16.1 Introduction

Trigeminal neuralgia (TN) is defined by the International Classification of Headache Disorders-3 (ICHD-3) as a condition characterized by recurrent unilateral brief electric shock-like, shooting, stabbing, or sharp pain, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve, and triggered by innocuous stimuli. In ICHD-3 a new subclassification of TN into three subtypes was proposed: idiopathic TN with no neurovascular contact or neurovascular contact without morphological changes of the trigeminal nerve and without significant electrophysiological findings; classical TN with neurovascular compression with morphological changes of the trigeminal nerve; and symptomatic TN when there is another underlying neurological disease such as multiple sclerosis or a space-occupying lesion affecting the ipsilateral trigeminal nerve in the root entry zone [1].

The clinical picture is characterized by painful paroxysms lasting from seconds to minutes, with highly variable frequency ranging from a few to hundreds of attacks per day. Long remission periods that can last years are seen in most patients. The pain is sharp and severe, and it can be triggered by trivial non-painful sensory stimuli in the area of trigeminal nerve distribution, such as light touch and cold wind, or by simple actions including chewing, talking, washing the face, or brushing the teeth. During the refractory period typically following a pain attack, patients can remain completely asymptomatic or experience background dull pain of variable intensity.

16.2 Pathophysiology

The finding of a neurovascular conflict at brain magnetic resonance imaging (MRI) in a high percentage of patients and the prolonged pain relief achieved by the microvascular decompression have suggested that nerve compression could have a primary role in the pathogenesis of TN [2, 3]. However, the presence of a neurovascular conflict does not necessarily induce TN, and not all the patients diagnosed with TN have a neurovascular conflict. Therefore, it is possible that individual susceptibility and/or specific conditions are needed to determine the development of TN. Moreover, how vascular compression can cause the clinical picture and explain its course remains speculative. Repetitive pulsatile microvascular compression has been proposed to cause nerve demyelination, as supported by neuropathology studies and the increased incidence of TN in multiple sclerosis patients with brainstem demyelinating lesions in the trigeminal root entry zone [4]. In TN patients with multiple sclerosis, one study found that both brainstem plaque and neurovascular compression were associated with the painful side thus suggesting a dual crush mechanism in this patient category [5].

The analysis of the pathophysiological mechanisms should consider the following crucial issues: (1) How do abnormal sensory impulses occur either spontaneously or triggered by non-painful stimuli and spread beyond the trigger area? (2) How do attacks abruptly stop and the triggering mechanism become temporary refractory?

Pathological findings confirming demyelination of trigeminal fibers and electrophysiological evidence of spontaneous discharge generation in focally demyelinated axons suggest that pulsatile compression of demyelinated axons may be responsible for initiating aberrant discharges in some patients. Nerve injury triggers the release of inflammatory mediators inducing alteration of primary afferent neurons. Changes in the expression of Na⁺, K⁺, and Ca²⁺ channels can increase nerve excitability, enhance ectopic and spontaneous activity, and reduce nociceptors threshold making them more responsive to low-intensity stimuli [6, 7]. Demyelinated nerve fibers can acquire the ability of producing after discharges, namely, bursts of spontaneous firing triggered by brief low-intensity stimulation lasting for tens of seconds after the stimulus removal. At the site of vascular compression, the close apposition of myelin-devoid axons is thought to facilitate the ephaptic transmission of the impulses. The ephaptic cross-talk between nerve fibers conveying light touch and those conveying pain has been proposed as a possible explanation for the generation of excruciating attack in response to light mechanical triggering stimuli. The spreading of nerve impulses can cause the recruitment of nerve fibers conveying pain in a synchronous fashion, amplifying the neural response and inducing the spread of the lightening sensation.

