Trigeminal neuralgia: opportunities for research and... : PAIN (original) (raw)
1. Introduction
The clinical hallmark of trigeminal neuralgia (TN) is a sudden, excruciating paroxysm of pain in the distribution of the trigeminal, or fifth cranial, nerve (Loeser, 1989; Zakrzewska, 1997). The intensity is so severe that patients wince, thereby giving rise to the original name for the condition, tic douloureux. The paroxysmal pain of TN is initiated by innocuous stimulation of discrete areas, the so-called ‘trigger zones’, which concentrate near the lower central portion of the face (cheek, chin, lips, or tongue). The median age at diagnosis is 67 years (Katusic et al., 1990). The diagnosis of TN depends strictly on clinical criteria (Merskey and Bogduk, 1994). There are no objective laboratory or pathological tests for diagnosis. The anticonvulsant drug carbamazepine is considered the drug of choice. However, carbamazepine's effectiveness may taper, and side effects are a major problem. Several other drugs, usually other anticonvulsants used for neuropathic pain, are also somewhat effective (Fromm, 1994). Many patients who eventually become refractory to medication are candidates for one of several surgical options.
The etiology of most cases of TN has been suggested to be vascular compression of the central axons of the trigeminal nerve at the level of the pons, resulting in focal demyelination (Jannetta, 1967). Demyelination of the trigeminal nerve also appears to account for the 2–4% of TN patients with multiple sclerosis (Jensen et al., 1982). The etiological roles of compression and demyelination are, however, only inferred from clinical observations rather than from experimental manipulations. Thus, a foremost research question is to confirm compression and demyelination in the etiology of TN. Confirmation of etiology and identification of pathophysiological mechanisms have been hampered by the lack of an animal model with key features of TN (Loeser, 1989; Rappaport and Devor, 1994).
2. Epidemiology
There is a paucity of population-based and clinical epidemiologic research on TN. Much of the available epidemiologic information has emerged from two studies of treated cases in the US. One study from Minnesota identified 75 patients receiving medical or surgical treatment over a 40-year period (1945–1984) (Katusic et al., 1990), and the other from Massachusetts compared 526 patients receiving neurosurgical treatment for TN over nearly 20 years (1955–1974) with a control group of patients receiving spinal surgery (Rothman and Monson, 1973). Both studies found an overall incidence rate of about three to five cases per year per 100 000 persons. The studies also agreed that incidence rates increased with age. The findings diverged somewhat with respect to gender: Katusic et al. (1990) found an age-adjusted female to male ratio of 1.74, whereas Rothman and Monson (1973) found a ratio of 1.17. While there is a widespread clinical observation of higher occurrence of TN in women, it may be that the composition of the clinical population is more a reflection of age as a clear risk factor (given that the proportion of women in the population increases with age).
Multiple sclerosis (MS), according to both studies, was also a risk factor. Additional risk factors were identified in only one of the two studies, and thereby require confirmation in future research, i.e. hypertension (Katusic et al., 1990), being non-Jewish, US born, non-smoking, and non-drinking (Rothman and Monson, 1973). Reports about familial clustering have been contradictory. Further research is clearly warranted on risk factors in order to furnish pivotal clues to pathophysiology.
There also is scant study of the natural history of TN through longitudinal studies. Clinical experience, for example, suggests that TN worsens over time, with duration of pain episodes becoming longer and pain spreading to larger areas of the face (Loeser, 1989; Barker et al., 1996). Further, little is known about comorbidity and prodromal symptoms (Fromm et al., 1990). Only recently have researchers begun to measure the impact of TN on psychological well-being (Zakrzewska et al., 1999).
2.1. Opportunities for epidemiological research
A concerted program of epidemiologic studies is needed to identify these key features of TN: prevalence and public health impact, especially among women and members of minority groups; risk factors; comorbidity; prodromal symptoms; and natural history. Population-based epidemiological studies are essential to determine the spectrum of TN symptoms in the population, identifying individuals in whom symptoms are mild enough that they do not seek treatment. Potentially useful approaches in studying the epidemiology of TN include multi-site population-based studies (e.g. in HMOs) and patient registries using standardized case definitions.
3. Diagnosis and assessment
Problems surround patient diagnosis and assessment, in spite of the availability of diagnostic criteria. The rare occurrence of TN, the absence of objective tests, and the range of facial pain syndromes make diagnosis difficult for non-specialists. One study of referral patterns for facial pain (of all types) found patients to have sought help from an average of 4.88 providers before referral to a pain clinic. At some point in the referral process, about 70% saw a general dentist or a dental specialist, and about 30% saw a physician (Turp et al., 1998b). Few, if any, studies have expressly examined referral patterns for TN patients, nor the accuracy of diagnosis. Education about TN diagnosis is essential for dentists and primary care physicians.
