The Changing Face of Trigeminal Neuralgia

A Narrative Review

Stine Maarbjerg MD, PhD; Rafael Benoliel BDS (Hons)

Headache. 2021;61(6):817-837.

Pathophysiology of Trigeminal Neuralgia

Paroxysmal, short-lasting pain is the common feature across the subtypes of TN. We must keep in mind that the "idiopathic" subgroup is differentiated by the absence of NVC and "continuous pain" is part of the phenotype in a large proportion of both CTN and ITN.

Neurovascular Compression

For CTN, there are several lines of evidence supporting compression of the trigeminal root at or near the dorsal root entry zone (DREZ) by a blood vessel as a major causative or contributing factor.^{[47,68,104,105]} The DREZ is the point where the peripheral and central myelin sheaths of Schwann cells and astrocytes meet and is postulated to be significantly more susceptible to pressure effects. The compression is often arterial but may be venous or combined.^[106] Early studies, searching for the etiology in TN not due to disease or pathology, revealed a high rate of vascular compression of the DREZ when using imaging methods and surgical observations.

This etiologic concept received wide support from imaging and correlated surgical findings^[107–109] and ultrastructural analysis of neuronal tissue^[65,66,110] that confirm NVC in many patients with resultant clear histologic damage to neurons and their myelin sheaths. Biopsy specimens of trigeminal roots demonstrate pathologic changes such as axonal loss and demyelination.^[47,110] Within zones of demyelination, groups of axons are closely apposed without an intervening glial process. The location of the zone of demyelination matches the point of vascular indentation and extends about 2 mm in each direction.^[47] Juxtaposed axons have also been demonstrated in MS patients with CTN. Using the nociceptive blink reflex and pain-related evoked potentials, impairment of the trigeminal nociceptive system due to demyelination and/or axonal dysfunction on the symptomatic side was located close to the DREZ in the brainstem.^[111]

There must be significant NVC with related, secondary anatomical/structural changes in the nerve to establish CTN. This also increases the specificity and positive predictive value of imaging.^[104] Neurovascular contact is reported in pain-free controls and in patients with ITN, but with no significant secondary anatomical/structural changes in the nerve.^{[104,112–115]} These studies underscore the use of accurate imaging techniques.

Neurophysiology and Sensory Changes

Despite the findings indicating dysfunction of the trigeminal system, patients with CTN do not always have clinically detectable neurosensory dysfunction. When present, any dysfunction is mild and primarily involves touch and thermal sensation. The findings are usually in the symptomatic division but may occur in the other two ipsilateral trigeminal branches, which suggests central mechanisms.^[45] Brainstem reflexes are usually normal in CTN, but not in TN due to systemic disease or regional pathology and are, therefore, useful for diagnosis. Patients with STN usually all have abnormal laser-evoked potentials (LEPs), whereas only a proportion of patients with CTN showed this abnormality,^[42] and thus brainstem reflexes are more consistent in distinguishing CTN from symptomatic TN. In terms of elucidating neuronal dysfunction in CTN, LEPs are obviously superior. Indeed, the finding that some patients with CTN have abnormal LEPs indicates a dysfunction of nociceptive fibers or of CNS pathways evoked by nociceptive afferent stimulation. Nociceptive fiber dysfunction may be a peripheral mechanism for the establishment of trigger points in CTN (pain induced by innocuous stimuli).

MVD of the nerve leads to prolonged pain relief in more than 90% of the cases^[116,117] and reversal of sensory loss in many patients.^[118] The outcome is often related to the presence and degree of NVC.^[119,120] Moreover, MVD results in sustained pain relief for about 10 years in ~70% of patients with TN,^[16,121] supporting NVC as the source of neuronal damage and pain.

