Introduction

The neuralgias are characterized by paroxysmal, brief, and intense pains described as sharp, lancinating, stabbing, or lightning-like within the distribution of a particular nerve. They are often associated with triggers that may take the form of trivial stimuli, such as brushing teeth or shaving. The paroxysms of pain often have characteristic triggers and are generally followed by pain-free periods known as refractory periods. Tenderness over the involved nerve is typical as is abolishment of pain by local anesthetic blockade. The clinical course may be monophasic, relapsing and remitting, or chronic in nature. Each neuralgia may be classified as primary (classical) or secondary (symptomatic) and distinguishing between the 2 is critical for developing an appropriate diagnostic and therapeutic plan.

An important distinction in terminology is between neuralgia, which refers to pain in the distribution of a nerve and neuropathy, implying neuronal injury. Patients with neuralgia may or may not have a secondary cause. However, evidence of neuronal injury, often in the form of sensory loss, necessitates a neurodiagnostic evaluation to identify secondary etiologies [1]. Highlighting the importance of this is the “numb-chin” sign of trigeminal branch mental neuropathy—associated with a high mortality because of a frequent association with malignancy [1].

The International Classification of Headache Disorders (ICHD) recognizes these disorders in the recently published third edition under section 13, “Painful cranial neuropathies and other facial pains” [2•]. The specific diagnoses recognized by the ICHD-3 beta version include trigeminal neuralgia (TN), postherpetic neuralgia (PHN), glossopharyngeal neuralgia (GN), nervus intermedius neuralgia (NIN), and occipital neuralgia (ON). The International Association for the Study of Pain (IASP) Classification of Chronic Pain. 2nd Edition additionally recognizes superior laryngeal neuralgia [3]. Other neuralgias (eg, lacrimal neuralgia) are not yet considered sufficiently validated entities but will still be discussed here as they may be encountered clinically. Our goal is to provide a clinical overview of the most commonly encountered neuralgias as organized by diagnosis for relatively common entities (eg, TN) and then by topography (eg, periorbital and auricular) for the more unusual neuralgias. Detailed discussion of cranial neuralgia pathophysiology can be found elsewhere [4, 5].

The Neuralgias

The most commonly encountered neuralgias are trigeminal, postherpetic, glossopharyngeal, and occipital neuralgia. Although the epidemiology of these conditions is incompletely defined, there appears to be an age-related increase in incidence [6]. Overall incidence estimates for these conditions are as follows: 4.3/100,000/year for TN [7], 3.3/100,000/year for PHN [8], 0.7/100,000/year for GN [9], and 3.2/100,000/y for ON [10]. These neuralgias differ in their pathophysiology, topography, complications, and treatment approach, necessitating awareness of their individual presentations.

Trigeminal Neuralgia

TN is uncommon before the age of 40 (overall incidence of 0.2/100,000/year), and increases in incidence with advancing age, occurring in 25.9/100,000/year in individuals after the age of 80 [7]. In general, the disorder appears to be slightly more common among women. The disorder has both classical and symptomatic (~15 % of cases) subtypes with the former most often associated with neurovascular compression of the trigeminal nerve in the prepontine cistern [11]. When the disorder is associated with a young age of onset bilateral symptoms, lack of triggered pain, absence of a refractory period, or an abnormal neurologic exam (eg, trigeminal sensory loss), secondary causes such as multiple sclerosis should be suspected [11]. When the classical form is seen in younger patients, venous neurovascular contact is more frequently observed [12]. Bilaterality may be seen in 5 % of classical cases, but even in these cases, synchronous pain is not observed. Patients with bilateral TN often have a positive family history [13].

The pain of TN is most commonly felt in V2 and V3, involving V1 alone in less than 5 % of cases [14]. Brief, intense, electrical pain is characteristically triggered by chewing, talking, and light touch (eg, wind). Interictal pain may be seen, especially in severe cases with negligible amounts of pain-free intervals. Interestingly, patients may present days to years prior to the onset of TN with prodromal side-locked intra-oral achy pain, which can be carbamazepine-responsive [15]. The overall clinical course has a relapsing-remitting nature with at least 50 % of patients reporting at least a 6-month remission during their clinical course [16]. This provides the rationale for periodically tapering therapy to avoid over-treatment. Unfortunately, the disorder often becomes medication-refractory, requiring surgical intervention in an estimated 50 % of cases [14].

