cerebellopontine angle tumor, which compressed the trigeminal nerve and stretched the glossopharyngeal nerve.
Ten years later, Sicard and Robineau described 3 patients who had “algie velo-pharyngee essentielle” (pain in the distribution of the glossopharyngeal nerve of unknown cause). These patients failed treatment with pharmacotherapy and sedatives and then underwent a resection of the glossopharyngeal nerve with subsequent pain relief.
A year later, Wilfred Harris coined the term “glossopharyngeal neuralgia,” as it resembled classic trigeminal neuralgia in the severity and suddenness of onset, brevity, and duration (127).
Working separately in 1910, Weisenburg established glossopharyngeal neuralgia as a clinical entity, distinct from trigeminal neuralgia, with which it was often confused. Furthermore, two so-called variants have been described: an otitic form with pain mainly deep in or near the ear and an oropharyngeal form with the pain in the pharynx, tonsil, soft palate, and back of the tongue (127).
Nervus intermedia neuralgia. Nervus intermedius neuralgia, also known as geniculate neuralgia, is an extremely rare form of a cranial neuralgia. The nervus intermedius nerve was first identified in 1563 and also has been known as the intermediary nerve, intermediate nerve, geniculate ganglionitis, or Wrisberg’s nerve. Professor Heinrich August Wrisberg described the nerve in detail and in 1777 named it “portio media inter comunicantem faciei et nervum auditorium.” In 1857, John Nottingham introduced the term “tic douloureux of the ear” to describe the sudden paroxysms of pain accompanied by flushing of the auricle. In 1907, Ramsay Hunt noted cutaneous manifestations of patients with herpes zoster of the ear. He described the “zone of Ramsay Hunt” that correlated to the innervation from the nervus intermedius. The “tic douloureux of the ear” became known as geniculate neuralgia (08; 27).
Occipital neuralgia. Occipital neuralgia, or Arnold neuralgia, was first described in 1821 as recurrent headaches localized in the occipital region (28).
Tolosa-Hunt syndrome. Tolosa-Hunt syndrome is a rare, granulomatous inflammatory disorder presenting with a unilateral severe headache followed by or simultaneously occurring with very painful and restricted eye movements. It is recognized by the National Organization for Rare Disorders and was first described in 1954 by the Spanish neurosurgeon Dr. Edward Tolosa (118). He described a patient who had orbital pain in the left area, ipsilateral ophthalmoplegia, significant loss of visual acuity, and hypoesthesia in the first branch of the trigeminal nerve. Autopsy revealed granulomatous inflammation of the cavernous sinus. A few years later, in 1961, William Hunt and his coworkers presented the first report in the American literature of a syndrome characterized with similar signs and symptoms (77). Finally, in 1966 Smith and Taxal were the first authors to describe this collection of signs and symptoms as the Tolosa Hunt Syndrome. They had encountered similar cases that previously had been given alternative diagnoses; however, given these symptoms and the dramatic response to systemic steroid therapy, they realized that this is a definite clinical entity (144). Since this syndrome was coined, there have been numerous cases and studies reported around the world (11). The exact etiology is unclear, although it shares histopathological features with idiopathic orbital pseudotumor (107).
Raeder syndrome. Raeder syndrome was first described in 1918 by the Norwegian ophthalmologist George Raeder and later extended by the same author. One of the first cases in the Norwegian Magazine of Medical Science described an 18-year-old male patient with left eye, temple, and occipital pain as well as miosis of the left pupil and left jaw deviation. This particular patient eventually was found to have a middle cranial fossa tumor contributing to this syndrome; however, since then many idiopathic cases have been reported that often have a self-limited course.
In the 1950s, Boniuk and Schlezinger further subdivided the Raeder syndrome into Groups 1 and 2. Group 1 involved patients such as those described above with oculosympathetic paresis and trigeminal and potentially other cranial nerve involvement. Group 2 patients consisted of those with painful postganglionic Horner syndrome who often had a more benign and self-limited course that lasted few weeks.
Later, Mokri drew attention to the fact that an internal carotid artery dissection can often cause painful postganglionic Horner syndrome as well (139).
Thus, Raeder syndrome, also known as the paratrigeminal syndrome, can be subdivided into groups. The first group, Group IA, has primary trigeminal, oculomotor, or other cranial nerve involvement; this group typically requires a thorough neuroradiologic or diagnostic work up and usually carries a poor long-term prognosis. The second group, Group IB, has no oculomotor involvement and usually experiences a much better outcome. Group II is typically a painful postganglionic Homer syndrome with a self-limited course and excellent prognosis (139).
Burning mouth syndrome. Although medical science has been aware of burning mouth syndrome for more than a century, it was not formally categorized as a distinct headache disorder until the ICHD-2 was released in 2004 (156).
Idiopathic facial pain. Prior to adopting formal diagnostic criteria, persistent idiopathic facial pain included many variants that were considered atypical of trigeminal neuralgia as well as migraine. As a result, a wide variety of patients over the years have been considered to have persistent idiopathic facial pain (26).
Classic trigeminal neuralgia. Classic trigeminal neuralgia is a disorder characterized by recurrent unilateral brief electric shock-like pains abrupt in onset and termination limited to the distribution of the trigeminal nerve. The maxillary and mandibular branches are most often affected. The sharp or electrical paroxysms last seconds to minutes and may occur in rapid succession. Painful attacks may be followed by a brief refractory period. The pain is often triggered by innocuous stimuli (eg, a simple touch, washing, or shaving the skin) or simple facial movements (eg, eating, drinking, smiling or talking). In some cases, the pain can be triggered by other sensory stimuli, such as bright lights, particular tastes, and loud noises. Over time the attacks can become more frequent and disabling. Patients can often have significant psychosocial and functional impairment secondary to the severe disabling lancinating pains.
The ICHD-3 beta diagnostic criteria for trigeminal neuralgia are at least 3 attacks of unilateral facial pain occurring in 1 or more divisions of the trigeminal nerve with no radiation beyond the distribution of the trigeminal nerve and pain with at least 3 of the 4 following characteristics:
(1) Recurring in paroxysmal attacks lasting seconds to minutes
There is typically no clinically evident neurologic deficit other than hyperalgesia on the involved side. If hypoalgesia is present, this is evidence of axonal damage, and a thorough investigation of symptomatic causes is necessary.
Trigeminal neuralgia type 2 (atypical trigeminal neuralgia). As indicated in IHS-3 beta, this is essentially similar in presentation to classic trigeminal neuralgia, in addition to a persistent background facial pain in the affected area. Central sensitization may account for the persistent facial pain. MRI is less likely to show neurovascular compression in this variant of trigeminal neuralgia. Also, this variant typically responds more poorly to conservative and neurosurgical treatment.
Secondary trigeminal neuralgia is essentially trigeminal neuralgia caused by a major neurologic disease. This is typically readily identified by MRI or other further work up. The IHS-3 beta further subdivides this into various categories.
Painful trigeminal neuralgia attributed to acute herpes zoster. This is unilateral head or facial pain lasting less than 3 months and starting less than 7 days preceding herpetic eruption in the same trigeminal nerve root. The ophthalmic division of the trigeminal nerve is affected 80% of the time. However, herpes zoster itself affects the trigeminal nerve root 15% of the time.
Herpes zoster affecting the V1 distribution can also be associated with cranial nerve III, IV, and VI palsies. This is more common in immune-compromised patients.
Postherpetic neuralgia. This is unilateral head or facial pain in the distribution of the trigeminal nerve, persisting or recurring for over 3 months and associated with pain developed in temporal relation to acute herpes zoster.
The patient must also have a history of acute herpes zoster affecting the trigeminal nerve branches.
Similar to acute herpes zoster detailed above, this also affects the ophthalmic division more commonly. Patients often describe the pain as burning and itching in nature. It is more common to see sensory changes on exam including allodynia. There can also be pale light purple scars as evidence of herpetic zoster eruption sequelae.
The pathophysiology of postherpetic neuralgia is not clearly understood. However, it is somewhat different than that of classic trigeminal neuralgia. It does appear to involve both the peripheral and central nervous system.
After resolution of the primary varicella zoster virus infection, replication of latent varicella zoster virus in the sensory ganglia leads to inflammatory neural damage, resulting in acute zoster pain and afterward postherpetic neuralgia.
Motor paresis can occur due to spread of infection and inflammation from the dorsal to the anterior horn. Research also suggests that voltage-gated sodium channels are increased and that GABA receptors are reduced in the dorsal root ganglia, leading to excessive activation of nociceptive neurons and peripheral sensitization and, over time, central sensitization resulting in spontaneous pain, allodynia, and hyperalgesia in postherpetic neuralgia (85).
Painful trigeminal neuropathy attributed to space-occupying lesion. This is essential classic trigeminal neuralgia with or without concomitant persistent facial pain that has developed due to contact between the trigeminal nerve and a space-occupying lesion. Most often, this can be elucidated by MRI. Tumors causing trigeminal neuralgia are often benign and most often occur at the cerebellopontine angle. From most to least common, these include schwannomas, meningiomas, epidermoid cysts, acoustic neuromas, and cholesteatomas. These tumors compress the nerve root at its entry in the pons. Studies suggest that 8% of secondary trigeminal neuralgia comes from tumors. However, 20% of cerebellopontine angle tumors cause trigeminal neuralgia (Cruccu 2017).
Painful trigeminal neuralgia attributed to a multiple sclerosis plaque. This is classic trigeminal neuralgiform pain induced by multiple sclerosis plaque affecting the trigeminal nerve and associated with other signs and symptoms of multiple sclerosis. Unlike other variants of trigeminal neuralgia, this is more often associated with bilateral trigeminal neuralgiform pain.
In this case, a multiple sclerosis plaque affecting the trigeminal nerve has been demonstrated by MRI or routine electrophysiological studies (blink reflex or trigeminal nerve-evoked potentials) indicating impairment of the trigeminal nerve (Cruccu 2017).
Posttraumatic trigeminal neuropathy (anesthesia dolorosa). The distribution of pain is localized to the trigeminal nerve distribution, developing within 3 to 6 months of a traumatic event, which can be mechanical, chemical, or radiation-induced in etiology. There should be history of an identifiable traumatic event to the trigeminal nerve as well as associated trigeminal nerve dysfunction (hyper- or hypoalgesia) noted on examination (73). Typically, after radiation injury, pain may take 3 months to develop and may be due to postganglionic injury. The paroxysms of trigeminal neuralgiform pain in this situation are typically longer lasting, and there is more often a continuous background pain described by the patient.
Painful trigeminal neuropathy attributed to other disorder. This is typically more persistent and continuous than the classic trigeminal neuralgiform pain and is often associated with an underlying connective tissue disorder or genetic in etiology. This can also be secondary to an underlying infection, such as herpes zoster virus, varicella zoster virus, Lyme disease, syphilis, or an initial manifestation of a neoplastic process. This is associated with abnormal sensation on examination in the trigeminal nerve distribution and absent or delayed trigeminal nerve reflexes (73).
Glossopharyngeal neuralgia. The International Headache Society defines glossopharyngeal neuralgia as at least 3 attacks of unilateral pain located in the posterior tongue region, tonsillar fossa, pharynx, beneath the angle of the jaw, or the ear, with at least 3 of the 4 following characteristics:
(1) Recurring in paroxysmal attacks lasting from a few seconds to 2 minutes
Typically, the neurologic examination is otherwise normal.
Some authors have proposed distinguishing between pharyngeal, otalgic, and vagal subtypes of neuralgia and suggested using the term vagoglossopharyngeal neuralgia when pain is accompanied by asystole, convulsions, and syncope. Glossopharyngeal neuralgia is experienced in the distributions of the auricular and pharyngeal branches of the vagus nerve as well as in branches of the glossopharyngeal nerve. Prior to its development, unpleasant sensations can be experienced in aﬀected areas for weeks to several months (73).
Typically, the pain in glossopharyngeal neuralgia is brief and excruciating, with a potential underlying dull ache residual between the debilitating paroxysmal attacks. Some studies suggest the mean duration of the attack is 30 seconds. These paroxysms typically occur in the daytime and can recur over days, weeks, or months with remission for months or years. Swallowing is the most common trigger factor, and cold liquids can induce pain. Chewing, talking, sneezing, cleaning the throat, and touching the gums or oral mucosa, even sudden movements of the head, raising the arm on the side of the pain, and the lateral movement of the jaw may also trigger the paroxysms. Several patients found that touching the external auditory canal, the side of the neck, and the skin anterior to the ear triggered the pain on the same side (143).
Due to the relatively rare and atypical nature of this neuralgia, the trigger zone is often left unrecognized until much later in the disease course. Some patients can have the pain triggered by sweet, acidic, cold, or hot food. Associated symptoms, including tinnitus, vomiting, vertigo, and swelling sensation, are also described. Furthermore, some patients can have asystole, convulsions, and syncope in association with the glossopharyngeal neuralgia, and this condition is termed vagoglossopharyngeal neuralgia (143).
Most often, glossopharyngeal neuralgia is idiopathic, but it may frequently be associated with a neurovascular loop, vascular malformation, cerebellopontine angle mass, oropharyngeal tumor, arachnoiditis, stylohyoid ligament ossification (Eagle syndrome), multiple sclerosis, or a Chiari Type 1 malformation (143).
In terms of clinical course, patients with glossopharyngeal neuralgia can have clusters of attacks with spontaneous remissions. Similar to trigeminal neuralgia, it initially may respond well to carbamazepine but generally tends to be more refractory to pharmacotherapy, especially over time. Refractory patients with presumed secondary glossopharyngeal neuralgia may respond well to microvascular decompressive surgery. Due to the close proximity of the cranial nerves, the vagus nerve is also commonly involved; however, these symptoms can be further underreported due to the lack of awareness of the associated bradycardia or dysrhythmia or a lack of correlation made by the patient between the neuralgiform pain and other symptoms, such as syncope.
In a case series by Gaul and colleagues looking at 19 consecutive patients with glossopharyngeal neuralgia, 2 of 19 patients showed associated trigeminal neuralgia (117).
In general, if treatment is successful, whether it is by pharmacotherapy or by neurosurgical intervention, such as microvascular decompression, all the neuralgiform symptoms improve, including syncope, bradycardia, and trigeminal neuralgiform pain.