Neuronal and CNS Changes

Volumetric assessment of the affected trigeminal nerve in patients with CTN shows it to be significantly reduced.^[122,123] This reflects atrophy of the nerve, often seen during surgery. Nerve degeneration, neuroinflammation, and edema have also been confirmed on diffusion tensor imaging.^[61,62,124]

Reduced gray matter volume was observed in a cohort of patients with CTN,^[125] similar to those described in other nerve injury models. The reduction of gray matter in some areas correlated with longer disease duration, suggesting a possible role for these structures in the long-term changes associated with CTN, such as increased pain and resistance to pharmacotherapy. Microstructural alterations in white matter have also been shown in CTN, and it is proposed that this is possibly a reactive change to the damage at the level of the root entry zone.^[124]

A case–control functional magnetic resonance imaging study compared patients with CTN before and after MVD surgery with healthy controls.^[126] The researchers assessed activation of primary (SI) and secondary (SII) somatosensory cortices on nonpainful tactile stimulation of lips and fingers in 18 patients with TN and 10 patients with TN relieved from pain after successful neurosurgical intervention in comparison with 13 healthy subjects. SI and SII activations in patients did not depend on the affected side of TN nor differ between operated and nonoperated patients. However, SI and SII activations, but not thalamic activations, were significantly reduced in patients compared with controls. These differences were most prominent for finger stimulation, an area not associated with TN. For lip stimulation, SI and SII activations were reduced in patients with TN on the contralateral side but not on the ipsilateral side to the stimulus. These findings suggest a general reduction of SI and SII processing in patients with TN, indicating a long-term modulation of somatosensory function and pointing to an attempt of cortical adaptation to potentially painful stimuli.

An earlier study investigated the changes in opioid receptor binding in patients with CTN before and after successful surgical treatment.^[127] The volume of distribution of opioid binding was significantly increased after thermocoagulation of the relevant trigeminal division in the anterior cingulate and prefrontal cortices (and other cortical areas), basal ganglia, and thalamus bilaterally. The changes in binding most likely resulted from the postsurgical pain relief. The significant increase in opioid binding within some of the cortical and subcortical components of the pain matrix is consistent with the concept of decreased occupancy by endogenous opioid peptides when pain free. Endogenous opioids are involved in modulating nociceptive responses, and these results reinforce the concept of an altered CNS in patients with TN.

The studies described in the sections above support a pathophysiologic model involving nerve injury, with a significant secondary contribution of CNS structures in the complex pathophysiology of CTN. Although no such injury is present in ITN, CNS mechanisms need to be researched and may play a role in ITN.

Triggering and the Trigeminal Ganglion

Intriguingly, the pain trigger in TN is often innocuous stimulation. How is the trigeminal system altered so that light mechanical touch results in disproportionate pain? The trigeminal ganglion of patients with TN demonstrates degenerative hypermyelination and microneuromata with no significant damage to neuronal soma;^[128,129] although unclear, the initiating event may be related to the injury induced by NVC.

Experimentally, following nerve injury, there is an increased proportion of neurons with subthreshold oscillations (pacemaker activity) that bring neurons close to firing threshold. These neurons often generate ectopic discharges spontaneously or following external stimuli.^[130] Ectopic discharges often last a number of seconds, termed "afterdischarge." Stimulation of the peripheral nerve (particularly A-β fibers) or the dorsal root produces a transient depolarization in passive neighboring C-fiber neurons in the same ganglion.^[131] In experimental setups, about 90% of neurons sampled responded with this "cross-depolarization." In injured nerves, this cross-depolarization leads to prolonged activity in neighboring neurons (crossed afterdischarge). These findings demonstrate a mechanism by which afferent nociceptors could be stimulated by activity in low-threshold mechanoreceptors, particularly following nerve injury. The "ignition hypothesis" was formulated based on these findings.^[132] According to the hypothesis, injury renders axons and axotomized somata hyperexcitable resulting in synchronized afterdischarge activity, cross-excitation of nociceptors, and pain paroxysms. CNS neuroplasticity will no doubt occur in the presence of such peripheral changes and will ultimately affect the clinical phenotype and response to therapy. Although explaining many of the phenomena in CTN, the ignition hypothesis awaits definitive proof.