The initial treatment of TN always involves pharmacotherapy with carbamazepine (target = 400–800 mg/d) generally regarded as the first-line treatment of choice. Based on 4 clinical trials with carbamazepine, a greater than 50 % reduction in attacks has been observed in at least 88 % of patients, giving a number needed to treat of less than 2 [11]. Carbamazepine can be increased by 200 mg every 3 days, and given up to 4 times daily in an effort to minimize dose-related side-effects, and target pain-predominant times of the day (eg, nocturnal attacks). Oxcarbazepine (target = 900–1800 mg/d) is likely equally efficacious, generally with a better side-effect profile but with less flexibility with titration [11]. Other medications to consider, often as add-on therapies, include phenytoin (target = 300–500 mg/d), baclofen (target = 40–80 mg/d), clonazepam (target = 1.5–8 mg/d), lamotrigine (target = 150–400 mg/d), gabapentin (target = 900–2400 mg/d), and pimozide (target = 4–12 mg/d) [14]. A 2013 Cochrane review of nonantiepileptic drugs for TN concluded that pimozide was more effective than carbamazepine and that 0.5 % proparacaine hydrochloride eye drops had no benefit over placebo [17]. Pimozide is not widely used due to potential cardiac and neurologic toxicity [18]. The clinical utility of certain agents, especially lamotrigine, is limited by the requirement for a slow titration.

Among medication-refractory cases, botulinum toxin type A (BTX) has been shown in 5 prospective studies and 1 double-blind, randomized, placebo-controlled study to be a generally effective treatment without major adverse events [19, 20]. The optimal injection strategy is yet to be determined, but subdermal trigger zones are most typically injected in published studies [20]. Opioids are sometimes used during acute exacerbations, although empiric data is lacking. Finally, rescue intravenous infusion of either fosphenytoin or lidocaine may provide transient relief while awaiting interventional procedures [21, 22].

Neurosurgical interventions for refractory TN include ablative (destructive) (eg, peripheral neurectomy, glycerol rhizolysis, sensory rhizotomy, and gamma-knife radiosurgery) and nonablative (nondestructive) (eg, microvascular decompression (MVD)) interventions [23]. These procedures generally provide rapid relief with the exception of radiosurgery, which often requires at least 6 weeks to see a peak benefit [23]. Major concerns with use of ablative procedures surround the development of anesthesia in the V1 distribution potentially resulting in neurotrophic keratopathy and/or anesthesia dolorosa in the face. Although there has never been a randomized trial, Dr. Peter Jannetta has reported on the outcomes of MVD in 1185 patients, where 75 % reported complete relief following the procedure, and 64 % continued to report excellent results at 10 years [24]. The recurrence rate was estimated to be between 1 %–2 % per year. In another series, 29 patients with persistent or recurrent TN underwent repeat posterior fossa exploration, where MVD was performed in 18 patients and partial nerve section in 11 [25]. Overall, excellent results were seen with 75 % being pain and medication-free at 3 years. Two of the patients who underwent nerve section developed anesthesia dolorosa. Therefore, repeat posterior fossa exploration should be a consideration prior to ablative procedures in patients with recurrent or persistent pain after a prior MVD. Gamma knife radiosurgery targeting 70–90 Gy to the proximal root and/or dorsal root entry zone is thought to provide pain relief to the majority of patients but carries a higher risk of recurrence than MVD [26, 27]. Gamma knife does not carry the risks associated with general anesthesia and craniotomy. Although trigeminal sensory dysfunction is relatively common after radiosurgery, anesthesia dolorosa is very rarely encountered [26, 27]. For the estimated 3 %–17 % of cases without root compression, the optimal treatment approach becomes more uncertain with partial sensory rhizotomy thought to impose a high remission rate of 88 % with 28 % recurrence after 5 years [28].