Nervus intermedius neuralgia. The clinical presentation of nervus intermedius neuralgia is varied. Classically, patients describe acute paroxysmal stabbing ice pick-like, or electric shock-like, pain deep within the auditory canal of the ear. Additionally, it can affect the more superficial structures of the ear, such as the pinna, retroauricular region, or oral structures including the soft palate, anterior two thirds of the tongue, or deep in the facial musculature. Pain can radiate at times to the angle of the mandible or the temple region. Attacks are usually intermittent and may last seconds to minutes. The trigger can be mechanical or sensory in nature, including touching the posterior wall of the auditory canal. The pain may be associated with disorders of lacrimation, gustatory sensation, and salivation. Salivation can be increased, taste may be perceived as bitter, and there can also be tinnitus, vertigo or loss of hearing (78; 148; 140).
There are 2 reports, one of a Swiss family and one of a Chinese family, with likely a familial geniculate neuralgia; one report suggests X-linked dominant inheritance of a causative trait (132; 162). Additionally, autosomal dominant inheritance has been speculated from family histories. There is one theory suggesting a mutation of the NAV 1.7 sodium channel with resulting nerve hyperexcitability (07).
Occipital neuralgia. The pain commonly begins in the suboccipital region and radiates over the vertex. It is characterized by paroxysmal stabbing or electric shock-type pain in the distribution of the occipital nerves (the greater occipital nerve, lesser occipital nerve, or third occipital nerve). It may be provoked by percussion or pressure over the occipital nerve. There are connections with cranial nerves VIII, IX, and X, and the cervical sympathicus, which can result in dysesthesia, hypoesthesia in the affected area, visual impairment, ocular pain, tinnitus, nausea, dizziness, and nasal congestion (34). Due to connections between the C2 dorsal root and the nucleus trigeminal subnucleus pars caudalis, the pain may also be felt retro-orbitally (Mason et al 2004). There is a study from 1978 showing that 90% of occipital neuralgia was in the greater occipital nerve distribution,10% in lesser occipital nerve, and 8.7% in both greater occipital nerve and lesser occipital nerve combined (69). Although the majority of cases are unilateral, many studies mention at least a third of occipital neuralgia patients with bilateral dysfunction (101).
Optic neuritis. Typical acute optic neuritis presents with subacute monocular vision loss and associated painful eye movement developing over hours to days with a typical nadir in vision by 14 days. The vision loss varies and includes reduced visual acuity, contrast acuity, and nonattitudinal visual field defects. The pain is typically mild, periocular, and exacerbated by movement. Dyschromatopsia is a common finding (53). Recovery begins within the first few weeks of symptoms and initially progresses quickly; however, slow improvements can continue for up to a year. The vast majority of patients make a good visual recovery with visual acuity of at least 20/40 or better despite some having residual deficits, including alterations in visual acuity, stereopsis, contrast sensitivity, and color vision. The majority have changes in pupillary reaction and visual-evoked potentials, and optic disc pallor is common despite even excellent recovery (53). Optic neuritis in the setting of suspected neuromyelitis spectrum disorders may have a more aggressive course, with up to 35% of patients having severe visual impairments noted in one Brazilian cohort (126). The clinical course of atypical causes of optic neuritis can include infection (eg, syphilis) or metabolic failure (eg, Leber hereditary optic neuropathy). Rheumatological disorders that can be associated with atypical optic neuritis include sarcoidosis, connective tissue disorders, and vasculitis (53).
Physical examination is consistent with optic neuropathy, with features including decreased visual acuity, color vision loss, visual field loss, and an afferent pupillary defect. An afferent pupillary defect may be difficult to recognize if there is involvement of the contralateral eye. Central scotomas are classically described; however, other visual field changes, including diffuse change and focal defects, can be seen. Altitudinal defects should raise concern for anterior ischemic optic neuropathy. Fundoscopy should be performed, and papillitis can be seen in one third of optic neuritis patients. Two thirds of patients with optic neuritis have no acute papillitis on fundoscopic examination, and they are said to have “retrobulbar” optic neuritis (17).
Headache attributed to ischemic ocular motor nerve palsy. Headache attributed to ischemic ocular motor nerve palsy is generally a unilateral frontal or periorbital headache that occurs concurrent with ischemic neuropathy of cranial nerves III, IV, or VI on the same side. This is nonspecific in terms of the cause of ischemia, the most common cause being diabetes. The pain may precede or accompany the onset of diplopia. Pain is most common with third nerve palsy, less so with sixth nerve palsy, and least often in fourth nerve palsy. In the ICHD-3, diagnostic criteria are as follows:
(A) Unilateral headache fulfilling criterion C
(1) Headache has developed in temporal relation to the motor nerve palsy
Tolosa-Hunt syndrome. At the clinical level, it this syndrome characterized by the presence or episodes of preorbital or hemicrania pain that generally precedes ophthalmoplegia; however, the episodes can occur at the same time. There can be an isolated paralysis of one nerve or multiple nerves, usually within the cavernous sinus. The sinus houses cranial nerves III, IV, and VI and the ophthalmic division of nerve V known as V1. Double vision is a common complaint, along with sensory loss in various facial areas. Cranial nerve III is most frequently reported to be affected, followed by cranial nerve VI, the V1 branch of cranial nerve V, and cranial nerve IV. In 20% of patients the sympathetic fibers are affected, causing Horner syndrome. There can also be parasympathetic involvement (33).
Less commonly, there is additional involvement with the maxillary and mandibular divisions of cranial nerve V, cranial nerve VII, and cranial nerve II. Some patients may have proptosis or ptosis. Inflammation involving the orbital apex can lead to optic nerve damage, with resulting disc pallor or swelling causing loss of visual acuity; although a rare occurrence, the vision loss is unpredictable and can be permanent.
The symptoms of this syndrome are usually unilateral, affecting only one side of the face; however, cases of bilateral involvement have been described (64).
A flare-up, or episode, can last up to 8 weeks without a therapeutic intervention (107). Tolosa-Hunt syndrome can last from a few months to several years; however, the condition is considered benign, and residual neurologic deficits are rare.
There are no documented cases of extension of neurologic symptoms. Some studies report nausea and vomiting, which are probably a result of the intense pain the patient experiences and tend to resolve with pain control. Chronic fatigue is reported (11).
Tolosa-Hunt syndrome appears to follow a similar course in children and adults. According to a clinical update, diagnostic approach and treatment require specific considerations, and further research is needed to optimize clinical detection and medical management in children with this disease (128).
Paratrigeminal oculosympathetic (Raeder) syndrome. Clinically, patients often describe a deep, piercing pain on the ipsilateral side, usually restricted to the ophthalmic division of the trigeminal nerve, at times with extension to the temporal, parietal, or maxillary region. These patients have signs of trigeminal nerve-ophthalmic division dysfunction, demonstrated by diminished corneal reflex. All patients essentially have ptosis and miosis as part of the oculosympathetic paresis, and less than one third of the patients have anhidrosis. Conjunctival injection, tearing, and blurry vision are also reported (145).
The International Headache Society’s latest 2013 guidelines outline the following criteria for Raeder syndrome:
(A) Constant, unilateral headache localized to the distribution of the ophthalmic division of the trigeminal nerve with or without spread to the maxillary division, aggravated by eye movement. The headache must develop in temporal relation to the underlying disorder.
(B) There must be imaging evidence of underlying disease of the middle cranial fossa or the ipsilateral carotid artery.
(C) Ipsilateral Horner syndrome
For cases with significant trigeminal nerve involvement in addition to the ophthalmic branch and potential other cranial nerve (often cranial nerve VI) involvement, a thorough investigation for other causes (eg, middle cranial fossa tumor), vascular etiology (eg, carotid dissection), or infectious etiology (eg, neurosyphilis) must be made as these cases tend to have a worse prognosis.
In cases where no organic cause is found, which is common, a benign course typically ensues with clinical resolution in 1 to 3 months, and follow-ups done between 8 months and 14 years showing no recurrence.
Recent studies show that the more common, benign idiopathic variant of Raeder syndrome is often associated with carotid disease--either carotid stenosis or carotid dissection. Case analyses also show a temporal association with mild head trauma or inflammatory disease, such as purulent sinusitis, pneumonia, tooth disease or abscess, other upper respiratory infection (145).
Burning mouth syndrome. Burning mouth syndrome is described as an intraoral sensation, often burning in quality, with no clear medical or dental cause. The pain is often similar to that seen in typical neuropathic dysesthesia. Many patients are free of pain at night or early in the morning, with pain that worsens throughout the day, but others have constant pain or other predictable schedules. In about half of patients, it starts spontaneously, but in about a third of patients, it is associated with a dental procedure or other medical trigger. There is no single pathognomonic sublocation or pattern to the pain as it does not follow the path of distribution of a single peripheral sensory nerve, but it frequently affects the anterior two thirds of the tongue, anterior hard palate, and lower lip. It may be accompanied by xerostomia (in 46% to 67% of cases, which can be objectively quantified) and dysgeusia (typically changes in the intensity of tastes or persistent foul tastes). In about half of cases, there is no identifiable precipitating factor; in approximately one third of patients it can be related it to a dental procedure, medication change, or infection. Once the pain starts, it tends to persist for a prolonged period of time with some daily fluctuation (02).
ICDH3 criteria for burning mouth syndrome:
A. Oral pain fulfilling criteria B and C
1. Burning quality
D. Oral mucosa is of normal appearance, and clinical examination, including sensory testing, is normal.
The International Association for the Study of Pain defines burning mouth syndrome as “burning pain on the tongue or other oral mucous membrane associated with normal signs and laboratory findings lasting at least 4 to 6 months” (14).
It has been proposed that one useful differentiating factor is the diurnal variation in symptoms. Type 1 represents pain that occurs daily but is not present on awakening and worsens throughout the day. Type 2 represents pain that occurs all day, every day and is most frequently linked to psychiatric factors including chronic anxiety; type 2 is felt to be the most resistant to treatment. Type 3 is pain that occurs intermittently and frequently involves unusual sites (potentially related to reactions to food additives). Considering this paradigm, it is felt that approximately 35% of burning mouth syndrome patients fit into type 1, 55% into type 2, and 10% in to type 3 (111).
Idiopathic facial pain. Persistent idiopathic facial pain often occurs in association with a minor dental or surgical procedure, which at times may precede the onset of pain and at other times may be pursued in an attempt to relieve the pain. Generally speaking, the neurologic examination should be normal; however, in quantitative analysis, decreased sensation may be apparent. The pain is often poorly localized, unilateral, and radiating but can be considered bilateral in up to 40% of cases. In character, it is often described as aching, burning, throbbing, and stabbing and usually ranges from 7 to 11 on a typical 10-point scale. Notably, the pain may be responsive to the emotional state of the patient; however, many patients may exhibit la belle indifference considering the severity of the pain that they report. The pain does not typically follow a dermatomal distribution, and location and character often change over time (26).
ICHD-3 criteria for idiopathic facial pain:
A. Facial or oral pain fulfilling criteria B and C
1. Poorly localized and not following the distribution of a peripheral nerve
D. Clinical neurologic examination is normal.
Recurrent painful ophthalmoplegic neuropathy. Originally mischaracterized as “ophthalmoplegic migraine,” it is felt that this does not represent migraine at all, but rather a recurrent painful neuropathy. The pain may precede the motor manifestations by up to 14 days and most often affects children, with an average age at onset of 10 years, although cases starting in infancy have been reported. More rarely, this can affect adults, and when it does so, the clinical presentation is similar. The motor paresis will often recover in anywhere from 4 to 84 days, but recurrent episodes may be associated with permanent motor changes (thought to be related to aberrant nerve regeneration). Most often, cranial nerve III is affected, but cranial nerves IV and VI can also be involved. The pain manifestation can be variable and mimic several different migraine variants. In addition to the ocular motor paresis, one important differentiating factor is the MRI, which will typically reveal enlargement and homogenous enhancement of the involved cranial nerve; findings may improve or resolve completely during periods of remission (Ambrosetto et al 2014).
ICHD-3 criteria for recurrent painful ophthalmoplegic neuropathy:
(A) At least 2 attacks fulfilling criterion B
Note that a single attack does not fulfill these criteria, but may be considered “probable Painful Ophthalmoplegic Neuropathy,” especially if accompanied by typical MRI findings (Ambrosetto et al 2014).
Central neuropathic pain. Central neuropathic pain can be described variably and includes burning, prickling, tingling, painful numbness, pin-and-needles, stabbing, shooting, and lancinating as well as tightness, squeezing, and swelling sensations. Chronic itching may be seen as a pain equivalent in a region with neurologic deficit. Timing should be either concomitantly or after neurologic insult, such as acute stroke in central post-stroke pain and acute demyelination in central neuropathic pain attributed to multiple sclerosis. The ICHD-3 diagnostic criteria requires central post-stroke pain to have occurred within 6 months after a stroke, with imaging demonstrating a vascular lesion in a clinically appropriate site (IHS Classification ICHD-3). The pain may occur immediately, but there is typically a delay of weeks to months. Cases of central post-stroke pain have been reported as far out as 3 or more years after original stroke, but these late-onset cases may be related to new unrecognized infarctions or other etiologies. Nonpainful sensory abnormalities may cooccur with the pain, and the pain may be paroxysmal or continuous. Craniocervical pain associated with a thalamic lesion may be associated with ipsilateral extremity pain, whereas hemifacial pain in lateral medullary lesions may occur in isolation but is more typically accompanied by contralateral body dysesthesias or pain (73).
Trigeminal neuralgia. Patients with idiopathic, classic trigeminal neuralgia can have periods of complete remission that can typically last for a few months; however, in some cases, remission can last for several years (Cruccu 2017). Autonomic symptoms, such as conjunctival injection or lacrimation, can occur in a small minority of trigeminal neuralgia patients; however, one must consider another potential diagnosis or conduct further neurologic workup to verify trigeminal neuralgia. Classic trigeminal neuralgia can respond well to oral medication treatment in a large percentage of patients; however, classic trigeminal neuralgia with concomitant persistent facial pain responds poorly to conservative treatment and to neurosurgical interventions. It is also less likely to be triggered by innocuous stimuli (73).
The presence of trigeminal sensory deficits or bilateral involvement of the trigeminal nerves are helpful for identification of patients with symptomatic trigeminal neuralgia.
There are only small case series reporting treatment outcomes in patients with multiple sclerosis, with a general tendency toward lesser efficacy with typical treatments in this population as compared to patients with classic trigeminal neuralgia (49).
In general, studies have shown that patients with chronic trigeminal neuralgiform pain experience more depression, anxiety, and functional limitations in their day-to-day life and work compared to healthy, pain-free control groups and even compared to other patients with atypical facial pain. There was no clear correlation between pain severity and degree of impairment in day-to-day functioning (74).
