Purely Paroxysmal or With Concomitant Continuous Pain
Most of the available data on clinical features have been published according to the definition of "CTN" in common use up till the publication of ICHD-3. Presently, according to ICHD-3, this would include the recently classified ITN. In general, the clinical features across the subtypes (CTN, ITN, STN) seem to be very similar and, as stated, support the use of imaging in all TN. Although most patients with TN report characteristic, paroxysmal attacks of pain, some patients present with a history of concomitant continuous pain and are classified separately (Table 1 and Table 2). TN with continuous pain may account for up to 30% of patients;[12,13] it has historically been referred to as "atypical" or "type 2."
Location. TN is a unilateral facial pain syndrome.[1,12,14,15] Bilateral cases have been reported in 2%–5% of cases, but one side usually precedes the onset of pain on the contralateral side by years.[13,16,17] Bilateral pain is considered an ominous sign that needs rapid investigation. Reviews of case series suggest that the right side is involved more often, but the clinical significance is doubtful. Pain location is usually described according to the major branches of the trigeminal nerve. Pain in one branch is reported by 36%–42% of patients: in 17%–19%, pain occurs in the maxillary or the mandibular branch, whereas pain solely in the ophthalmic occurs in about 2% (Figure 2). Most commonly, pain involves the maxillary and mandibular branches jointly (35%), and pain in all three branches occurs in 14% of patients. The jaws are, therefore, involved in most cases (Figure 3, dashed oval),[11,12,15,19–22] explaining why patients with TN so often seek help from dentists. Pain radiation is usually within the dermatome of origin.
Distribution of pain in classical or idiopathic trigeminal neuralgia. Pain is unilateral in the overwhelming majority of patients (>95%). On the right side of the face, the percentage of pain reported affecting single branches of the trigeminal nerve is shown. On the left side of the face, the percentage of pain occurring in combined branches is shown. The separation of percentages to the two sides of the diagram is for clarity only. The total as per the figure is not 100%: partly explained by the fact that the figures were drawn from multiple sources and that bilateral cases are not included. These figures are however secondary to the message they convey: The majority of patients with TN (about a sizable proportion) experience pain in trigeminal divisions II and III concomitantly. Isolated pain in either division II or III is very common. Thus, pain occurring singly in the mandible and/or maxilla accounts for 69% of patients (included within the dashed oval), partly explaining why patients often approach dental practitioners for an opinion. (This figure is an original drawing by the author (RB) using computer software.) [Color figure can be viewed at wileyonlinelibrary.com]
Trigger zone distribution in a cohort of 70 prospectively enrolled patients with classical or secondary trigeminal neuralgia. Upper panel: Extraoral territories. Lower panel: Intraoral territories. Left column: Trigger-zone contours. Right column: Trigger-zone overlap profiling. The number of superimpositions ranges from 2 (cyan) to 15 (dark orange). The number of trigger zones in the intraoral territory is smaller in comparison with the number of patients reporting talking or chewing as the main trigger maneuvers because of the patients' difficulty in identifying a circumscribed trigger-zone region within the mouth. From Di Stefano et al., 2018, with permission from the International Headache Society [Color figure can be viewed at wileyonlinelibrary.com]
Although the location, intensity, and triggers of TN vary across patients, they may be stereotyped within individual patients with TN, that is, each attack is similar in location, duration, and intensity. However, some patients may report differences in location within the same affected area as well as differences in duration and intensity.
Quality and Severity. Pain in TN is most often described as shooting, sharp, piercing, stabbing, or electrical in nature (70%–95%).[11,12,15,20,21,23] Pain severity in TN is extreme; with ratings of 9–10 on a 10-cm visual analog scale (VAS).[14,24] Less severe attacks may also occur.