Patients with TN secondary to multiple sclerosis often have more difficult to control pain and are less likely to have neurovascular trigeminal contact on imaging [29]. Unfortunately, even when neurovascular contact is present, the outcomes of MVD are very modest compared with that seen in classical TN [30, 31]. In patients with multiple sclerosis ablative procedures, such as gamma knife radiosurgery should be given [32].

Postherpetic Neuralgia

PHN is the most common complication of herpes zoster (also known as shingles), which results from reactivation of latent varicella zoster virus [33]. PHN is defined as pain persisting more than 4 months after the onset of rash in the area affected by herpes zoster. Herpes zoster ophthalmicus is estimated to occur in 10 %–25 % of cases [34]. PHN is more common among women, and its incidence increases with age, occurring in about 18 % at age 50 and 33 % at age 80 [33]. While most cases will be readily diagnosed by a history of the classic dermatomal rash, the syndrome of zoster sine herpete may be encountered [35]. In these cases, ancillary laboratory evaluation may be pursued to confirm diagnosis. A 2005 clinical trial demonstrated a reduced incidence of both zoster and PHN following administration of a zoster vaccine to immunocompetent hosts age 60 or older [36]. More recent clinical trial data suggests that these results may be extended to individuals 50–59 years old [37]. However, it is a live vaccine and, therefore, is contraindicated in immunocompromised patients. Oral acyclovir is not thought to reduce the incidence of PHN [38].

As recommended by a 2004 American Academy of Neurology practice parameter, first line therapies for PHN include tricyclic antidepressants (target = 25–150 mg/d), gabapentin (target = 1800–3600 mg/d), pregabalin (target = 150–600 mg/d), and topical lidocaine 5 % patch [39]. Divalproex sodium 1000 mg per day was shown to be beneficial in a randomized double-blind placebo-controlled study [40]. In refractory cases or in patients intolerant of first line agents, opioids and capsaicin may be considered. Combining the lidocaine patch with other agents has also proven effective. Intravenous acyclovir for 2 weeks followed by oral valacyclovir was reported as helpful in a small open label series, following the concept that latent ganglionitis is present and may contribute to pain [41].

Glossopharyngeal Neuralgia

GN (also known as vagoglossopharyngeal neuralgia) is less common than TN and may be associated with relatively less severe attacks [9]. The 2 disorders may occasionally co-exist. It is rarely seen in children and is most common in females and patients over the age of 50 [42]. Most cases of GN are idiopathic, where neurovascular compression may also be seen. GN is less commonly associated with MS than is TN [43].

GN is characterized by severe, transient, stabbing, unilateral pain in the ear, tongue base, tonsillar fossa and/or beneath the angle of the jaw [2•]. Although defined as unilateral by current diagnostic criteria, side switching and bilaterality have been described [44, 45]. Common triggers include talking, yawning, coughing, and swallowing. The latter may be severe enough to cause weight loss. It may also be triggered by touching the external auditory canal, the side of the neck, and the skin anterior to the ear [44]. The course may be relapsing and remitting similar to that of classical TN. GN may involve branches of the vagal nerve leading to bradycardia and syncope that may necessitate pacemaker placement. Although not recognized by the current diagnostic criteria for GN, vagally-mediated symptoms may rarely occur in patients without a history of neuralgic pain [46].

Management of GN mirrors that of TN. Pharmacotherapy should be tried initially with the preferred agents being the same as those used in TN (Table 1).

Table 1 Commonly used medications in the treatment of cranial neuralgia
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Occipital Neuralgia

ON is a neuralgia with pathology related to cervical rather than cranial nerves. The characteristic clinical presentation consists of brief, sharp shooting pain in the distribution of the occipital nerves, which is often associated with dysesthesia and allodynia. Due to connections between the C2 dorsal root and the nucleus trigeminal subnucleus pars caudalis, pain may also be felt retro-orbitally [47]. A 1978 study found that 90 % of ON was in the GON distribution, 10 % in LON, and 8.7 % combined GON and LON [48]. The lesser occipital nerve arises from the dorsal rami of C2 and/or C3 spinal nerves. This study may have neglected the possibility of third ON, which has been suggested to comprise the majority of occipital headaches due to trauma [49]. While often post-traumatic or idiopathic, diverse vascular (eg, giant cell arteritis), neurogenic (eg, C2 schwannoma), muscular/tendinous, and osteogenic mechanisms may underlie the nerve root irritation [50]. Further, the syndrome may rarely be mimicked by upper cervical myelitis [51].