Glossopharyngeal neuralgia. Harris and colleagues reported that glossopharyngeal neuralgia could be associated with cardiac dysrhythmia and instability (72). Patients can have associated hypotension, secondary cerebral hypoxia, slowing of EEG activity, syncope, or convulsions due to reflex activation of the dorsal motor nucleus of the vagal nerve in response to glossopharyngeal nerve afferent stimulation. The cardiovascular phenomenon is seen during the pain attack or immediately following it.
A subset of patients with demonstrable cardiac manifestations and without typical neuralgic symptoms have responded very well to glossopharyngeal nerve avulsion or microvascular decompression. Such syndromes have been called non-neuralgic glossopharyngeal neuralgia, in recognition of the fact that glossopharyngeal nerve irritability may not always give rise to pain (143).
Optic neuritis. Prognosis and chance of recovery from a single episode of optic neuritis is good to excellent, with 90% of individuals having 20/40 or better vision in 1 year, which is slightly correlated with severity of visual loss at initial presentation. The recurrence risk of optic neuritis in either eye was 28% for patients in the optic neuritis treatment trial; optic neuritis was also associated with development of multiple sclerosis (122).
Headache attributed to ischemic ocular motor nerve palsy. There is no significant systematic review to provide guidance in terms of the ultimate prognosis; however, in greater than 50% of patients, the palsy will disappear within 3 weeks, and the pain may follow.
Tolosa-Hunt syndrome. Overall prognosis is favorable despite the fact that this syndrome can last many years. Resolution of pain episodes occurs with or without the typical steroid treatment; however, with treatment the symptoms resolve sooner.
Symptom improvement, especially pain relief, is usually seen 24 to 72 hours after starting steroids, with the majority of patients reporting improvement within 1 week. Cranial nerve palsies improve gradually and can take anywhere from 2 to 8 weeks for recovery. It is unusual to have residual deficits after steroid treatment (167; 15; 04).
Relapses tend to occur in about 40% to 50% of patients and can be ipsilateral, contralateral, or bilateral. Relapses are more common in patients who were young at the time of their first attack or episode. Every relapse should ideally be investigated with a full work up, as Tolosa Hunt syndrome is a diagnosis of exclusion. It is unclear as to whether steroids help prevent relapses (167).
Raeder syndrome. Raeder paratrigeminal syndrome has been divided into two subgroups. Type 1, associated with other cranial nerve involvement (other than the subjective trigeminal neuralgiform pain and oculosympathetic paresis), is often associated with a worse prognosis. Type 2, associated with the classic trigeminal neuralgiform pain and oculosympathetic paresis only, is almost always self-limited and has a more benign course. This has been attributed to minor head trauma, hypertension, perivasculitis. migraine headaches, and other inflammatory conditions (115).
Burning mouth syndrome. Although many cases are refractory to treatment, the average duration of burning mouth syndrome is 2 to 3 years. Overall, 30% to 50% of patients may improve to a degree spontaneously or have complete resolution (111), whereas in 30% of patients it may be permanent (156). Ultimately, the natural history is still not well defined and may vary based on the ultimate etiology.
Recurrent painful ophthalmoplegic neuropathy. Most often this is a self-limited condition, but with recurrent episodes, the motor paresis may become permanent (Ambrosetto et al 2014).
Herein we present the fictitious case of a 49-year-old woman who was referred to us by her otolaryngologist with a prior medical history of a right lower extremity deep vein thrombosis felt to be related to oral contraceptive use, hypertension, and herpes zoster affecting the left forehead.
She presented with a 2-year history of paroxysmal stabbing pains deep in the ear on the left-hand side. She described the pain as stabbing, electric shock-like, and lancinating and at times radiating to the angle of the jaw, the back of the throat, or to the occipital region on the affected side. The pain was typically short-lived, lasting most often from 30 to 45 seconds but occasionally for a few minutes. She found the pain extremely debilitating. She reported triggers including facial stimulation on the affected side as well as cleaning the ear on the affected side; she was uncertain whether or not swallowing was a consistent trigger for pain. She denied any associated symptoms other than the debilitating pain, which as 11/10 in intensity. She reported that these episodes came in clusters that lasted for several months of hypersensitivity and then would spontaneously remit for a few months with no clear annual pattern.
On examination, her cranial nerves were symmetrically intact bilaterally with the exception of decreased sensation in the region anterior to her ear on the left-hand side and a degree of allodynia at the level of the mastoid process on that side. She had no nystagmus, with a normal head impulse test, and no other clear evidence of vestibulopathy. Her neurologic examination was otherwise nonfocal.
Her initial diagnostic evaluation consisted of an MRI of the brain with and without contrast with thin cuts through the internal auditory canal or cerebellopontine angle. Additionally, she had an MRA of the head and neck. Serum evaluation included a CBC, comprehensive metabolic panel, sedimentation rate, C-reactive protein level, Zoster titer, Lyme western blot with reflex to PCR, and an ANA with reflex to double-stranded DNA. The studies were all unremarkable, with the exception of a 3 mm left posterior communicating artery aneurysm, which was felt to be incidental. She was evaluated by vascular neurosurgery who confirmed that this aneurysm likely was not causative in terms of her pain and did not require surgical clipping or coiling.
She was given a presumptive diagnosis of nervus intermedius syndrome, and the decision was made to treat her symptomatically. An initial trial with carbamazepine unfortunately yielded intolerable side effects, as her sodium dropped to 119 after 3 weeks of treatment with no significant relief. She was then transitioned to gabapentin 300 mg twice daily and 600 mg at bedtime, which decreased the frequency and severity of her episodes of pain as well as provided assistance with sleep. Further increases in gabapentin unfortunately yielded significant somnolence, which was prohibitive while she was working. Protriptyline was added at a dose of 5 mg taken in the morning. This was effective at helping to relieve her additional pain, but she experienced significant palpitations. She was transitioned to nortriptyline 10 mg taken at bedtime with significant relief. She was maintained on the combination of gabapentin and nortriptyline for 2 years, after which a trial off her medication was performed. Unfortunately, she had a relapse within approximately 4 months and returned to treatment quickly, resulting in a plan for long-term medication management.
Trigeminal neuralgia. Classic trigeminal neuralgia is caused most often by neurovascular compression, typically by a redundant or tortuous loop of the superior cerebellar artery (Cheshire 2015). Over time, a pulsatile indentation induces a focus of demyelination, which leads to aberrant discharge of the nerve spontaneously or in response to a normally innocuous afferent stimulus. Studies show that demyelination of primary sensory trigeminal afferents in the dorsal root entry zone is the predominant pathophysiology. This may occur secondary to neurovascular contact; predominantly, however, a space-occupying lesion can compress the trigeminal nerve root and, thus, produce similar symptomatology. MRI may reveal neurovascular contact of the trigeminal nerve root. In a meta-analysis of double-blinded and controlled studies, neurovascular contact was found in 471 of 531 symptomatic patients and in 244 of 681 asymptomatic patients, thus, suggesting an increased sensitivity but low specificity in this regard. The presence of nerve dislocation or atrophy increased specificity to 97%. In addition, inflammatory activity might be one mechanism. Immunological protein levels, such as TRAIL and TNF-β, in the cerebrospinal fluid from patients with trigeminal neuralgia decreased after microvascular decompression surgery (52).
The incidence of trigeminal neuralgia itself increases with age, with an incidence of 4 to 13 per 100,000 persons per year, with a large part of the cases reported after the age of 50 years (110). Epidemiological studies suggest incidence of 16.3 to 30.6 in patients older than 80 years (152).
In cases of trigeminal neuralgia caused by multiple sclerosis, the age of onset is typically much younger, and patients with multiple sclerosis have 20-fold increased risk of trigeminal neuralgia than the general population. Whereas idiopathic or neurovascular trigeminal neuralgia is almost always (97%) unilateral, when trigeminal neuralgia occurs in multiple sclerosis, it may be bilateral in up to 30% of patients (Cheshire 2015). The mechanism of injury in this population is a proposed “double crush” phenomenon, with the formation of a pontine plaque and neurovascular compression both playing a role (49).
Glossopharyngeal neuralgia. Vascular compression of the nerve root entry zone is thought to cause demyelination and ephaptic transmission, similar to trigeminal neuralgia. Alternatively, it may cause repetitive activation of primary afferents in the nerve, causing hyperexcitability in central neurons. Activation of N-methyl-D-aspartic acid receptor has been invoked as a possible factor (127).
Intense irritability and hyperstimulation of glossopharyngeal nerve feedback onto the nucleus of the tractus solitarius of the midbrain and via collaterals reach the dorsal motor nucleus of the vagus nerve. The activation of this abnormal loop during severe neuralgic pain would be responsible for heightened vagal response, such as cardiac dysrhythmia, bradycardia, and hypotension (143).
Sophisticated MRIs have suggested that neural grooving, distortion, or deviation are more likely to cause neuralgia. As with trigeminal neuralgia, however, precisely how pain is caused and relieved is an incompletely resolved question (127).
Clinically, it is important to exclude secondary causes that can compress or irritate the glossopharyngeal nerve, resulting in neural hyperexcitability and neuralgia, such as tumor, mass, abscess, vascular malformation, or a demyelinating plaque. One possible cause is Eagle syndrome, or stylalgia, in which the glossopharyngeal nerve is compressed by an elongated styloid process (greater than 25 mm) or calcification of the stylohyoid ligament; thickening or ossification of those structures may be more important as an occasional cause of glossopharyngeal pain, often treated by stylectomy (127).
Nervus intermedius neuralgia. The cause of nervus intermedius neuralgia appears to be varied and poorly understood. Vascular compression of the nervus intermedius in its entry zone of the brainstem is widely reported as an etiology (78); there is no consensus, however, that this is the primary etiology. Vascular compression of the root entry zone of the eighth and ninth cranial nerves is also implicated (22). According to one paper, this compression leads to demyelination at the root entry zone (140). In cases where vascular compression does not exist, the etiology of the pain remains unknown. The vascular structures that more commonly are the culprits for compression are the anterior inferior cerebellar artery, vertebral artery branches, and the posterior inferior cerebellar artery. The anterior inferior cerebellar artery is usually the main culprit.
Herpes viral infection at the geniculate ganglion, known as Ramsay Hunt syndrome, is another cause in which, in addition to the nervus intermedius neuralgia, there are vesicles of the herpes zoster infection located in the external auditory canal. This is the same virus that causes chickenpox and shingles (67).
The main difficulty in understanding this condition is that there is overlapping innervation of the ear as otalgia can arise from cranial nerves V, VII, IX, X, or the occipital nerves. Additionally, there are peripheral anastomotic connections between the cranial nerves supplying the craniofacial region (cranial nerves V, VII, IX, X, and the 2nd and 3rd cervical nerves). The diagnosis is, therefore, often difficult and not definitive (36).
In one case report, a patient had a synchronous presentation of trigeminal, glossopharyngeal, and geniculate neuralgias with the superior cerebellar artery compressing the trigeminal root zone and the anterior inferior cerebellar artery in close proximity of the cranial VII/VIII complex (76).
Another case report describes laryngeal neuralgia combined with intermediate nerve neuralgia (170), and another report describes a case wherein epicrania fugax lead to both migraine without aura and nervus intermedius neuralgia while spreading over the nervus intermedius (161).
Occipital neuralgia. Occipital neuralgia is most commonly idiopathic. There are various secondary etiologies (50). In one study of 55 patients, 44% had an idiopathic etiology, followed by posttraumatic 27%, postsurgical 22%, postcerebrovascular accident 4%, postherpetic 2%, and postviral 2% (59).
Arthritic changes in the spine, such as atlantoaxial lateral mass osteoarthritis, can cause compression of the upper cervical roots with compression of the C2 nerve root being a key culprit postsurgery. Fibrositis, myositis, Chiari malformation, trauma (eg, whiplash), cervical cord tumor, dural arteriovenous fistulas, cervical cord cavernous angiomas, multiple sclerosis, and infectious etiologies (eg, hypertrophic cervical pachymeningitis and neurosyphilis) can also cause occipital neuralgia (50; 35). Furthermore, vascular etiologies (eg, giant cell arteritis), neurogenic etiologies (eg, C2 schwannoma), muscular or tendinous etiologies, and osteogenic mechanisms have been reported. Occipital neuralgia can rarely be mimicked by upper cervical myelitis. Any stretching or entrapment of the occipital nerve from the second cervical vertebra (C2) to the outlet of the nerve from the occipital muscle can evoke chronic pain. Myofascial spasm has been described as an explanation for the entrapment and irritation, and there is literature describing the occipital nerves undergoing irritation by chronically contracted muscles. Everyday activities that compress the occipital nerve have been reported to cause occipital neuralgia (42; 50).
Postoperative occipital neuralgia after posterior upper cervical spine surgery can cause significant morbidity. Posterior upper cervical spine surgery, such as atlantoaxial or occipitocervical fusion, is commonly used to treat diseases in the occipitocervical region (66). According to Janjua and colleagues, posterior C1-C2 fusion is a highly successful treatment, with fusion rates approaching 95% to 100% (83). It is explained that poor visualization of the lateral masses of C1 secondary to the course of the C2 nerve root along with blood loss from the venous plexus and compression of the C2 nerve from lateral mass screws are technical obstacles that can arise during surgery.
A systematic review of 16 articles found that of the 591 total patients identified to have postoperative occipital neuralgia, 93% had undergone C1 lateral mass screw (C1LMS) fixation and 7% had undergone occipitocervical fusion without C1 fixation. This review found that after posterior upper cervical spinal surgery, postoperative occipital neuralgia had an incidence ranging from 1% to 35% and was transient in 34% but persistent in 66%. In some cases, the exact cause of postoperative occipital neuralgia could be identified, and in cases that it could not, it was seen that the resulting refractory neuralgia can last for years. Possible causes include excessive manipulation and traction of the dorsal ganglion during surgery, irritation of the C2 nerve root by C1LMS, instrumentation or lamina decompression, nerve root transection, and overgrowth of implanted bone.
Long-term compression of the C2 nerve has been reported to produce reactions at the dorsal root ganglion and spinal cord, which can eventually induce chronic pain. These reactions include microglia proliferation, inflammation, neurotransmitter changes, cytokine responses, and ionic channel changes (169).
There is a convergence of the nociceptive information from trigeminal and upper cervical regions at the second order neurons level known as the trigeminocervical complex (130). This connection is one of the reasons why it is difficult to identify occipital neuralgia from other headache etiologies. Occipital neuralgia can provoke a migraine or be a late complication of it. One study showed that out of 383 patients with a migraine diagnosis, 184 (48%) had headaches caused by irritation of the greater occipital nerve, which could be eliminated by injecting the nerve with local anesthetic (13). There is a growing acceptance that irritation of the occipital nerves can produce referred pain in various cranial structures in the distribution of the C2 nerve roots from which the greater occipital nerve and lesser occipital nerve arise, but also within other nerves including the v1 or ophthalmic division of the trigeminal nerve. Neurons that provide afferent nociceptive input from the meninges and cervical structures synapse with relay neurons in the trigeminocervical complex. The relay neurons serve as the neural substrates of head pain. This trigeminocervical complex is the mechanism by which irritation of the occipital nerves can be associated with migraines (21).