Triggering. The diagnostic criteria for TN include that pain is precipitated by light, innocuous stimuli in trigger areas (Figure 3). Spontaneous pain is reported by some patients (68%–98%),[15,25,26] but it is unclear whether these reflect triggering by subconscious day-to-day activities, such as swallowing and lip movement, that may go unnoticed. When attacks are reported as spontaneous, the precise location of the trigger areas may be difficult to identify clinically. A short gap between stimulation of a trigger area and pain onset may be observed and is termed latency. Trigger areas in TN are usually in the distribution of the affected trigeminal branch (Figure 3), particularly around the lips but may rarely be extratrigeminal,[4,14,25] usually multiple and even change location. The triggering stimuli are innocuous and include talking (76%), chewing (74%), touch (65%), temperature (cold 48%, heat 1%), wind, and shaving.[14,15] The most common extraoral trigger areas are the nasolabial fold, the lips, the cheek, and the chin. Intraoral TN triggers and pain are more often associated with the alveolar gingivae[14,28] (Figure 3).
Figure 3 clearly illustrates the density of trigger areas around the lips, nasolabial folds, and intraoral areas. These are typical areas for pain of dental or otolaryngologic origin and, together with pain location (Figure 2), partly explain the misdiagnoses made between TN, dental, and otolaryngologic pain.
The triggering of TN-like pain by gustatory stimuli is an interesting phenomenon that has been described as both primary and secondary (postsurgical) syndromes. The initiation of pain by sweet or salty foods is usually associated with dental pathology so that these cases present a difficult diagnosis.
Temporal Pattern. TN may begin abruptly, and the patient usually recalls the exact day, or via a rarer preceding syndrome termed pre-TN described below. Individual attacks are characterized by a rapid onset and peak, and then subside, lasting overall from a few seconds up to 2 min. Longer-lasting attacks have been reported, but the significance is unclear.[1,12] Pain is followed by a refractory period during which pain is impossible or extremely difficult to trigger. Attacks occur mostly during the day, but there are reports of nocturnal TN.[33,34]
Long-term follow-up of patients with TN reveals that there are well-defined periods of pain attacks variably followed by periods of remission that may last from weeks to years. This pattern complicates the research and management of TN as often temporary remission is misinterpreted by patients/carers as treatment success. The median active period is reported at about 49 days followed by remission of some months (36%), weeks (16%), or even days (16%). Only 6% may look forward to remissions of more than a year, and about 20% experience incessant attacks.[11,35,36] Following a first attack of TN, it has been calculated that 65% of patients will have a second attack within 5 years and 77% within 10 years.
Natural History and Prognosis. TN has historically been considered a progressive disease with a poor prognosis. The available data at the time suggested that 90% of TN cases eventually reported increased attack frequency and severity.[14,38] It must be stressed that the inclusion criteria of the historical data may not reflect current classification groupings. Based on the same type of data, the initial response to carbamazepine was cited at around 70% and by 5–16 years the response rate dropped to 20% with 44% of patients requiring drug combinations or alternative medication. Long-term follow-up of oxcarbazepine (OXC)-treated TN cases demonstrated a high failure rate necessitating surgery.
More recent data suggest that typical paroxysmal TN acts quite differently. Of 95 patients treated with carbamazepine and 83 with OXC (at usually acceptable dosages), the initial response was 98% and 94%, respectively. Side effects were common in both drugs and reduce QoL that may lead to cessation of therapy.[40,41] Drug resistance at the 13-month time point was rare, and 7% required a neurosurgical intervention. This suggests that the immediate response rate is better than previously thought and that the short-term prognosis is good. The data, which were collected from paroxysmal patients with TN exclusively, strengthen current thinking that different TN subgroups respond differentially to standard therapy. We are still in need of long-term, high-quality studies on the natural history of TN in its various forms and the long-term response to various therapies.
Associated Sensory Signs. Although clinically detectable neurological changes suggest STN, mild sensory disturbances, particularly hypoesthesia, have been documented in TN. These deficits, that may go unnoticed in gross examination, may be more readily detected when using sophisticated examination techniques, particularly quantitative sensory testing (QST).[15,42–45] Reflex and evoked potential studies reveal nociceptive fiber dysfunction in TN. Following successful microvascular decompression (MVD), nerve conduction properties return to normal, but clinical improvement is often delayed. More recently, examination of a large series of patients with TN revealed sensory abnormalities in around 30%. The authors suggest that clinically detected sensory abnormalities should form part of the spectrum of TN.