Nerve block with a local anesthetic and corticosteroid may provide temporary relief (Table 2), while a neuropathic pain medication (eg, gabapentin) and physical therapy are initiated. If this conservative treatment is ineffective, pulsed radiofrequency ablation, occipital nerve stimulation, or a trial of BTX may be considered [50].

Table 2 Peripheral nerve blocks for cranial neuralgias
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Periorbital and Auricular Neuralgias: Topographic Diagnoses

When confronted with a short-duration headache with neuralgic features, knowledge of peripheral nerve dermatomes can be helpful in establishing a diagnosis based on the topography of pain (Fig. 1). The primary regions where this becomes important are in the periorbital and auricular distributions. Cranial neuralgias which can cause periorbital pain include: supraorbital/supratrochlear neuralgia, infraorbital neuralgia, and lacrimal neuralgia. While these disorders represent trigeminal branch neuralgias, they are considered distinct from TN, which invariably spreads to involve other dermatomes over time. The differential diagnosis of auricular pain is even more challenging given the complex sensory innervation of the ear [53]. The differential diagnosis of deep neuralgic ear pain includes primarily glossopharyngeal, vagal (Arnold’s), and nervus intermedius neuralgia. Superficial neuralgic otalgia can be caused by ON, as well as auriculotemporal neuralgia. These disorders will be discussed as follows, with the exception of glossopharyngeal and ON, which are discussed above.

Fig. 1
figure 1

Sensory innervation of the scalp. Lateral view of the head depicting the course of superficial trigeminal and cervical nerve branches. Reproduced under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. (From Kemp WJ III, Tubbs RS, Cohen-Gadol AA. The innervation of the scalp: a comprehensive review including anatomy, pathology, and neurosurgical correlates. Surg Neurol Int. 2011;2:178 [52])

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Periorbital Neuralgias

Supraorbital/Supratrochlear Neuralgia

The supraorbital and supratrochlear nerves are the 2 branches of the frontal nerve, which is in turn a branch of the V1 division of the trigeminal nerve. They supply sensation to the forehead and upper eyelid, which are the affected areas in these conditions. Due to their superficial location, most cases are secondary to trauma, which may be minor in nature (eg, wearing a tight hat). The disorders have female predominance, and can have either a spontaneously remitting or continuous phenotype, neither of which is associated with autonomic features [54, 55]. Although trigger points are absent, tenderness is often noted over the supraorbital notch. Though the syndrome is generally thought of as benign, associated pain has led to suicidal thoughts among some reported individuals [56].

Infraorbital Neuralgia

The infraorbital nerve is a division of the maxillary branch of the trigeminal nerve. Like the other periorbital nerves, its superficial location makes it prone to trauma. Cases are rarely reported, and little is known about this condition [57, 58]. Once secondary causes have been ruled out, the diagnosis can be confirmed with an infraorbital nerve block.

Lacrimal Neuralgia

The medial branch of the lacrimal nerve provides sensory innervation to a small portion of the anterior temple as well as the lateral eyelid. Lacrimal neuralgia is a recently reported pain syndrome involving continuous pain in the lacrimal nerve distribution, where tenderness can be observed at the superoexternal edge of the orbit [59, 60]. Intra-orbital injection may be complicated by blindness, making blockade of the nerve at the point of exit a preferable approach [60, 61].

Neuralgic Otalgia

Auriculotemporal Neuralgia

Auriculotemporal neuralgia (ATN) is an uncommon syndrome characterized by paroxysms of lancinating pain anterior to the tragus, which may be accompanied by facial sweating and flushing (eg, Frey’s syndrome or gustatory sweating) [62]. Frey’s syndrome is not uncommon following parotidectomy or trauma to the area and responds well to BTX administration [63, 64]. A recent case report documented symptomatic ATN secondary to a temporomandibular joint synovial cyst [65].