Occipital neuralgia appears to be a multifactorial problem in which multiple anatomic areas or structures may be involved with the pathology (35).
Optic neuritis. The pathophysiology of optic neuritis depends on the primary etiological cause. The most common is demyelination. Demyelinating optic neuritis is presumed to be mediated by activation of microglia and a mixed humoral and T-cell mediated response. There are significant similarities to acute multiple sclerosis lesions with inflammatory demyelination causing conduction block and visual loss. Acute inflammation abates, and recovery ensues in a few weeks. Imperfect remyelination occurs, and sodium channels are redistributed over demyelinated segments (53; 25). Multiple modalities have emerged to delineate structure and electrophysiological damage associated with optic neuritis, including spectral domain OCT, scanning laser polarimetry, diffusion tensor imaging, multifocal visual-evoked potentials, and multifocal electroretinography (25).
Raeder syndrome. The pathophysiology of Raeder syndrome often involves oculosympathetic paresis due to involvement of the sympathetic fibers distal to the bifurcation of the common carotid artery, noted clinically by ptosis and miosis. If the lesion occurs proximal to the bifurcation, a complete Horner syndrome results because sweat fibers accompany the external carotid artery while the fibers destined for the pupil and eyelids travel with the internal carotid artery.
If a secondary cause for Raeder syndrome is found, involvement of the trigeminal nerve and oculomotor nerve can occur intracranially based on the location of the lesion. For instance, in the case of the first patient described by Raeder in 1924, autopsy revealed a skull-based tumor between the Gasserian ganglion and the hypophyseal stalk. In this particular case, the oculomotor and abducens nerves were deviated by the tumor, accounting for the patient’s diplopia. The internal carotid artery was encroached by the tumor, accounting for the involvement of the sympathetic fibers. The Gasserian ganglion was pushed laterally, explaining the trigeminal neuralgiform pain and the weakness of pterygoid muscles (139).
Cases of internal carotid artery dissection have shown selective damage of A-delta ﬁbers of the ophthalmic part of trigeminal nerve, conﬁrmed by eliciting the nociception speciﬁc blink reﬂex (nBR) with a new concentric electrode that selectively recruits cutaneous trigeminal A-delta ﬁbres and is, therefore, speciﬁc to changes in trigeminal nociception (89).
Burning mouth syndrome. Several conditions have been historically implicated as having a causal association with burning mouth syndrome. In their 2012 review, Aggarwal and Panat divided etiologic factors for so-called secondary burning mouth syndrome into 3 main categories. Local factors include poorly fitting prosthesis, dental treatments, para functional habits (clenching, bruxism, etc), contact stomatitis, infections, and xerostomia or salivary gland dysfunction. Systemic factors include endocrine disorders such as diabetes, vitamin deficiencies (B12, B6, folic acid, zinc), anemia, Sjogren syndrome, gastroesophageal reflux, and medications (antihistamines, neuroleptics, antiarrhythmics, benzodiazepines, and some antihypertensives including Ace inhibitors). Psychological disorders are considered a 3rd category and could include anxiety, depression, compulsive disorders, etc.
There are 3 main theories regarding the cause of primary burning mouth syndrome, including peripheral small fiber neuropathy, trigeminal neuropathy, and central dopaminergic (pain modulation pathway) nerve dysfunction. Trigeminal small-fiber neuropathy may be contributory in 20% to 25% of cases of primary burning mouth syndrome (111), co-occurring with abnormalities of blink reflex. In one study, it was suggested that 25% to 36% of primary burning mouth syndrome patients may have striatal dopamine deficiency, pointing to a more central cause (111). Other evaluations have uncovered high levels of neural growth factors in saliva, alterations in capsaicin (TRPV1) receptors or central pain receptors (P2X3), and changes in the central response to heat stimulus (156). In one retrospective large dataset in Taiwan, both obstructive sleep apnea and non-apnea sleep disorders were significantly associated with burning mouth syndrome. Another study showed that patients with primary burning mouth syndrome often had poor sleep quality and experienced daytime somnolence (111).
Attempts have been made to differentiate or classify patients with burning mouth syndrome into categories using various criteria, such as primary versus secondary burning mouth syndrome or based on daily fluctuation of symptoms (02).
Idiopathic facial pain. Considering its association with minor trauma, persistent idiopathic facial pain is felt to exist along a continuum with painful traumatic trigeminal neuropathy. Studies have demonstrated changes in excited tori responses in the brainstem as well as in the descending dopaminergic pain modulation pathway. In some patients, there may be alterations in blink reflexes (26). Ultimately, it may be akin to certain types of complex regional pain syndrome, which can occur after minor trauma but result in significant neuropathic pain.
Recurrent painful ophthalmoplegic neuropathy. At this point, the pathophysiology of recurrent painful ophthalmoplegic neuropathy is not completely understood. There have been several theories regarding the ultimate cause of painful ophthalmoplegic neuropathy, including vascular compression, nerve infarction, and “pituitary swelling,” but none of these have been borne out. The edema and enhancement of the involved cranial nerve suggests disruption of the blood-brain barrier, which is likely transient considering the radiographic resolution and clinical recovery. More current theories include viral infection (akin to that which is considered to cause Bell palsy at times, but like Bell palsy there is often “no preceding or concurrent viral illness,” and CSF is normal), recurrent demyelination, or bouts of vasospasm leading to ischemic breakdown of the blood-brain barrier (Ambrosetto et al 2014).
Central neuropathic pain. Central neuropathic pain may be related to any insult to the brain or spinal cord. It can result from any insult to the central nervous system, including postinfectious, posttraumatic, neoplastic, vascular (ischemic or hemorrhagic) insults, or demyelination. Mechanisms are poorly understood. Although etiologies of the primary neurologic insult differ, the underlying pain mechanisms may be similar, and the clinical characteristics of central post-stroke pain can resemble other central and peripheral neuropathic pain syndromes. There is little correlation between treatment response and mechanism, location, lesion pathology, and clinical manifestations (93).
Trigeminal neuralgia. The most common cranial neuralgia involves the trigeminal nerve (cranial nerve V). Onset is most often after the age of 50 years, and its incidence increases with advancing age. The incidence ranges from 12.6 to 26.8 per 100,000/year, with the incidence increasing with age (16.3 in the fourth decade, 30.6 in patients older than 80 years). Women are affected 1.7 times more often than men (Cheshire 2015).
Glossopharyngeal neuralgia. Glossopharyngeal neuralgia is a rare condition, occurring with a frequency of about 1% of that of trigeminal neuralgia. Its reported incidence is approximately 0.8 per 100,000 people; however, this is suspected to be underreported because it is commonly unrecognized. It often occurs in individuals over the age of 40 and more often in the sixth decade of life. There is no clear male or female predominance.
Nervus intermedius neuralgia. Nervus intermedius neuralgia is extremely rare, and precise data regarding its prevalence are not available. It tends to affect middle-aged patients and is more common in women than in men. According to one paper, the number of cases found between 1932 to 2012 was less than 150 (148).
Occipital neuralgia. The incidence and prevalence of occipital neuralgia is unknown. There is one study by Koopman and colleagues that was cited by Jeon and Choi in a 2016 paper on occipital neuralgia (94; 38). The study reported a low incidence of 3.2 per 100,000 people, with female predominance. It was also mentioned that there was no time or seasonal variation found.
Optic neuritis. Two thirds to three quarters of patients with optic neuritis are women, with typical age of onset between 20 and 40 years. Incidence of unilateral optic neuritis ranges from 0.94 to 1.18 per 100,000 people (53). This may be an under-representation, however, with greater awareness and evolving diagnostic criteria. Additional studies out of Spain suggest a mean incidence rate of 5.36 cases per 100,000 person years, a rate much higher than previously reported (108).
Headache attributed to ischemic ocular motor nerve palsy. The actual incidence of headache attributed to ischemic ocular motor nerve palsy is not well defined. The most common palsy is of the sixth cranial nerve (60%, with 20% each for the third and fourth cranial nerves); however, palsy of the third cranial nerve is more frequently painful.
Tolosa-Hunt syndrome. The estimated incidence is 1 to 2 cases per million people worldwide (03). According to the National Organization for Rare Disorders, Tolosa-Hunt syndrome presents equally between men and women, with the average age of onset being 41 years of age, but some cases before the age of 30 years have been documented along with sporadic cases of children under the age of 10 years.
Although usually unilateral, either side can be affected, and there have been case reports about bilateral involvement (approximately 5%). There is no male-to-female predisposition (149).
Because Tolosa-Hunt syndrome rarely causes sequelae and because it shows a course with a good prognosis in general and limits itself, it does not receive much attention. Because most of the cases are not diagnosed or are misdiagnosed, the frequency of Tolosa-Hunt syndrome in the literature has been reported to be low (04).
Raeder syndrome. Raeder syndrome has a higher incidence in the male population, affecting middle-aged and older men, typically over the age of 50 years. Given the rarity of the disease, the exact incidence in the United States or the world could not be noted in literature review.
Burning mouth syndrome. Burning mouth syndrome has a reported prevalence ranging from 0.6% to 15%, affecting women more than men (anywhere from 3:1 to 16:1), most typically in the fifth to seventh decade with a mean age of 55 to 60 years old. In both men and women, the prevalence seems to increase with age. The prevalence is particularly high in peri- and postmenopausal females, up to 12% to 18% (02; 14). There is an apparent association with sleep disorders, including both obstructive sleep apnea and non-apnea sleep disorders, which was evaluated in a retrospective national health insurance database in Taiwan, although no clear causal association has been proposed or evaluated (98). Patients with burning mouth syndrome have a higher rate of depression and anxiety as well as type C personality disorders (Jaaskelainen and Woda 2017).
Idiopathic facial pain. Epidemiology is difficult to characterize because persistent idiopathic facial pain previously represented a rather “catch-all” diagnosis. Lifetime prevalence is felt to be approximately 0.03% with in incidence rate of 4.4 per 100,000 persons per year. It may be seen rather frequently in dedicated oral facial pain clinics and neurologic tertiary care centers. There appears to be a female predominance, with a mean age of onset in the mid 40s (26).
Recurrent painful ophthalmoplegic neuropathy. This is a rare condition with an estimated annual incidence of 0.7 per million. It most often occurs in infancy or childhood, with an average age of onset of 10 years, but can also affect adults. There is no clear male-to-female predominance (Ambrosetto et al 2014).
Central neuropathic pain. Almost 800,000 strokes occur annually in the United States, and the overall incidence of central post-stroke pain is unclear, somewhere between 8% and 45.8%. Of all strokes that include somatosensory deficits, up to 18% develop central post-stroke pain (12; 121; 155). Central post-stroke pain is by far the most common cause of central neuropathic pain. Age, sex, and lesion laterality are not consistent predictors of central post-stroke pain. Central pain can also be seen in multiple sclerosis. In a Swedish study of 429 definite patients with multiple sclerosis, 27.5% had central pain, including 4.9% with trigeminal neuralgia. Data on facial pain in isolation other than trigeminal neuralgia are limited (12; 123).
Trigeminal neuralgia. The differential diagnoses for trigeminal neuralgia and its subtypes are broad.
Dental pain. Ideally, one must exclude dental pain secondary to a structural cause or infection. The majority of dental pain is acute, and most are likely to be unilateral and located within the mouth. A lighted examination of the teeth, the attached gingiva, and the soft tissues of the oral mucosa typically elucidate a cause in these cases, such as a cracked tooth or a periodontal abscess. Diseases of the oral mucosa are painful and will be associated with a lesion, such as lichen planus, herpes zoster, herpes simplex, or recurrent oral ulceration.
Maxillary sinusitis. Another differential diagnosis is maxillary sinusitis; however, this is often acute secondary to a bacterial or viral cause. It can also occur secondary to a dental infection or a dental extraction procedure. Pain in this case would resolve after sinusitis treatment.
Temporomandibular joint disorders. Temporomandibular disorders must be excluded, as these can result in acute or chronic pain. A careful history needs to be elicited, and the chronic temporomandibular disorders are often associated with fibromyalgia, headache, and back pain as well. In the acute setting, temporomandibular disorders can occur after dental treatment or trauma. Patients have associated limited jaw opening, crepitus, clicking of the jaw, or muscle pain involving the neck and muscles of mastication. The symptoms here are improved with soft diet and analgesics.
Salivary duct blockage. Tumors, duct blockage, and subsequent infection of the salivary glands can also elicit pain in the trigeminal nerve distribution. The pain is intermittent and characteristically occurs just before eating. There may be associated tenderness of the involved salivary gland. Bimanual palpation will enable the stone to be palpated. If it is in the duct, then salivary flow from the duct will be slow or absent. Imaging and ultrasound are useful, and referral for further management to oral or maxillofacial surgeons is indicated.
Trigeminal autonomic cephalgias. Trigeminal autonomic cephalgias are a group of unilateral episodic pains, some of which can easily be mistaken for trigeminal neuralgia. These include short unilateral neuralgiform pain with conjunctival injection, tearing, and redness (SUNCT); and short unilateral neuralgiform pain with cranial autonomic features (SUNA) (eg, unilateral tearing, meiosis, sweating, nasal blockage or rhinorrhea, and ear fullness). Detailed history and the prominent associated autonomic symptoms help differentiate this from the classic trigeminal neuralgia and its other variants.
Glossopharyngeal neuralgia. Given the location of the pain, trigeminal neuralgia involving the mandibular branch can be confused with glossopharyngeal neuralgia.
Most often, glossopharyngeal neuralgia is idiopathic, but it may frequently be associated with a neurovascular loop, vascular malformation, cerebellopontine angle mass, oropharyngeal tumor, arachnoiditis, stylohyoid ligament ossification (Eagle syndrome), multiple sclerosis, or a Chiari Type 1 malformation (143).
Nervus intermedius neuralgia. There are many conditions that can mimic nervus intermedius neuralgia.