Interesting findings emerge from a blinded QST study on patients with TN with no clinically detectable sensory abnormalities. They found generalized subclinical hypoesthesia (increased mechanical detection threshold), which was more pronounced on the symptomatic side, in trigeminal and extratrigeminal sites relative to controls. This would suggest generalized, rather than segmental, somatosensory plasticity.
Accompanying Autonomic Signs. Characteristically lacrimation is not considered a sign of neuropathic type pain. However, lacrimation and rhinorrhea have been reported in TN. Lacrimation has been described in ophthalmic, maxillary, and mandibular TN.[12,50–52] This presentation is diagnostically challenging vis-à-vis the short-lasting trigeminal autonomic cephalgias (see below). The appearance of lacrimation in TN is inconsistent occurring in about a quarter of cases and seems to correlate with increasing pain severity—possibly by initiating the trigeminal autonomic reflex. The presence of lacrimation indicates a poorer prognosis for surgery and pharmacotherapy.[51,53] Evidence of autonomic activity in TN is also found in reports of facial flushing (vasodilation), increased salivation, and swelling.[51,54] The true significance of tearing in TN is, however, unclear.
Investigations. There are no specific diagnostic tests for TN. Mostly, tests are aimed at excluding alternate diagnoses. A neurologic examination should be routine and thorough evaluation with adequate testing by relevant specialists is appropriate. In all cases, dental examination with radiographs of oral structures should be considered to rule out oral pathology.
Preparing for Pharmacotherapy. All patients to be treated with anticonvulsants need baseline and follow-up of hematologic, electrolyte, and liver function tests. Baseline ECG is highly recommended. Anticonvulsants increase the risk for suicidality and careful follow-up of patients, particularly of at-risk individuals and close collaboration with the family physician should be maintained. In patients of Asian ancestryto be treated with carbamazepine, HLA-B*1502 testing to assess the risk of Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is recommended by the FDA. Patients at risk for SJS/TEN with carbamazepine also carry an increased risk with other antiepileptic drugs (AEDs). Women in child-bearing years should be informed of the teratogenic potential of AEDs and advised regarding contraception and pregnancy.[55,56]
Imaging. Imaging in TN has two aims: to establish and assess NVC and to exclude disease and tumors in the central nervous system (CNS), thereby establishing diagnosis. Some clinical centers do not or are not equipped to image their patients with TN on a routine basis. However, the European Academy of Neurology states, "magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN." The ICHD-3 does not specifically address the issue other than to stress that imaging is the only way to establish the precise diagnosis. The American Academy of Neurology rates imaging as level C diagnostic evidence. Their data reiterate that STN will occur in about 15% of TN cases and, thus, our recommendation would be to always image when possible.
For routine diagnosis and treatment planning in TN, MRI is the method of choice. NVC is clearer using 3-Tesla resolution although lower resolutions may be used and are good enough at depicting space-occupying lesions. To reliably detect and accurately grade the severity of neurovascular contact, three high-resolution sequences are recommended: 3D T2-weighted, 3D time-of-flight, and MR angiography with 3D T1-weighted gadolinium.
Neural structure is best studied with diffusion tensor imaging, for now largely restricted to the research field. This technique has shown altered nerve structure as a result of NVC. Fractional anisotropy, an indicator for white matter integrity, is altered in the nerve root entry zone of patients with TN.[60–64] This would suggest demyelination or dysmyelination as is seen in histological samples of nerve root biopsies from patients with TN.[65,66]
Quality of Life. The severity of TN has resulted in patients committing suicide; however, TN does not alter life expectancy. QoL is much reduced in patients with TN either as a direct effect of the pain or secondary to drug side effects.[14,41] Patients with TN are often depressed and anxious and need family and possibly professional support.
Headache. 2021;61(6):817-837. © 2021 Blackwell Publishing