Nervus Intermedius (Geniculate) Neuralgia

Nervus intermedius neuralgia (NIN) (also known as geniculate neuralgia) is a rare disorder characterized by brief paroxysms of pain felt deeply in the auditory canal. The pain lasts seconds to minutes and may have a trigger area in the posterior wall of the auditory canal. Although previously required as a diagnostic criterion, triggers have been noted to be commonly absent among surgically-validated cases [66]. This condition may be accompanied by disorders of lacrimation, salivation, and/or taste and has been associated with herpes zoster. The diagnosis of NIN is challenging due to the complex sensory innervation of the ear and may easily be misdiagnosed as GN, which can present as deep ear pain alone [53, 66]. Cocainization of the tonsillar fossa to block the glossopharyngeal nerve can serve as a useful diagnostic tool in differentiating the disorders.

Differential Diagnosis of Cranial Neuralgias

Structural Lesions

Although many cases of cranial neuralgias are primary in nature, imaging should be pursued to rule out an underlying structural cause. Cranial neuralgias may be secondary to neoplasms, demyelinating disease, arterovenous malformations, brainstem infarction, synringobulbia, or inflammatory diseases [14]. Imaging of the brain (upper cervical spine in the case of ON) should be pursued, especially in treatment-refractory cases or if sensory loss is present.

Primary Stabbing Headache

Primary stabbing headache (PSH) is recognized by the ICHD-3 beta as a distinct entity [2•]. It is defined by head pain in the form of a single stab or series of stabs, each lasting up to several seconds and recurring irregularly up to many times per day. The pain location may move but occurs in a fixed location in up to 57 % of patients [67]. It may appear as an isolated entity or be comorbid with other primary headaches, most commonly migraine [2•]. PSH most commonly occurs in a V1 distribution but can be occipital, parietal, temporal, or nuchal in location [68]. Cutaneous triggers and autonomic symptoms are absent. Unlike the cranial neuralgias, PSH is often responsive to indomethacin and other COX-2 inhibitors. Gabapentin, nifedipine, and melatonin are other reported treatment options [69–71]. Paracetamol has been used successfully in children and adolescents [72].

Short Lasting Unilateral Neuralgiform Headache with Conjunctival Tearing and Injection (SUNCT)

Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are classified as trigeminal autonomic cephalalgias but share certain clinical symptomatology with first division TN. Diagnostic criteria for SUNCT require the presence of 3 to 200 daily attacks, each lasting 5–240 seconds, associated with ipsilateral conjunctival injection and lacrimation [2•]. Although overlap does exist, the median attack duration of first division TN (4 seconds) is much less than that noted in patients with SUNCT (40 seconds) [73]. Further, although autonomic signs may be seen in first division TN, they are much less pronounced than in patients with SUNCT [74]. Refractory periods have traditionally been thought to be absent in SUNCT, although recently cases have been reported with refractory period preservation [75, 76]. However, SUNCT commonly is associated with cutaneous trigger zones, creating further diagnostic confusion [77]. These diagnoses exist on a pathophysiologic continuum, and single patients with both disorders are reported [78, 79].

Despite certain clinical similarities, patients with SUNCT often do not respond well to carbamazepine, although this can be tried [80]. Lamotrigine (100–300 mg per day) is considered to be the treatment of choice with topiramate (50–300 mg per day) and gabapentin (800–2700 mg per day) being other options [81]. Intravenous lidocaine infusion can be used for acute treatment of SUNCT status [81]. For intractable cases, surgical options range from occipital nerve stimulation to MVD [82, 83].

Conclusions

The neuralgias represent painful conditions of the head occurring in a specific nerve dermatome. These disorders may be recognized by their characteristic clinical presentations, including pain in a restricted topography. Although many cases are classical (primary), secondary etiologies are not uncommon. Pharmacologic agents remain the first line treatment for many of the neuralgias, but nerve blocks, surgery, and other procedures may be necessary in refractory cases.