Trigeminal neuralgia (3rd division, mandibular branch), glossopharyngeal neuralgia, Jacobson neuralgia. The most common differential diagnoses include trigeminal neuralgia (3rd division mandibular branch) and glossopharyngeal neuralgia. Jacobson neuralgia is a form of glossopharyngeal neuralgia where the tympanic branch of this nerve causes ear pain and can easily be mistaken for nervus intermedius (148). In general, pain characteristics are similar among the nervus intermedius, trigeminal, and glossopharyngeal neuralgias, but the location and distribution help differentiate between them (76). Other conditions include temporomandibular joint dysfunction, nasopharyngeal carcinoma, petrous bone osteoma, neuroborreliosis, multiple sclerosis, intracranial lesions in the cerebellopontine angle, dental lesions, otitis externa, otitis media, and malignancies of the pinna, external auditory canal, and temporal boneEagle syndrome is another mimicker. Additionally, salivary gland pathology and migraine headaches can present similarly to nervus intermedius neuralgia (22).
Occipital neuralgia. There is overlap in presentation between occipital neuralgia and other headache disorders. Mimickers include migraine, cluster headache, tension headache, hemicrania continua, C2 neuralgia, temporal arteritis, and postherpetic neuralgia. C2 neuralgia is more likely to have ipsilateral lacrimation and ciliary injection. Cervicogenic headache is also in the differential but presents as a dull, achy occipital pain and results from referred pain from structures innervated by the first 3 upper cervical spinal nerves, such as the atlantoaxial joints, zygapophyseal joint, and C2-C3 intervertebral disc. Cervical medial branch blocks can help distinguish if the neck pain originates in these zygapophyseal joints (31; 50).
Optic neuritis. Differential diagnosis is broad and includes ischemic optic neuropathy (nonarteritic and arteritic), optic nerve compression, Leber hereditary optic neuropathy, toxic optic neuropathy, drug-induced optic neuropathy, nutritional optic neuropathy, infectious optic neuropathy (Lyme disease, viral syndromes including HIV, Epstein-Barr virus, cytomegalovirus), toxoplasmosis, bacterial infection (tuberculosis, bartonella), neuroretinitis, traumatic optic neuropathy, retinopathy, central retinal artery or vein occlusion, uveitis, chorioretinitis, closed angle glaucoma, herpes simplex keratitis, posterior scleritis, orbital cellulitis, optic perineuritis, or functional impairment (12).
Headache attributed to ischemic ocular motor nerve palsy. The differential diagnosis of headache attributed to ischemic ocular motor nerve palsy is more related to determining the etiology of the motor nerve palsy itself.
Tolosa-Hunt syndrome. This collection of signs and symptoms can be caused by a large number of etiologies including vascular diseases, traumatic events, tumor, infectious/inflammatory processes, migraine, and diabetic neuropathy to name a few with the full list below. Because it is very rare, the majority of patients who present with painful ophthalmoplegia will not have Tolosa-Hunt syndrome.
Painful ophthalmoplegia is essentially a result of a mass effect produced in the cavernous sinus, which can be caused by many processes. Tolosa-Hunt syndrome is ultimately a diagnosis of exclusion (15; Ilgen Uslu Ozkan 2015; 04; 11).
Clinicians should be aware of the differential diagnoses for painful ophthalmoplegia given that Tolosa-Hunt syndrome is less likely. Such causes include trauma, vascular (intracavernous carotid artery aneurysm, posterior cerebral artery aneurysm, carotid-cavernous fistula, carotid-cavernous thrombosis, posterior communicating artery aneurysm, basilar artery aneurysm, internal carotid artery dissection). Additionally, various masses include neoplasm, primary intracranial tumor, pituitary adenoma, meningioma, craniopharyngioma, primary cranial tumor, chordoma, local and distal metastases, nasopharyngeal tumor, squamous cell carcinoma, and lymphoma. Additional diagnoses include multiple myeloma, carcinomatous metastases, inflammation, bacterial infection, contiguous sinusitis, mucocele (sphenoid sinus), periostitis, abscess, viral, herpes zoster, fungal, mucormycosis, actinomycosis, spirochetal, treponema pallidum, mycobacterial, mycobacterium tuberculosis, sarcoidosis, Wegener granulomatosis, eosinophilic granuloma, orbital pseudotumor, diabetic ophthalmoplegia, ophthalmoplegic migraine, and giant cell arteritis (04).
Meningioma and diabetic ophthalmoplegia do not respond to steroid treatment. Steroid response as improvement clinically, as well as radiologically, is known to occur with other disease processes such as malignancies, infection, or vasculitis; therefore, steroid response cannot be assumed to be Tolosa-Hunt syndrome without full workup.
An angiographic procedure is necessary for the diagnosis of Tolosa-Hunt syndrome and to exclude aneurysms of the intracavernous carotid artery and posterior cerebral artery.
Raeder syndrome. Differential diagnosis for Raeder syndrome is broad. One must consider diseases of the carotid artery, including carotid dissection, occlusion, inflammation, and fibromuscular dysplasia. In the largest review of carotid dissection to date, Biousse and associates reported Horner syndrome with ipsilateral head pain in 65 of 146 cases (44%), with this being the only presenting feature in half of the patients (30).
Often in the past, especially prior to the 1950s, cluster headache, paroxysmal hemicrania, hemicranias continua, and Tolosa-Hunt syndrome were inaccurately identified as Raeder syndrome.
Unlike Raeder syndrome, cluster headache, paroxysmal hemicrania, and hemicrania continua have significantly more severe, short-lived pain, are recurrent, and almost as a rule are associated with autonomic features such as conjunctival injection, tearing, rhinorrhea, or nasal congestion.
Unlike Raeder syndrome, Tolosa-Hunt syndrome has a characteristic ophthalmoplegia as well as involvement of several other cranial nerves--once again not noted in Raeder syndrome (73).
A middle cranial fossa lesion must be considered.
Burning mouth syndrome. Primary burning mouth syndrome is considered a clinical diagnosis and a diagnosis of exclusion. Secondary burning mouth syndrome is felt to be related to a potentially wide variety of etiologic factors, including abscess stomatitis, infections (herpes, candida, HIV, zoster, Coxsackie virus), tumors, autoimmune disease, atrophic glossitis, allergic contact stomatitis, dental prostheses, endocrine disorders (diabetes, thyroid disease), hormonal changes (eg, menopause), and psychiatric disorders (111).
Persistent idiopathic facial pain. Persistent idiopathic facial pain is often considered a diagnosis of exclusion. Many patients with persistent idiopathic facial pain may have been previously diagnosed as having myofascial pain, atypical trigeminal neuralgia, facial migraine, or an atypical trigeminal autonomic cephalgia (26).
Recurrent painful ophthalmoplegic neuropathy. There are several important diagnostic considerations. Compression from a vascular source (aneurysm, arteriovenous malformation, etc.) should be ruled out by imaging. It may be confused with Tolosa-Hunt syndrome; however, Tolosa-Hunt syndrome often will have more extensive nervous system involvement with soft tissue enhancement on MRI.
Central neuropathic pain. By ICHD-3 criteria, central post-stroke pain and central neuropathic pain attributed to multiple sclerosis should not be better accounted by another diagnosis. This may be broad; peripheral neuropathic pain mechanisms and other painful cranial neuropathies should be considered as well as musculoskeletal or joint pain. A lack of correlating lesion on imaging should lead to suspicion of other etiologies.
Trigeminal neuralgia (Classic trigeminal neuralgia). Classic trigeminal neuralgia is caused most often by neurovascular compression, typically by a redundant or tortuous loop of the superior cerebellar artery (Cheshire 2015). Classic symptoms may also be induced by multiple sclerosis plaques.
Trigeminal neuralgia, type 2 (Atypical trigeminal neuralgia).
Acute herpes zoster
Intracranial mass lesions
Multiple sclerosis plaque
Posttraumatic trigeminal neuropathy (anesthesia dolorosa)
Intracranial mass lesions
Multiple sclerosis plaque
Stylohyoid ligament thickening
Nervus intermedius neuralgia.
Lesions of the temporal bone
Intracranial neurovascular compression
Lesions in the cerebellopontine angle
Traumatic neck injury
Osteoarthritis of the spine
Spinal mass lesions
Dural arteriovenous fistulas
Cervical cord cavernous angiomas
Giant cell arteritis
Trigeminal neuralgia. Trigeminal neuralgia is diagnosed on the basis of typical history and clinical features. Neurologic examination is often normal, other than potential allodynia or hyper- or hypoalgesia in the trigeminal nerve distribution ipsilateral to the facial pain. Although there are no specific investigations to confirm the diagnosis, a contrast-enhanced MRI with thin cuts through the trigeminal nerve is highly recommended to look for potential causes such as cerebellopontine angle meningiomas, schwannomas, pontine gliomas, arteriovenous malformation, saccular aneurysms, or multiple sclerosis plaques and solitary pontine lesion (150) that would contribute to symptomatic trigeminal neuralgia. A cause may be identified in up to 15% of patients through these investigations. This is important to note, as no clinical features have been shown to exclude secondary trigeminal neuralgia, although younger patients with bilateral deficits do appear to be at higher risk. If there is a contraindication to MRI, trigeminal reflexes or evoke potentials can be considered (24).
MRA of the head is also recommended to further evaluate for a potential vascular etiology. Evoked potentials, quantitative sensory testing, and electrophysiological studies can also help detect symptomatic trigeminal neuralgia, but more research is needed before these studies can be routinely recommended. Preoperative magnetic resonance tomographic angiography has been suggested as useful in patient selection and outcome prediction for microvascular decompression surgery (158).
Although not routinely recommended, if there is a high suspicion for underlying autoimmune disorder, blood work including ANA, dS- DNA, SSA-SSB, Scl 70, and Scl 86 in the case of scleroderma as well as erythrocyte sedimentation rate can be helpful. If there is a high suspicion for metastatic carcinomatosis, cerebrospinal fluid studies with cytology and flow cytometry are also recommended (142).
Glossopharyngeal neuralgia. The diagnosis of glossopharyngeal neuralgia is best made by patient’s history and may be confirmed by provocative testing, such as precipitation of symptoms by stimulation of the tonsils, posterior pharynx, or the base of the tongue. Another option would be to apply a topical anesthetic to the ninth nerve dermatome, which would then cause transient pain relief. Following this procedure, the pain is no longer precipitated by stimulation, and patients can swallow food without discomfort (134).
In cases of glossopharyngeal neuralgia, MRI (including T2, T1, and FLAIR) is suggested for the exclusion of symptomatic forms and for a first hint of neurovascular compression. MR-angiography can show the anatomical relationship between cranial nerve and vessels (in particular arteries) (61).
Laboratory tests, including erythrocyte sedimentation rate, serum chemistry, complete blood count, and antinuclear antibody, are helpful to determine if infection, inflammation, and neoplastic malignancy occur. To determine if vascular compression, any malignancy, or hard tissue change has occurred, magnetic resonance angiography and 3D CT-angiography can be useful. These imaging techniques may help elucidate vascular compression that can typically occur from the posterior inferior cerebellar artery in cases of glossopharyngeal neuralgia. If the offending vessel is the anterior inferior cerebellar artery, the diagnosis of glossopharyngeal neuralgia is a challenge without surgery. Glossopharyngeal neuralgia secondary to Eagle syndrome is identified by a panoramic radiograph (91).
Nervus intermedius neuralgia. All other possible nonneurologic causes of otalgia must be eliminated. Careful ontological, neurologic, and ENT, and dental examinations must be performed. Ancillary tests may help, such as vestibular function tests, auditory-evoked brainstem responses, pure tone audiometry, and fine cut CT imaging.
Fine-cut magnetic resonance imaging of the cerebellopontine angle and internal auditory meatus, although not 100% sensitive, can identify a vascular loop compressing the nervus intermedius. A sizable portion of asymptomatic individuals can also have a vascular loop; therefore, the specificity is poor (148).
A definite diagnosis of nervus intermedius neuralgia in context of the vascular loop compression was made according to one paper when the nervus intermedius was found to be compressed by vessels intraoperatively and when the patient achieved consistent pain relief after microvascular decompression (36).
When there is no underlying etiology, the nervus intermedius neuralgia is referred to as classical nervus intermedius neuralgia. In addition to herpes zoster, an etiology mentioned earlier, other secondary etiologies include temporomandibular joint dysfunction, nasopharyngeal carcinoma, petrous bone osteoma, neuroborreliosis, and multiple sclerosis (56; 46). However, some literature labels these conditions as nervus intermedius neuralgia mimickers and not as secondary etiologies.
Occipital neuralgia. There is significant overlap between occipital neuralgia and migraine. Greater occipital nerve blockade with anesthetics or corticosteroids can aid in confirming the diagnosis and providing therapeutic relief. Given that nerve blocks are also effective in migraine headache, misdiagnosis can result in false positives. Therefore, a careful history and physical examination are critical components to accurately distinguish occipital neuralgia from other headache disorders that present in a similar manner (50).
Neurologic and musculoskeletal examinations should be performed as part of the physical examination. Careful history taking should include past medical history and family history. Tenderness to palpate and allodynia of the occipital region can help place occipital neuralgia in the differential; however, is also common in migraine. Additional clues may be the avoidance of activities such as wearing a hat, brushing one’s hair, or lying on a pillow. A positive Tinel’s test occurs when the numbness or tingling is elicited with percussion over the occipital condyle. Literature suggests the Tinel’s sign is more specific for occipital neuralgia than the patient’s description of pain or tenderness on examination (166).
Laboratory tests include erythrocyte sedimentation rate, folate, b12, and human immunodeficiency virus serology as well as screening for syphilis, Epstein-Barr virus, herpes simplex, and cytomegalovirus. Imaging should include gadolinium-enhanced brain and cervical spinal cord magnetic resonance scans (34).
Optic neuritis. Diagnosis is made based on history and physical examination findings. A high quality ophthalmological examination is critical in the diagnosis and to rule out other differential diagnoses.
Further diagnostic workup for optic neuritis is aimed at assessing for risk of multiple sclerosis and neuromyelitis optica and ruling out other diseases. It involves gadolinium-enhanced MRI of the brain and orbits with fat saturation to look for enhancement and enlargement of the optic nerve and to assess for other areas of active or previous demyelination or lesions characteristic of multiple sclerosis. Lumbar puncture is not necessary in typical cases but may be performed. CSF may be sent for immunoglobulin G (IgG) synthesis, IgG ratio, myelin basic protein, oligoclonal bands, and aquaporin 4 antibodies in addition to routine CSF studies (WBC, CBC, protein, and glucose) and can be utilized to assess for and rule out other entities (eg, infectious, neoplastic) in the appropriate clinical setting (12; 133; 151).
CSF results did not affect management in the Optic Neuritis Treatment Trial. All glucose levels were normal and 9.4% of CSF had protein levels greater than 50 mg/dl. CSF pleocytosis with greater than 6 WBC/ml was seen in 36% of patients with a maximum of 27 WBC/ml (133). Significant pleocytosis should lead to consideration of other differentials.