In a study examining the effects of triggering pain in CTN on CNS structures,^[133] evidence was found for pathological hyperexcitability of the trigeminal nociceptive system. The pain neuromatrix showed significant activation during nonpainful stimulation of the trigger zone, suggesting a state of persistent sensitization of the trigeminal nociceptive system in CTN.^[133] This finding supports the involvement of central mechanisms in the triggering phenomenon of CTN.

Trigeminal Neuralgia With Concomitant Continuous Pain

In a substantial number of patients with CTN and ITN, a constant background pain accompanies paroxysmal pain. Possibly, central mechanisms may be more involved in these cases. One study showed no differences in CNS structures in patients with CTN with or without continuous pain,^[125] but further imaging, neurophysiological, and psychophysical studies are needed on these subgroups.

The etiology of such continuous pain is unclear, and a faulty pain modulation system or central sensitization has been proposed.^[134,135] Patients with CTN with continuous pain experienced no experimental induction of conditioned pain modulation, suggesting a deficient descending inhibitory system.^[135] Additionally, they had more tender points relative to both controls and purely paroxysmal CTN patients, indicating central sensitization extending beyond the trigeminal system.^[135] Central facilitation of trigeminal nociceptive processing was observed in patients with TN with continuous chronic facial pain indicating overactivation of central sensory transmission.^[111]

There are indications that continuous background facial pain is a clinical predictor of poorer treatment response, both pharmacologic and surgical.^{[13,68,69,91,136]} Nearly half of these patients have clinical sensory loss,^[13] and this is a negative predictor for the long-term outcome of MVD^[137] and gamma knife surgery.^[138] MVD provided absolute postoperative pain relief in CTN for 80%–87% of cases and for 47%–79% of CTN cases with background pain.^[91,137] Long-term follow-up (>5 years) revealed excellent results in 75%–80% of paroxysmal but only in 35%–54% of CTN cases with continuous facial pain.^[91,137] The presence of background pain is also a negative prognostic factor in patients with CTN treated by rhizotomy.^[139] In contrast, other centers report no differences in surgical or gamma knife outcomes,^[140,141] and this may be related to different inclusion criteria.

Genetics

Familial clustering^[142–145] has been observed, and a recent review suggests that familial TN is more common than previously considered.^[143] Genetic variants within a 173-gene panel, comprising channel genes encoding sodium, potassium, calcium, chloride, transient receptor potential channels, and gap junction channels were studied in 11 patients with TN with a positive family history.^[143] They demonstrated variants in genes encoding voltage-gated ion channels and transient receptor potential channels within these patients. A correlation has been observed between the serotonin transporter gene, pain severity, and response to carbamazepine.^[146] Together with previous genetic studies,^[147–151] it seems that there is a significant genetic component in signal transduction channels involved in this disorder's pathophysiology.^[15,152]

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Table 1. Subtypes of trigeminal neuralgia and their coding as per the International Classification of Headache Disorders, 3rd edition (ICHD-3)
13.1 Pain attributed to a lesion or disease of the trigeminal nerve
13.1.1	Trigeminal neuralgia (TN)		Note: Clinically established
	13.1.1.1	Classical TN (CTN)
		13.1.1.1.1	CTN, purely paroxysmal
		13.1.1.1.2	CTN with concomitant continuous pain
	13.1.1.2	Secondary TN (STN)
		13.1.1.2.1	TN attributed to multiple sclerosis
		13.1.1.2.2	TN attributed to space-occupying lesion
		13.1.1.2.3	TN attributed to other cause
	13.1.1.3	Idiopathic TN (ITN)
		13.1.1.3.1	ITN, purely paroxysmal
		13.1.1.3.2	ITN with concomitant continuous pain