The abrupt termination of the pain attack and the ensuing refractory period are thought to occur because of a prolonged hyperpolarization shift triggered by the repetitive firing of primary sensory neurons in the dorsal root ganglia (DRG). Ca²⁺ ions that enter the neuron during the burst activate calcium-activated potassium channels and increase the outflow of potassium ions which produce the neuronal hyperpolarization, firing termination, and refractoriness of the nerve fibers to further excitation. However, in experimental setting, the duration of the refractory period is much shorter than that experienced by the patients, suggesting that other unknown factors likely intervene.

16.3 Ion Channels and Trigeminal Neuralgia

The clinical evidence that carbamazepine and oxcarbazepine, which are sodium channel blockers, can provide fast and prolonged control in the majority of TN patients is used as an indirect clue in support of the role of sodium channel altered functioning in the pathophysiology of TN.

Most of the experimental studies suggesting that sodium channels could play key roles in the pathophysiology of TN have been performed applying the chronic constriction injury method to the infraorbital branch of the trigeminal nerve, providing a model to recapitulate human TN [8]. However, such model probably better mimics the nerve damage seen in painful posttraumatic trigeminal neuropathy.

Genetic mutations of sodium channel genes have been described in rare Mendelian disorders affecting pain perception, ranging from extremely painful conditions to complete insensitivity to pain. In particular, homozygous or compound heterozygous mutations inactivating SCN9A gene, which encode for Na_v1.7 α-subunit, and mutations of SCN11A encoding for Na_v1.9 α-subunit result in congenital insensitivity to pain [9–11]. Conversely, missense heterozygous gain-of-function mutations in SCN9A produce dominantly inherited pain syndromes such as inherited erythromelalgia and paroxysmal extreme pain disorder [12]. Further clinical studies have demonstrated the association between heterozygous gain-of-function mutations of SCN9A, SCN10A, and SCN11A genes, encoding for Na_v1.7, Na_v1.8, and Na_v1.9 α-subunits, respectively, and painful idiopathic small fiber neuropathy, a condition characterized by burning and paroxysmal pain, neuropathic pain, hyperalgesia, allodynia, and autonomic dysfunctions usually presenting with a length-dependent “gloves and stockings” distribution [13–15]. Gene mutations identified in the context of SFN are best described as variants, since some of them can have a minor allele frequency up to 3–7% and their penetrance is not yet known. At electrophysiological testing, these mutations produce a range of dysfunctions including enhanced excitability of nociceptor membrane, hypoexcitability of sympathetic neurons, and altered channel functioning such as impaired slow inactivation or impaired fast and slow inactivation [16]. Overall, these sodium channel gene variants might be part of a complex genetic and molecular mosaic predisposing individuals to develop neuropathic pain.

Recently, sodium and calcium channel genes have been sequenced in a small series of patients with TN. A de novo missense mutation of SCN8A encoding for the Na_v1.6 α-subunit has been described in one patient with TN and neurovascular compression. The Na_v1.6 subunit is widely expressed in the central and peripheral nervous system and is crucial for the initial membrane depolarization that occurs during the generation of the action potential in excitable cells. Gain-of-function mutations in Na_v1.6 have previously been linked to epilepsy and cognitive impairment with or without ataxia. The electrophysiological characterization of the mutated Na_v1.6 revealed that the p.Met136Val substitution potentiates transient and resurgent sodium currents and leads to increased excitability of trigeminal ganglion neurons expressing the mutant channel, therefore suggesting a pathophysiological role of Na_v1.6 [17].

Other studies investigated the expression of three different sodium channels in TN patients. The quantification of mRNA extracted from homogenized gingival biopsies from patients and controls demonstrated the upregulation of Na_v1.3 and the downregulation of Na_v1.7, whereas no differences emerged in the expression of Na_v1.8 [18]. Interestingly, other works showed the upregulation of Na_v1.3 and the downregulation of Na_v1.7, Na_v1.8, and Na_v1.9 in the CION model [15]. Conversely, no changes in Na_v1.3, Na_v1.8, and Na_v1.9 expression have been found in DRG neurons after transection of the centrally projecting axons by dorsal rhizotomy.