Out of 35 patients in a cohort of optic neuritis patients with CSF studies, 14 had normal CSF whereas 21 had abnormalities, and there was no correlation between the presence or absence of overall abnormal CSF and subsequent development of multiple sclerosis. However, there was a relationship between CSF IgG levels and development of multiple sclerosis (82). Other investigations including spectral domain OCT, scanning laser polarimetry, diffusion tensor imaging, multifocal visual-evoked potentials, and multifocal electroretinography are being utilized in research settings.
Headache attributed to ischemic ocular motor nerve palsy. An evaluation for diabetes is always appropriate in this setting as are evaluations for inflammatory causes (including MRI and potentially CSF analysis), and vascular imaging can be used to rule out localized compressive vascular lesions, such as aneurysm.
Tolosa-Hunt syndrome. Tolosa Hunt syndrome is diagnosed through the clinical presentation as well as neuroimaging studies and patient’s response to steroids. Laboratory tests and CSF studies are supportive tests that help in ruling out other causes of ophthalmoplegia. Tissue biopsy is diagnostic but is considered a procedure of last choice and rarely performed, given the high risk and technical difficulties.
When there is suspicion of Tolosa-Hunt syndrome on clinical presentation, MRI, blood, and CSF studies should be performed to rule out other causes of painful ophthalmoplegia. Blood tests include complete blood count, comprehensive metabolic panel, HbA1C, erythrocyte sedimentation rate, C reactive protein, angiotensin converting enzyme, anti-nuclear antibody, anti-nuclear cytoplasmic antibody, anti-dsDNA antibody, anti-sm antibody, Lyme panel, serum protein electrophoresis, fluorescent treponemal antibody test, and HIV. CSF studies include glucose, protein, cell count and differential, cytology, culture and gram stain, angiotensin-converting enzyme, syphilis, and Lyme serology (15; 04).
Blood, as well as CSF studies, are expected to be normal in cases of Tolosa-Hunt syndrome. If there are abnormalities found, another diagnosis should be considered.
Brain MRI with contrast with focus on the coronal view is an important diagnostic study. It helps exclude other disease processes that produce painful ophthalmoplegia. MRI can show thickening of the cavernous sinus because of the presence of abnormal soft tissue, which is isointense on T1 and iso- or hypointense on T2 and enhances with contrast. Other MRI findings include convexity of the lateral wall of the cavernous sinus and extension into the orbital apex. High-resolution computed tomography (HRCT) can also show changes in the soft tissue, but it lacks sensitivity. Thus, MRI should be performed for better visualization of the region of the cavernous sinus or superior orbital fissure (04; 163).
Despite the importance of MRI, findings have low specificity, and the above-mentioned findings can also be found in lymphoma, meningioma, and sarcoidosis. One study advocates for the use of a dynamic contrast MRI instead of the conventional contrast MRI (04). This study enrolled 7 patients who all had contrast conventional MRI of the brain, which was normal except that the dynamic contrast MRI showed 4 of the patients had cavernous sinus lesions, 1 patient had both cavernous sinus and superior orbital fissure lesions, and 1 patient had just a superior orbital fissure lesion. The authors of this study concluded that because dynamic MRI can show the space and soft tissues in cavernous sinus better, it should be used in cases with an initial diagnosis of Tolosa-Hunt syndrome. There was a case report further suggesting that the conventional MRI is not up to par. Constructive interference steady state is a high-contrast and high-spatial resolution MRI sequence that helps in differentiating small lesions in the cranial nerves within CSF filled spaces using T2-weighted imaging; the authors mentioned that conventional spin-echo T2W MRI in coronal plane did show the cavernous sinus lesion, but the bulk of the lesion and its true extent were not delineated by coronal and axial T2-weighted MRI. Axial CISS MRI revealed the lesion and its extent completely. CISS appears to be more sensitive than conventional T2-weighted MRI, showing the true extent of the lesion as seen on contrast-enhanced MRI (163).
There was a retrospective study of a total of 22 patients diagnosed with painful ophthalmoplegia and Tolosa–Hunt syndrome. Pain and diplopia were found in 22 (100%) and 20 cases (91%) (70). The sympathetic nerve was involved in 6 cases (27%). Paresis followed the pain for an average of 8 ± 5.87 days. Serial magnetic resonance imaging (MRI) revealed granulomatous lesions that were visible in 20 patients (91%). Nineteen patients (86%) demonstrated the lesions located in the cavernous sinus, orbital apex, or superior orbital fissure. One lesion extended to the intracranial structure. Pain was relieved in 20 cases (91%) within 72 hours, and no patient had complete relief from paresis. The researchers concluded that the time course of relief should be undefined and that normal MRI should be involved in Tolosa-Hunt syndrome diagnoses. The time interval between headache and paresis can exceed 2 weeks according to their review. Another retrospective study showed that only 24 of 48 patients with Tolosa-Hunt syndrome had abnormal MRIs and, furthermore, that although there was an average of 2 days between pain and onset of cranial palsy; 5 patients had an interval range from 16 to 30 days (168). This further suggests that the conventional contrast MRI is not entirely helpful and that the 2-week time frame may be inaccurate. Additionally, there is a case report showing the workup done to exclude other conditions, and by exclusion the diagnosis is Tolosa-Hunt syndrome despite a normal MRI (01).
Raeder syndrome. Diagnosis of Raeder syndrome is typically based on history. It characteristically affects men in middle to old age. MRI with contrast and MRA or CTA with and without contrast of the head and neck are typically recommended to look for potential tumors or carotid arterial dissection. Raeder syndrome has been noted to be the presenting symptom of internal carotid artery dissection.
Blood work may be done to rule out underlying inflammatory or other infectious etiologies similar to other cranial neuralgias (84).
Burning mouth syndrome. The diagnosis of burning mouth syndrome is one of exclusion mainly. Clinical history demonstrating typical features including onset, accompanying symptoms, and clinical course establishes the strong suspicion. A comprehensive history including chronic systemic disorders, allergies, and current and prior medications is crucial. Patients often describe the onset of pain as being sudden or intermittent; in the lower lip, tongue, or hard palate; typically bilateral; not present on awakening; and relieved somewhat by eating and sleeping, but otherwise persistent or progressive. A thorough intra-oral and extra-oral examination is warranted with objective measurement of salivary flow rates and taste function. The presence of atypical symptoms, such as sensory, motor, or autonomic changes may trigger neurologic consultation and CNS imaging. Appropriate additional testing may include a CBC, glucose levels, nutritional factors, autoimmune panel, cultures for appropriate organisms, allergy testing, gastric reflux studies, and diagnostic trials of medication discontinuation (02; 14).
Persistent idiopathic facial pain. A thorough history and clinical examination is warranted as is a full dental or otolaryngology examination, depending on the location and character of the pain. Furthermore, persistent idiopathic facial pain is not associated with neurovascular compression at the level of the trigeminal nerve, which should be ruled out by imaging. History should be sufficient to differentiate persistent idiopathic facial pain from posttraumatic trigeminal neuropathy, in that the latter is often a result of significant and documented trauma to the trigeminal nerve with regional sensory changes that localized to the dermatome of the injured nerve; with the injury potentially demonstrable on imaging (26).
Recurrent painful ophthalmoplegic neuropathy. Diagnostic evaluation should include MRI with and without contrast, which will most often show thickening and enhancement of the affected cranial nerve. Vascular imaging via CTA or MRA is also indicated, as is CSF analysis, although these would be expected to be normal. A Tensilon test or, more often, an antibody evaluation to rule out myasthenia gravis and related disorders would be reasonable (Ambrosetto et al 2014).
Central neuropathic pain. Workup should include complete neurologic examination and radiographic evaluation, typically MRI to look for central lesions that would correlate with the pain. If timing and examination is consistent with central poststroke pain, then no contrast is necessary for imaging, whereas in central pain in multiple sclerosis a contrast enhanced study is recommended.
Trigeminal neuralgia. Pharmacotherapy is often the first-line treatment for the severe neuropathic pain of trigeminal neuralgia and any of it variants.
Carbamazepine currently has Level A evidence, and a dosage of 100 to 600 mg twice daily is recommended. It is recommended to start at a low dose and increase gradually to help minimize adverse effects and improve patient tolerability of the medication. Testing for HLA B1502 allele is also recommended in patients of Asian ancestry as there is an increased risk with this allele of developing Stevens Johnson syndrome or toxic epidermal necrosis.
Literature review suggests that 300 to 2400 mg a day is effective in attaining near complete or complete pain control in 58% to 100% of patients based on studies. It reduced both the frequency and intensity of painful paroxysms and was equally efficacious for spontaneous and trigger-evoked attacks. The number needed to treat in studies is 2.
Oxcarbazepine, a cousin of carbamazepine, has Level B evidence. A dosage of 300 to 900 mg twice daily is typically used, once again starting at the lowest possible dose and increasing it gradually to minimize adverse effects.
Baclofen has Level C evidence, and a starting dose of 5 mg every 8 hours is initially used with a maximum daily dose of 80 mg.
Lamotrigine also has Level C evidence, with a starting dose of 50 mg daily and maximum dose of 400 mg daily recommended.
Phenytoin, valproic acid, gabapentin, pregabalin, topiramate, tricyclic antidepressants, and capsaicin gel or patches are other alternative options that have some studies showing benefit.
In addition to these traditional pharmacologic agents, a novel agent, vixotrigine, is currently being prepared for a phase III trial in the treatment of trigeminal neuralgia. This agent is a selective Na v1.7 sodium channel blocker and has been shown in a phase II randomization withdrawal study to decrease both pain severity and the number of paroxysms that occurred (120).
Topical ambroxol 20% cream acts as a strong local anesthetic to inhibit the Na channel expressed in nociceptive C-fibers. In a report of 5 cases, pain reduction was 2 to 8 points within 15 to 30 minutes and lasted for 4 to 6 hours (90).
Botulinum toxin injections have shown increased promise in the treatment of trigeminal neuralgiform pain. A randomized controlled trial of 42 subjects receiving 75 units versus 22 subjects with normal saline showed 69.18% responders in the botulinum toxin group versus 15% in the placebo group. There were no significant adverse effects in the treatment groups (110).
For refractory cases, and in cases of a clear structural anomaly noted in neuroimaging causing the trigeminal neuralgia, more aggressive, interventional techniques are warranted.
As a large part of classic trigeminal neuralgia patients have a neurovascular cause, microvascular decompression is recommended, especially as no true nerve destruction occurs with this technique. Patients tend to have a quicker recovery and longer periods between relapse with this technique compared to other surgical interventions. The microvascular decompression procedure has proven to be an effective and durable treatment option for patients with trigeminal neuralgia. Initial pain relief was reported as high as 98% (137). In a large series, 70% of the patients have been free of pain and medications for 10 years (19). The most significant complications following microvascular decompression for trigeminal neuralgia are cerebellar swelling/hematoma, arterial/venous infarct of the cerebellum and/or the brain stem, hearing loss, and CSF leak (138). Unfortunately, there are no randomized controlled trials comparing microvascular decompression to neuroablative techniques, though a nonrandomized study did show a higher proportion of patients to be pain free at 36 months with microvascular decompression than with radiofrequency thermocoagulation or with rhizolysis (71).
Other options include percutaneous rhizotomy and stereotactic gamma knife radiosurgery (110). Less invasive than microvascular decompression, percutaneous rhizotomy involves penetration of the foramen ovale with a cannula and then controlled lesion of the trigeminal ganglion or root by various means: thermal (radiofrequency thermocoagulation), chemical (injection of glycerol), or mechanical (compression by a balloon inflated into Meckel’s cave) techniques. Ninety percent of patients attain pain relief from these procedures; however, studies suggest that at 5 years only 50% remain pain free.
Gamma knife radiosurgery is a noninvasive outpatient procedure, delivered at the trigeminal root entry zone, which over time causes axonal degeneration and necrosis and, thus, interrupts pain signals (Sheehan at al 2005). In case series, 69% of patients are pain free at 1 year after radiosurgery, and 52% are still pain free at 3 years. Pain relief can be delayed (mean 1 month) with this procedure. Side effects are facial numbness (9% to 37%) and sensory loss or paresthesia (6% to 13%), which may develop with a delay of up to 6 months (05).
Given significant psychosocial impact from trigeminal neuralgia, a multifaceted treatment approach involving referrals to psychology or psychiatry and speech or swallow therapies as warranted is highly recommended.
In regard to the treatment of painful trigeminal neuralgia associated with acute herpes zoster, the United States has 3 drugs approved for treatment of acute herpes zoster: acyclovir, valacyclovir, and famciclovir. Meta-analyses show that acyclovir is significantly superior to placebo for reducing the duration of zoster-associated pain, with about 19% of patients reporting neuropathic pain after oral treatment at 6 months. Oral treatment with the above medications also reduces ocular complications associated with herpes zoster ophthalmicus from 50% down to 20% to 30%. A consultation with an ophthalmologist or corneal specialist is highly recommended (62). In addition to antiviral agents, expert opinion recommends a multimodal approach, including typical first-line anticonvulsants, topical agents, and relaxation techniques (54).
Glossopharyngeal neuralgia. Carbamazepine, gabapentin, and pregabalin are first-line pharmacological treatments for glossopharyngeal neuralgia. Additionally, the dibenzazepine anticonvulsant, eslicarbazepine, has shown promise for use in glossopharyngeal neuralgia in multiple open-label and observational studies, although large-scale trials must be conducted to confirm this observation (06). Vitamin B12 and a low-dose selective serotonin reuptake inhibitor such as paroxetine (20 to 50 mg/day) or sertraline (50 to 200 mg/day) are also helpful.
If pain relief cannot be achieved, different medications such as baclofen and dextromethorphan can be used. The combination of 2 or multiple agents is effective with physical therapy or psychological treatment.
A glossopharyngeal nerve block is an excellent adjunct to the pharmacological treatment of glossopharyngeal neuralgia for rapid pain. A nerve block can be performed using a local anesthetic agent such as lidocaine (2%) and bupivacaine (0.5%) with or without steroids, ketamine, phenol, glycerol, and alcohol.
Microvascular decompression is one of the best options for surgical treatment. Certain large series studies have shown that microvascular decompression can lead to complete pain relief in 76% of subjects and substantial improvement in a further 16% in 48 months of follow up (127).