Table 2. Diagnostic criteria for trigeminal neuralgia
Diagnostic criteria		Notes
A	Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond,¹ and fulfilling criteria B and C	In a few patients, pain may radiate to another division, but it remains within the trigeminal dermatomes Classical trigeminal neuralgia may be preceded by a period of atypical continuous pain termed "pretrigeminal neuralgia" in the literature Pain is overwhelmingly unilateral and does not cross the midline. Bilateral pain may indicate disease (e.g., multiple sclerosis) Most patients suffer pain in the distribution of the second or third division or both Pain may be accompanied by spasm of the facial muscles Periods of remission from days to years may occur
B	Pain has all of the following characteristics: 1. Lasting from a fraction of a second to 2 min 2. Severe intensity 3. Electric shock-like, shooting, stabbing, or sharp in quality	Duration can change over time, with paroxysms becoming more prolonged. A minority of patients will report attacks predominantly lasting for >2 min Attack duration, distribution, etc. may vary between patients but are highly consistent within cases, that is, attacks are stereotyped in the individual patient Pain may become more severe over time Mild autonomic symptoms such as lacrimation and/or redness of the eye may be present
C	Precipitated by innocuous stimuli within the affected trigeminal distribution	Some attacks may be, or appear to be, spontaneous, but there must be a history or finding of pain provoked by innocuous stimuli to meet this criterion. Ideally, the examining clinician should attempt to confirm the history by replicating the triggering phenomenon. However, this may not always be possible because of the patient's refusal, awkward anatomical location of the trigger, and/or other factors A short gap between trigger and pain may be observed (latency). Following an attack, a refractory period occurs where pain cannot be triggered
D	Not better accounted for by another ICHD-3 diagnosis	Other causes are ruled out by history, physical examination, and special investigations. Imaging (preferably MRI) should be done to exclude secondary causes and, in the majority of patients, to demonstrate neurovascular compression of the trigeminal nerve (i.e., establish classical trigeminal neuralgia) Sensory testing may reveal mild deficits in the distribution of the trigeminal nerve

Note: With permission from the International Headache Society.

Table 3. Diagnostic criteria for classical trigeminal neuralgia
Criteria		Comments
A	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 Trigeminal neuralgia	Typically nerve root atrophy and/or displacement due to neurovascular compression (NVC), which are independently associated with the signs and symptoms of trigeminal neuralgia. Classical trigeminal neuralgia is caused by neurovascular compression, most frequently by the superior cerebellar artery. The common site of neurovascular compression is at the root entry zone, with compression by an artery more clearly associated with symptoms than compression by a vein. MRI techniques to measure volume and cross-sectional area of the root are available. Atrophic changes may include demyelination, neuronal loss, changes in microvasculature, and other morphological changes
B	Demonstration on MRI or during surgery of neurovascular compression (not simply contact), with morphological changes in the trigeminal nerve root
Diagnostic criteria for classical trigeminal neuralgia, which is purely paroxysmal or with concomitant continuous facial pain
Purely paroxysmal		With concomitant continuous facial pain
A	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1.1 Classical trigeminal neuralgia	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1.1 Classical trigeminal neuralgia
B	Pain-free between attacks in the affected trigeminal distribution	Concomitant continuous or near-continuous pain between attacks in the affected trigeminal distribution

Note: With permission from the International Headache Society.