Silencing of the Na_v1.9 subunit was found to prevent mice from developing CION-induced mechanical and thermal allodynia [19]. Intriguingly, mutations in this α-subunit can result in enhanced pain or complete loss of pain perception in man [11, 15]. However, this finding appears to be in contrast with other reports revealing only a minor role for this sodium channel subunit in other somatic neuropathic pain models, thus prompting possible distinct mechanisms of neuropathic pain [20, 21].

The emerging concept of “channelopathy” in several painful conditions prompted investigating further families of ion channels involved in the pathway of pain sensation. In particular, transient receptor potential (TRP), calcium, and potassium channels have been studied in a TN model.

TRP channels are a wide group of nonselective ion channels among which specific subtypes are involved in pain and thermal stimuli transduction. The capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) activated by capsaicin, heat, and other painful stimuli has been the first identified [22]. In the CION model, TRPV1 was found to be overexpressed in trigeminal neurons and involved in heat hyperalgesia but not in mechanical allodynia. The antagonist capsazepine could abolish the heat hyperalgesia without changing the behavior related to mechanical stimuli. Cold allodynia is known to be associated with TRPM8 activation, which is enhanced by the receptor agonist menthol and abolished by its antagonist capsazepine [23, 24]. TRPA1, also involved in painful cold sensation, has been studied in trigeminal neuropathic pain models. TRPA1 knockout mice do not develop non-evoked nociceptive, mechanical allodynia and cold hypersensitivity behaviors. Consistently, TRPA1 selective antagonists showed the rescue of the painful phenotype in CION mice. Conversely, loss of TRPA1 channel in knockout mice does not prevent heat hyperalgesia that therefore appears not to be related to this TRP channel subtype [25].

The painful phenotype of CION model has been also associated with a significant downregulation in trigeminal neurons of large-conductance, calcium-activated potassium channels (BKCa) both at mRNA and protein level. On the electrophysiological ground, it reflected into a decreased BKCa current and lower threshold intensity of action potential in neurons [26].

Second-line pharmacological treatments of TN include gabapentinoids. These compounds block the α₂δ₁calcium channels (Ca_vα₂δ₁) of nociceptors at presynaptic level, reducing the release of neurotransmitters at the dorsal horn where they exert the pharmacological action. Ca_vα₂δ₁ channels have been demonstrated to be upregulated in the trigeminal neurons of the CION model. The increased expression in the dorsal horns was associated with increased excitatory synaptogenesis and increased frequency of miniature excitatory postsynaptic currents in dorsal horn neurons that can be blocked by gabapentinoids [27]. This evidence provided further experimental support for their clinical use in TN.

The role of calcium channels has also been investigated in central processing of pain. Electroencephalogram and magnetoencephalogram studies revealed an increase of low-frequency thalamocortical oscillations in patients with neuropathic pain compared to healthy controls. This activity is thought to be mediated by T-type Ca²⁺ channels inducing thalamic burst firing which is a well-defined underlying mechanism for low-frequency oscillations. The CION model of Ca_v3.1 knockout mice has been used to investigate the role of T-type calcium channel in trigeminal neuropathic pain. Results revealed a decrease of trigeminal neuropathic pain associated with reduced low-frequency rhythms in mice lacking of Ca_v3.1 channel compared to wild type, therefore suggesting a possible role of Ca_v3.1 channels in pathophysiology of trigeminal neuropathic pain [28].

While disentangling the role of ion channels in TN can provide a better understanding of its pathophysiology, the identification of new molecular mechanisms represents the opportunity to identify new druggable target.

16.4 Treatment

Recommendations for medical treatment are generally the same in classical, idiopathic, and symptomatic TN [29]. Figure 16.1 outlines a proposed work-up and treatment algorithm. An MRI of the brain and brainstem, ECG, and laboratory testing should be part of early work-up.

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