Stylectomy is usually conducted for Eagle syndrome after ruling out the primary cause of glossopharyngeal neuralgia. Pulsed radiofrequency neurolysis, gamma-knife surgery, and stereotactic radiosurgery have also shown beneficial effects in both idiopathic and secondary glossopharyngeal neuralgia (91; 102). Specifically, pulsed radiofrequency ablation was shown to reduce both overall pain scores and opioid consumption in patients with glossopharyngeal neuralgia secondary to oropharyngeal carcinoma (29).
Nervus intermedius neuralgia. Medical management is the mainstay and first-line treatment. Anticonvulsants, such as carbamazepine, gabapentin, or lamotrigine, have been used; however, carbamazepine has been the initial medication most commonly trialed (148). Given that there haven’t been enough cases of this neuralgia, pharmacologic treatment has been modeled based on the other cranial neuralgias, with trigeminal neuralgia being the blueprint. Other medications used for nervus intermedius neuralgia include amitriptyline and baclofen. Investigations have shown that, in many cases, these medications have been ineffective, and some may cause disabling side effects (36). Some medications demonstrate decreased effectiveness over time, with long-term use causing resistance. One paper mentions that carbamazepine and oxcarbazepine are more effective for symptom onset but that the effect decreases and the dosage increases. Many patients eventually then evaluate their surgical options (103).
Surgical treatment may be necessary in patients who do not respond to pharmacotherapy or who have vascular loops, also known as nerve vessel conflicts, which are arterial structures compressing the nervus intermedius (78). The two most common surgical procedures are sectioning and microvascular decompression. Surgical exploration of the cerebellopontine angle is necessary. While exploring the entry zone of the nervus intermedius for vascular compression, the entry zones of cranial nerve 5, 9, 10 should be explored due to clinical similarity of the pain syndromes (67).
When no vessel is found as a possible cause of pain, then sectioning of the nervus intermedius should be the next step. Transections, also known as sectioning of the nervus intermedius, intracranially or at the geniculate ganglion, have been extensively done over the course of many years. Sectioning was utilized in most of the early cases identified; however, it has had many neurologic side effects. In 1909, Clark and Taylor were the first to report success in treating facial pain with resection of the geniculate ganglion (40). Hearing impairment was the most frequent, serious complication after sectioning of the nervus intermedius (135). Additionally, there have been reports of decreased lacrimation, salivation, and taste after sectioning (136). Another article states that the efficacy of exploratory surgery with transection for long-term relief remains unconvincing and states that patient selection remains especially important as the risk of vestibulocochlear nerve dysfunction and resultant persistent dizziness and balance dysfunction should be carefully considered during manipulation of the cranial nerve 7/8 complex (153; 154). The nervus intermedius is in close proximity to the vestibular division of the vestibulocochlear nerve, which makes intraoperative identification tricky. In one paper, it was reported that in 30 of the 73 examined nerves, the intermediate segment contained more than one rootlet. If some of the rootlets then adhere to the vestibulocochlear nerve, they may then be missed. It also mentions that in 20% of cases, the nervus intermedius couldn’t be identified along its intracisternal course due to becoming attached to the vestibular part of the vestibulocochlear nerve as mentioned above. The nervus intermedius does not separate from it until the internal acoustic meatus (131). This could be an explanation as to why nerve transection may fail to alleviate neuralgia.
Another treatment option commonly performed is microvascular decompression of the nervus intermedius at its root entry zone to the brainstem if there is compression by a vascular loop. The artery in close contact can be identified by high resolution MRI or MRA, and surgical exploration via retromastoid craniotomy can show the actual compression that then leads to the microvascular nerve decompression. Given its small size, the nervus intermedius itself is not visible. Overall, the literature suggests that these procedures are effective, but that the evidence base is poor as experience with this procedure is quite limited. Neurologic deficits, such as transient facial nerve palsy or partial hearing loss, may result from this surgery (148; 140; 80).
There have also been certain combination surgical treatments that have been tried. According to a review article, if medical therapy is a failure, there is a recommendation for intratemporal division of the cutaneous branches of the facial nerve. If this is unsuccessful, then resection of the nervus intermedius is advised, and at the same time, if there is also vascular compression, there should be simultaneous microvascular decompression. Another approach when no vascular loop was identified was to section the nervus intermedius, chorda tympani, or geniculate ganglion along with a division of the glossopharyngeal nerve and upper rootlets of the tenth cranial nerve. This team was able to demonstrate 75% pain relief with this technique, with the main shortcoming being the inability to fully conclude the main pain generator (136). A single center review showed that the combination of sectioning of the nervus intermedius combined with neurovascular decompression resulted in longer-term pain relief, with patients experiencing 4.8 years of pain freedom on average, with pain reduction lasting 6.2 years on average (75).
For the case mentioned earlier with laryngeal neuralgia combined with intermediate neuralgia, the treatment undertaken was not only to sever the laryngeal nerve, but additionally the glossopharyngeal nerve, nervus intermedius, and the upper first to second rootlets of the vagus nerve (170). These nerves are in the vicinity, and severing just the laryngeal nerve will not eliminate the pain.
Physical therapy, nerve block, radiofrequency gangliolysis, retrogasserian glycerol injections, and gamma knife are other treatment modalities (46).
For nervus intermedius neuropathy attributed to herpes zoster, the treatment is cortisone and acyclovir as early as possible, according to the International Headache Society.
There is a paper describing 2 cases where tractotomy of the nervus intermedius was done under intraoperative nerve electrophysiology monitoring (103). A retrosigmoid approach was used with general anesthesia. Brainstem auditory evoked potential (BAEP), resting EMG and stimulating EMGs of the orbicularis oculi, orbicularis oris, and masseter muscles were done while performing intraoperative monitoring during surgery to prevent accidental injury of the facial nerve, motor fibers, and auditory nerve that can lead to facial paralysis and hearing loss, amongst other complications after operation. In both cases, the patients had complete resolution of pain and no complications. Additionally, there was no recurrence of symptoms during various follow-ups over the course of a year. The authors mention that this treatment is a safe and effective method for treating nervus intermedius neuralgia.
Most cases of surgical failure are due to diagnostic error involved with the possibility of confusing the different syndromes associated with otalgia. The use of functional MRI or fMRI are being investigated currently by research teams to try to help explain mechanisms in order to get a more definite diagnosis and uniform treatments (27). Overall consensus amongst the literature is that prospective studies are needed to define the true extent of microvascular decompression and sectioning in order to be able to offer patients surgical alternatives in a more objective manner and explain the procedure consequences. However, this has proven to be difficult, as we are dealing with a very rare neuralgia syndrome. According to one paper, the literature addressing the efficacy of proposed treatment strategies is scare because of the small sample size of a heterogeneous population (116). This, in turn, makes it difficult to conclude which is the most effective way to manage patients.
Occipital neuralgia. Occipital neuralgia poses challenges as no criterion standard exists. Conservative methods are generally employed first. Physical therapy, massage therapy, chiropractic manipulation, yoga, rest, heat application, muscle relaxants or antiinflammatory medications, and opioid and nonopioid analgesia are utilized. Additionally, effective pharmacological treatments include tricyclic antidepressants and antiepileptics, including pregabalin, gabapentin, carbamazepine, and amitriptyline.
If these noninvasive measures do not help, interventional management such as botulinum toxin injections, acupuncture, and percutaneous occipital nerve blocks can be tried. Occipital nerve blocks are usually the preferred treatment among practitioners (16).
If there is still no improvement, then neuromodulation with percutaneous pulsed radiofrequency energy (PRFE) treatment or subcutaneous neurostimulation of the occipital nerve (occipital nerve stimulation as one form of peripheral nerve stimulation) may be considered. If these do not help, then the last options remain surgical and include microvascular decompression, neurectomy, C2-C3 decompression, and partial posterior rhizotomy (146).
There is one case study describing how dry needling has successfully improved clinical outcomes in a patient diagnosed with occipital neuralgia (32).
Botulinum toxin injection into the occipital nerves has been utilized with some success, although this treatment has not yet been well studied. There is one retrospective study of 111 patients, of which 78 had been treated by radiofrequency, 37 by botulinum toxin injection, and 5 by occipital nerve stimulation (55). It was found that 89.4% of the radiofrequency treated patients had good results compared to 80% in the other two categories. Although the occipital nerve stimulation group in the study was small as a sample size, there was a sizeable group who responded to botulinum toxin in a similar percentage to the radiofrequency group. The authors conclude that in terms of innocuousness and production costs and similar effectiveness, botulinum toxin may represent the preferred initial treatment.
There is one report that palmitoylethanolamide (PEA) up to 1200 mg/day was effective with gradual and significant improvement of one patient’s pain after 2 weeks of treatment (34). It is hypothesized that it may induce relief of neuropathic pain through its action on different receptors located on the nociceptive pathway and that it has a weak affinity for cannabinoid CB1 and CB2 receptors.
The blockage of greater occipital nerve and lesser occipital nerve can help with diagnosis and treatment. Landmark-guided blocks are the mainstay. Several studies have demonstrated the efficacy of occipital nerve block in alleviating occipital neuralgia (50). In terms of mechanisms of action, in addition to the local effects of anesthesia on the nerve, there has been a proposed concept of additional pain alleviation from central modulation via the interactions between afferent input into the cervical dorsal horn and trigeminal nucleus caudalis (63). The effect appears to be variable, lasting from days to years. One paper describes using 1 ml of an anesthetic or a solution containing an anesthetic plus a corticosteroid. It’s mentioned that if one session of lidocaine injection doesn’t work, repetitive nerve blockage with lidocaine once a week for 3 consecutive weeks can be tried. The contraindications to the nerve block are infection and malformation at the injection site, such as hemangioma, allergy to anesthetics and corticosteroids, patients under anticoagulation, or with diseases with increased bleeding time. Also, nerve block is contraindicated in patients with arrhythmias or liver failure. Another paper gives more specifics and suggests using a 25- to 30-gauge needle with 1% to 2% lidocaine and bupivacaine 0.25% to 0.5% in a 1:1 volume ratio with or without triamcinolone 20 mg for both greater occipital nerve and lesser occipital nerve. The landmark for greater occipital nerve is a line from the occipital protuberance to the mastoid process and moving one third of the way laterally. To identify lesser occipital nerve, the same line is used to localize greater occipital nerve, but by moving two thirds of the way laterally from the occipital protuberance. Potential complications include alopecia, pain, infection, hematoma, and lightheadedness (57).
In pregnant and breastfeeding women, nerve block should not be done regularly, and smaller doses of lidocaine may need to be used. The most common side effects of the nerve block are pain, ecchymosis, and hematoma. Nerve trauma can also occur. The clinical result of the nerve block is reduction in frequency, intensity, and duration of pain and improved patient satisfaction (44).
There are studies demonstrating multiple methods for better visualizing the greater occipital nerve as opposed to the standard landmark-guided blocks. One prospective study demonstrated that MR tractography through track-weighted imaging is a promising technique for therapeutic management (86). There is another prospective study by the same research team showing that greater occipital nerve infiltration under MR guidance is a feasible technique offering similar results of success and can, therefore, be helpful with specific populations, such as young people and people who have undergone repeated infiltrations (88).
CT-guided infiltration of the greater occipital nerve is another option. According to one prospective study carried out over a 3-year period, there was a clinical success rate of 86% with a mean pain relief duration following the procedure of slightly more than 9 months. This method appeared to be faster and safer compared to other methods in addition to the high efficacy rate and long-lasting relief (87).
In addition to MR and CT guidance, ultrasound-guided greater occipital nerve blocks have been demonstrating success (157; 160). There is a prospective open label study demonstrating how ultrasound-guided greater occipital nerve blocks at the level of C2 produced significant reductions in pain scores over a 4-week period, with no reported adverse events (129).
Occipital nerve stimulation is one of the leading forms of neurostimulation for occipital neuralgia. This therapy utilizes neurostimulating electrodes placed subcutaneously in the occipital region and connected to a permanently implanted programmable pulse generator identical to those used for dorsal column or spinal cord stimulation (104).
Occipital nerve stimulation has the advantages of having a high success rate, adjustability and reversibility as well as being minimally invasive and less likely to have complications. Occipital nerve stimulation may have widespread effects on the central nervous system, resulting in pain relief (101). According to a systematic review, occipital nerve stimulation has shown continued efficacy with long-term follow up (147).
According to a 6-year retrospective review of occipital nerve stimulation, all 3 of the occipital neuralgia patients reported more than a 50% reduction in pain intensity or frequency at 28 to 31 months (125). Additionally, 9 of 19 patients diagnosed with refractory chronic migraines reported this during long-term follow up at 11 to 77 months. There are certain hardware-related complications, such as skin erosion, lead breakage, lead migration, and pain around the battery site. These can dramatically increase healthcare expenditure, as new equipment and further surgical procedures are often required, especially as lead migration and lead breakage are major causes of surgical revision. Neuromodulation is both invasive and expensive and should be reserved for specific subsets of chronic pain patients, with this retrospective study suggesting occipital nerve stimulation is a therapeutic option for refractory chronic migraine or occipital neuralgia. The paper suggests a multidisciplinary team approach involving headache, psychology, and neuromodulation specialists to refine patient selection for occipital nerve stimulation and to optimize medical, psychological, and surgical management at all stages.
The exact mechanism of action of occipital nerve stimulation for treating occipital neuralgia is not fully understood. It has been demonstrated that neurons in the C2 spinal dorsal horn receive input from the ipsilateral and contralateral occipital nerves (20). There was a case where unilateral nerve stimulation for bilateral occipital neuralgia was successfully used (101).
It appears that occipital nerve stimulation can stimulate many pain-related areas of the brain. One study showed that with 3 Tesla MRI scan of one subject, there was activation of the thalamus, hypothalamus, orbitofrontal cortex, prefrontal cortex, inferior parietal lobe, periaqueductal gray, and cerebellum (95). Additionally, the primary motor, auditory, visual, somatosensory areas, amygdala, paracentral lobe, hippocampus, secondary somatosensory area, and supplementary motor areas experienced deactivation, whereas the structures mentioned previously were activated. Changes in blood flow were also noted in the pons, cuneus, anterior cingulate cortex, and left pulvinar after bilateral occipital nerve stimulation (18).
The other main form of neurostimulation is pulsed radiofrequency. This treatment appears to have shown short-term to intermediate-term pain control; however, reports mainly have been observational cohort studies without controls (68; 38). According to one review paper, pulsed radiofrequency is described as a minimally invasive percutaneous technique with minimal or no neurodestruction and a favorable side-effect profile, making this treatment appealing (105). Through clinical studies, pulse radiofrequency has shown sustained pain improvement, quality of life, and adjuvant pain medication usage; however, despite this, conclusive evidence in support of this treatment method awaits to be seen.