Table 4. Diagnostic criteria for secondary trigeminal neuralgia
Criteria		Comments
A	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 Trigeminal neuralgia, either purely paroxysmal or associated with concomitant continuous or near-continuous pain	In many cases, clinically indistinguishable from classical or idiopathic trigeminal neuralgia Clinical examination shows sensory changes in a significant proportion of these patients
B	An underlying disease has been demonstrated known that is to be able to cause, and explaining, the neuralgia	1. Recognized causes are tumor in the cerebellopontine angle, arteriovenous malformation, and multiple sclerosis (MS)
C	Not better accounted for by another ICHD-3 diagnosis 1. Recognized causes are tumour in the cerebellopontine angle, arteriovenous malformation and multiple sclerosis 2. MRI is best equipped to detect an underlying cause for Secondary trigeminal neuralgia. Other investigations may include neurophysiological recording of trigeminal reflexes and trigeminal evoked potentials, suitable for patients who cannot undergo MRI	2. MRI is best equipped to detect an underlying cause for 13.1.1.2 Secondary trigeminal neuralgia. Other investigations may include neurophysiological recording of trigeminal reflexes and trigeminal evoked potentials, suitable for patients who cannot undergo MRI
Most common forms of secondary trigeminal neuralgia
Trigeminal neuralgia attributed to MS		Trigeminal neuralgia attributed to space-occupying lesion
A	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 Trigeminal neuralgia	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 Trigeminal neuralgia
B	B. Both of the following: 1. MS has been diagnosed 2. An MS plaque at the trigeminal root entry zone or in the pons affecting the intrapontine primary afferents has been demonstrated by MRI, or its presence is suggested by routine electrophysiological studies showing impairment of the trigeminal pathways	Both of the following: 1. A space-occupying lesion in contact with the affected trigeminal nerve has been demonstrated 2. Pain has developed after identification of the lesion or led to its discovery
C	Not better accounted for by another ICHD-3 diagnosis	Not better accounted for by another ICHD-3 diagnosis

Note: A third type is defined by ICHD: "Trigeminal neuralgia attributed to other cause." This is designed to be a flexible diagnosis that may include various causes of secondary TN with criteria that clearly link the disorder to the signs and symptoms.
With permission from the International Headache Society.

Table 5. Diagnostic criteria for idiopathic trigeminal neuralgia
Criteria		Comments
A	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1 Trigeminal neuralgia, either purely paroxysmal or associated with concomitant continuous or near-continuous pain	A contact between a blood vessel and the trigeminal nerve and/or nerve root is a common finding on neuroimaging in healthy subjects. When such a contact is found in the presence of 13.1.1 Trigeminal neuralgia but without evidence of morphological changes (e.g., atrophy or displacement) in the nerve root, the criteria for 13.1.1.1 Classical trigeminal neuralgia are not fulfilled and the condition is considered idiopathic
B	Neither 13.1.1.1 Classical trigeminal neuralgia nor 13.1.1.2 Secondary trigeminal neuralgia has been confirmed by adequate investigation including electrophysiological tests and MRI
C	Not better accounted for another ICHD-3 diagnosis	Electrophysiological tests nor MRI showing significant abnormalities
Diagnostic criteria for idiopathic trigeminal neuralgia, which is purely paroxysmal or with concomitant continuous facial pain
Purely paroxysmal		With concomitant continuous facial pain
A	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1.3 Idiopathic trigeminal neuralgia	Recurrent paroxysms of unilateral facial pain fulfilling criteria for 13.1.1.3 Idiopathic trigeminal neuralgia
B	Pain-free between attacks in the affected trigeminal distribution	Concomitant continuous or near-continuous pain between attacks in the affected trigeminal distribution

Note: With permission from the International Headache Society.

Table 6. Drugs commonly used in the treatment of trigeminal neuralgia
Drug	Initial dose (mg)	Target dose (mg)^a	#Dose increase (titration)	Schedule
Carbamazepine	100–200	1200–1800	100–200 mg/2 days	x2–4/days
Carbamazepine-CR	200–400	1200	Usually transfer from regular format at equivalent dose	x2/days
OXC	300	1200–2400	300–600 mg/week	x2–3/days
Baclofen	5–15	30–60	5 mg/3 days	x3/days
Gabapentin	300	900–2400	300 mg/2–3 days	x3/days
Pregabalin	150	300–600	50 mg/2–3 days	x2–3/days
Lamotrigine	25	400–600	25–50 mg/week	x1–2/days