There are relatively few studies comparing the various treatments. One study compared occipital nerve blocks with an anesthetic/steroid mixture versus pulsed radiofrequency and concluded that adverse events between the two were similar. Pulse radiofrequency provided greater pain relief; however, there was no clear comparable improvement in other outcome measures (41).
There are a few other treatments that are being investigated. In patients who have received repeated invasive procedures with the risk of generating further complications, one case report demonstrated that linear accelerator-based frameless stereotactic radiosurgery can provide an accurate, noninvasive treatment method, which warrants additional prospective studies for further evaluation (47). A retrospective study showed that cryoablation is a safe and effective treatment that should be further explored (92).
The overwhelming consensus is that surgical options are reserved if all else fails. There is a retrospective study of 68 patients who underwent C2 ganglion decompression, with 83.9% of these patients having excellent or good results 1 year after surgery and 69.1% after 5 years (39). The team concluded that it should be used as an initial surgical treatment before attempting occipital nerve stimulation, as they state it is minimally invasive and nondestructive. Another retrospective study suggests that greater occipital nerve excision is a valid option for being refractory to both medical treatment and surgical decompression (51). The most common adverse side effect was numbness or hypersensitivity in the denervated area, and this occurred in up to 31% of the 71 patients in the study.
There is a retrospective study that evaluated the long-term outcomes of intradural cervical dorsal root rhizotomy for refractory occipital neuralgia (59). Fifty-five patients were included in the study, and the average follow-up period was 67 months. Thirty-five patients reported full relief, and 11 patients had partial relief, thus, 64% and 20% respectively. The extent of pain relief was not associated with occipital neuralgia etiology. The most common acute postoperative complications were infections and CSF leaks. The overall conclusion is that this procedure may lead to optimal outcomes with a relatively low risk of complications in the appropriately selected patient.
The treatment of postoperative occipital neuralgia was varied, depending on the symptoms and causes. In patients with nerve root compression by lamina or screw, revision operation could eliminate the postoperative occipital neuralgia. Ganglion or epidural block as a diagnostic and therapeutic measure was used commonly for postoperative occipital neuralgia. Pharmacologic options, just as in other etiology of occipital neuralgia or in idiopathic situations, were used in postoperative occipital neuralgia as well. Similarly, occipital nerve stimulation was used to treat refractory postoperative occipital neuralgia and was effective in significantly reducing the pain. The review, however, did not see the occipital neuralgia treatments pulsed radiofrequency, botulinum toxin injections, and C2 root sectioning utilized consistently in postoperative occipital neuralgia. On the contrary, although there have been studies suggesting C2 root transection producing good results for occipital neuralgia, there is one paper recommending against this transection in postoperative occipital neuralgia patients given a significantly higher prevalence and intensity of postoperative occipital neuralgia (165). Another paper mentions that the transection was associated with increased occipital numbness but had no effect on patient-reported outcomes or quality of life and no negative consequences during the C1-C2 stabilization (48). According to Janjua and colleagues, C2 nerve root transection is associated with occipital numbness, but this often has no effect on health-related quality of life (83). Furthermore, it is stated that C2 nerve root preservation is often associated with entrapment neuropathy, causing occipital neuralgia, which greatly affects health-related quality of life. The team reviewed cadaveric dissections on 4 adult specimens and studied both intradural and extradural courses of C2 in detail along with the tentative site of C2 nerve root compression during placement of C1 lateral mass screws. The conclusion of this study was that C2 transection helps in better visualization, minimizes estimated blood loss, aids in optimal placement of C1 lateral mass screws, and improves surgical outcome with successful fusion. The overall conclusion of this review is that reducing the incidence of postoperative occipital neuralgia can be realized by improving technique and that more high-quality prospective studies are needed to evaluate the effect of C2 nerve root transection of postoperative occipital neuralgia (66).
Optic neuritis. Despite lack of long term benefit from hypothalamic-pituitary-adrenal axis modulation or corticosteroids, intravenous corticosteroids remain the mainstay of therapy for optic neuritis and do speed up recovery. Three days of intravenous methylprednisolone (250 mg 4 times daily), followed by 1/mg/kg/day of oral prednisone for 11 days, was utilized in the Optic Neuritis Treatment Trial. Although there were early differences, after 1 year, there were no significant differences between treated and untreated groups in any functional outcomes (23). After the acute phase, no treatment is necessary unless there are signs of associated illness, such as multiple sclerosis or neuromyelitis spectrum disorder, each of which would be treated with specific therapy based on the disease. Patients should ideally be assessed by ophthalmology for residual visual deficits. It is important to note that the dosing of intravenous to oral arms in the seminal Optic Neuritis Treatment Trial were not bioequivalent and that studies showed an equivalent dose of 1250 mg oral prednisone to be equivalent to intravenous methylprednisolone based on recovery of visual evoked potentials and best corrected visual acuity at 1 and 6 months (112). This may be an important consideration, given the relatively reduced cost and convenience of oral corticosteroids.
Headache attributed to ischemic ocular motor nerve palsy. In contrast to other topics in this discussion, headache attributed to ischemic ocular motor nerve palsy can be treated with simple analgesics.
Tolosa-Hunt syndrome. Glucocorticoids have been the mainstay of treatment for Tolosa-Hunt syndrome since the syndrome was first described. There are no specific recommendations about dose, duration, or route of administration. Treatment involves initial high-dose therapy for a few days, followed by a gradual taper over weeks to months. Symptom resolution guides the degree and rapidity of the taper. Imaging studies like MRI can be repeated for follow-up but usually lag behind by a few weeks as compared to symptomatic improvement (167; 15; 04).
Treating with high doses of systemic steroids leads to a dramatic improvement in pain within 2 to 3 days. Cranial nerve dysfunction improves, and there is a reduction in abnormal tissue volume as well as signal intensity on MRI over the next few weeks of steroid treatment. Reduction in pain helps confirm the diagnosis and is further supported by cranial nerve dysfunction improvement and resolution of MRI findings.
A very small percentage of patients will require immunosuppression with other agents, either to avoid side effects of long-term steroid therapy or for long-term suppression of the disease process itself. These agents include methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, and infliximab. According to the National Organization for Rare Disorders, immunosuppressive drugs such as methotrexate are being studied. There have been instances where radiotherapy has been used as a second-line therapeutic option for patients with recurrent flare-ups that lead to steroid dependence or as a first-line therapy in the presence of contraindications to steroids. Usually, these patients would have had a biopsy-proven diagnosis of Tolosa Hunt syndrome before a second-line therapy is initiated.
There is a case report of a Tolosa-Hunt syndrome patient with steroid intolerance who underwent gamma knife radiosurgery and had significant improvement without relapse (99).
Raeder syndrome. Given the rarity of the disorder, there has been no double-blinded randomized clinical trials or definite protocols for the treatment of this syndrome. However, case study analyses have shown that steroids, oral or intravenous, can be used for acute treatment in cases of no parasellar pathology. For pain management, medications often used for neuropathic pain, such as gabapentin, pregabalin, carbamazepine, other anticonvulsants, and baclofen, can be effective.
Antidepressants and antiinflammatory agents can also be helpful.
If a middle cranial fossa or other lesions that can potentially be amenable to surgery are noted, a neurosurgery referral and treatment in that regard is advised (84).
Avoidance of vasodilators and alcohol is also recommended as this can potentially exacerbate pain.
Burning mouth syndrome. Considering the subjective and chronic nature of burning mouth syndrome symptoms, treatment is challenging. In cases of secondary burning mouth syndrome (note that some definitions require that there be no clear secondary cause for a diagnosis of burning mouth syndrome), the causative factors should be treated, corrected, or discontinued when possible. There is an overall paucity of evidence for any one treatment as superior. There is no treatment that is specifically FDA-approved for burning mouth syndrome; the suggestions that follow are based on review of the currently available evidence but would be considered off-label. This is further complicated by a high placebo response rate in randomized controlled trials of treatment for burning mouth syndrome. In one review of 12 randomized controlled trials, the placebo produced a change that was 72% as large as the active treatment arms, with some variability (97). Some commonly used treatments include:
(1) Local clonazepam 0.5 to 1 mg twice daily was effective in a 25-patient open study (164), and a small multi-enter placebo-controlled study of 1 mg three times daily topical clonazepam showed a significant improvement in pain scores with minimal serum benzodiazepine levels (65). Systemic clonazepam at a dose of 0.25 to 2 mg daily has also been found to be effective; however, side effects can be limiting. In one study of 98 patients who failed initial treatment with oral lubrication and parafunctional habit control measures, it was observed that oral clonazepam was most effective in those with T-scores 50 or lower in each psychological symptom dimension; worse initial symptoms, and other oral complaints (xerostomia and dysgeusia) seemed to reap the most benefit.
(2) Trazodone was found to be ineffective in one small randomized study, but in another study, paroxetine 20 mg, sertraline 50 mg, and amisulpride 50 mg (not available in the United States) were found to significantly reduce pain, and depression scores were improved in both (106). Duloxetine at a dose of 30 to 60 mg has also been used. Additionally, in a small scale study of 100 patients, fluoxetine was found to cause a statistically significant reduction in reported visual analogue pain ratings (171).
(3) Tricyclic antidepressants are considered helpful and even first-line treatments by some; however, they may worsen xerostomia and, thus, may paradoxically worsen the symptoms of burning mouth syndrome.
(4) Studies of gabapentin have had mixed results, and at least one study suggested that it may work synergistically with alpha lipoic acid. Pregabalin remains under investigation.
(5) Topical capsaicin may be effective but is often intolerable for the patient (with side effects including increased local burning immediately after application and, in the case of ingestion, an increase in gastric pain). However, systemic capsaicin has been shown to reduce pain compared with placebo. Some patients derive benefit from an oral rinse consisting of a 1:2 to 1:1 dilution of Tabasco sauce or hot pepper and water (02; 14).
(6) Alpha-lipoic acid at a dose of 200 mg 3 times per day was shown in one study to improve burning mouth syndrome symptoms in 97% of patients, but in another study, it was not more effective than placebo (45). Another review evaluated 8 studies of alpha-lipoic acid. Three failed to show a significant change in mean pain scores versus placebo; however, 5 of 6 studies did show improvement in pain scores versus placebo (101).
(7) Topical application of 0.5 mg of aloe vera gel (70%) twice daily combined with a tongue protection device was considered effective (14).
(8) Cognitive behavioral therapy has been shown to reduce pain scores, as has psychotherapy when combined with alpha-lipoic acid.
(9) In one study, vitamin supplementation with B-Complex was found to be effective in 44.4% of nearly 400 primary and secondary burning mouth syndrome patients (111). Other regimens of vitamin supplementation, including vitamin C, vitamin B-12, folate, and minerals (iron, zinc), may lead to remission of symptoms (14).
(10) Topical steroids and anti-inflammatories are not considered effective.
(11) Hormone replacement therapy was shown to be helpful in 12 of 22 patients treated with an estradiol-based regimen (45). It is thought that this is helpful for those with estrogen receptors in the oral mucosa and not so for those without them. There are other issues to consider in terms of estrogen-based hormone replacement therapy, however, including stroke risk.
(12) Low level laser or photo therapy has been proposed and shown to be effective in several trials (including 4 randomized trials vs. placebo and one randomized trial vs. topical clonazepam); however, there is significant heterogeneity in terms of the type of laser, wavelength, power output, duration of treatment, etc. Although it was felt to be effective overall, more work needs to be done to elucidate an optimal treatment regimen (09).
(13) Catuama (a herbal supplement in Brazil) was evaluated in a small study and found to be effective during an 8-week treatment trial (101).
(14) Benzydamine HCl (topical), lycopene-enriched extra-virgin olive oil, trazodone, urea (topical), and hypericum perforatum all failed to show benefit versus placebo, and the benefit of bupivacaine lozenges was minimal and likely not clinically relevant (101).
(15) Ultramicronized palmitoylethanolamide, an endogenous fatty acid, was found in one study to cause a statistically significant decrease in the sensation of burning mouth. This, coupled with its favorable side effect profile, allowed study authors to suggest it as a viable treatment for this condition (124).
Persistent idiopathic facial pain. There are few solid randomized controlled trials of treatment for persistent idiopathic facial pain. Treatment is aimed at neuropathic pain management and includes tricyclic antidepressants, anticonvulsants, nerve blocks, and low-level laser therapies, which have shown benefit in some small studies and open-label studies (26).
Recurrent painful ophthalmoplegic neuropathy. As with other disorders that may be inflammatory and related to blood-brain barrier disruption, steroids are thought to be helpful, but there is a paucity of guidance regarding dosing strategies and length of treatment. Long term, this is most often self-limited (Ambrosetto et al 2014).
Central neuropathic pain. Management of central neuropathic pain can be difficult. Pragmatically, most treatment is based on trial and error and on maximizing potential positive side effects and minimizing negative side effects. General treatment is similar to other types of treatment for neuropathic pain described, including utilizing medications that decrease nervous system excitability and modulate serotonergic and norepinephrine pathways as well as changing electrical activity in the brain with external or internal electrical or magnetic stimulation and, most extremely, neurosurgical intervention with potential thalamotomy and postcentral gyrectomy. Invasive neurostimulation may take the form of deep brain stimulation and invasive motor cortex stimulation. Lamotrigine was found effective for central post-stroke pain as was amitriptyline (100; 159). Carbamazepine remains the first line treatment for trigeminal neuralgia, regardless of etiology including multiple sclerosis or vascular damage at the trigeminal nucleus. A systematic review of randomized controlled therapies for central post-stroke pain, which included trials that test anticonvulsants, an antidepressant, an opioid antagonist, and acupuncture, suggested that all therapies had little to no effect on pain and other related outcomes (114). Studies have investigated the role of alternative neuroreceptors in the treatment of central neuropathic pain, including NMDA and cannabidiol; however, multiple meta-analyses have not proven a definitive benefit to these targets and, in the case of cannabinoids, the risk of adverse effect may outweigh the potential benefit (113; 96). Finally, there may be a role for repetitive transcranial magnetic stimulation in this population. Individual randomized controlled trials have shown a benefit to this therapy in central neuropathic pain, and meta-analysis suggests subjects may receive pain relief in a variety of conditions, including neuropathic pain, fibromyalgia, and complex regional pain syndromes. However, further large scale studies are likely warranted (58; 60).
Stephen D Silberstein MD
Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University, receives honorariums from Abbie, Curelator, Ipsen Therapeutics, Lundbeck Biopharmaceuticals, Supernus Pharmaceuticals, and Theranica for consulting. He is also the principal investigator for clinical trials conducted by Amgen, ElectroCore Medical, and Teva.See Profile
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