Few studies have furnished detailed assessment of the sensory features of TN and the nature of triggering stimuli. Pioneering studies were conducted by Kugelberg and Lindblom (1959) and Dubner et al. (1987). Though limited to small numbers of patients, these studies identified prominent clinical features as follows: (1) triggering only by non-noxious, mechanical stimuli; (2) temporal summation of trigger stimuli; (3) afterdischarge; (4) migration of trigger zone; (5) spatial radiation; and (6) trigger zone outside of affected trigeminal branch. Relatedly, there is scant assessment of abnormalities in sensory thresholds. While sensory loss (hypoesthesia) is detected in 37% of patients referred to neurosurgery (Barker et al., 1996), the degree is minimal enough to be overlooked during routine neurological examination (Dubner et al., 1987; Merskey and Bogduk, 1994). There also appear to be no studies in which patients' pain and sensory abnormalities have been mapped topographically, as has been accomplished for other pain conditions using several approaches (Turp et al., 1998a; Moriwaki and Yuge, 1999).
3.1. Opportunities for research on patient diagnosis and assessment
Diagnostic criteria for TN need validation, especially for accuracy and ability to distinguish between TN and related pain conditions. Novel approaches to diagnosis in the clinical setting need to be devised, especially through objective tests such as neuroimaging. Detailed assessment techniques, such as topographical mapping of pain and sensory thresholds, are needed to facilitate understanding of pain mechanisms and response to treatment.
4. Etiology and pain mechanisms
Vascular compression of the central axons of the trigeminal nerve, typically at the root entry zone near the pons, has been inferred to be a possible cause of TN in most patients. The resulting demyelination is postulated to alter the electrical activity of trigeminal neurons. Vascular compression combined with signs of demyelination or nerve injury are found in the overwhelming majority of surgical patients (Jannetta, 1967; Burchiel et al., 1981; Hamlyn and King, 1992). When the vessels (mostly arteries, but occasionally veins) are separated from the nerve and/or removed through microvascular decompression, patients' paroxysmal pain disappears almost immediately (Barker et al., 1996). Magnetic resonance imaging studies, which have only in the last few years permitted preoperative visualization of neurovascular relationships, reveal vascular contact with the nerve in a high proportion of surgical patients (Meaney et al., 1995). However, they also reveal contact in about 6–32% of nerves in asymptomatic controls (summarized in Majoie et al., 1997), although the resolution is not fine enough to demonstrate whether the contact represents compressive injury to the nerve.
What casts some doubt on the vascular compression hypothesis is that it is difficult to understand mechanistically how contact by arteries and veins of varying size, and with such different pressure differentials, could compress the axons sufficiently and uniformly to produce a distinct clinical syndrome. Further, since individuals without TN will not have surgical exploration of the entry point of the trigeminal axons into the pons, it is extremely difficult to estimate how often an asymptomatic association between vessels and the trigeminal pontine entry zone occurs. There is a major need to be able to identify non-invasively with high spatial resolution the incidence of contact between vessels and trigeminal axons in order to unravel whether compression alone is sufficient to account for TN.
Thus, while the evidence favors vascular compression as an important factor in TN, there is a lack of control data and no formal experimental evidence from model systems that such compression produces abnormal excitability. Several animal models have been developed (e.g. Black, 1974; Burchiel, 1980; Vos et al., 1994), but none has successfully exhibited the clinical hallmarks of paroxysmal pain and trigger points (Rappaport and Devor, 1994).
Assuming that a structural lesion sets the pathological process in motion does not by itself explain the pathophysiology of TN, i.e. the mechanisms giving rise to its clinical phenomenology (Loeser, 1989). There has been insufficient study of TN to answer the most fundamental questions about pathophysiology, i.e. which types of sensory fibers carry trigger stimuli, and what types of central and peripheral alterations underlie the experience of paroxysmal pain and the other clinical features? For many other neuropathic pain conditions, research has begun to uncover a wealth of neuroplastic mechanisms underlying pain at the functional, biochemical, and morphological levels (Levine and Taiwo, 1994; Woolf and Mannion, 1999). Research also has uncovered contributions to neuropathic pain from myelin and immune cells. Their pathophysiological contributions have been shown to be through direct effects on neuronal signaling or through indirect effects exerted by growth factors or inflammatory mediators (Woolf and Mannion, 1999). Yet the pathophysiological changes in neurons and non-neuronal cells are completely unexplored for TN.
Several theories of pathophysiology have been proposed to explain TN's clinical features and the efficacy of vascular decompression surgery. These theories, which focus on alterations either in the trigeminal ganglion or more centrally, include epileptogenic activity, reverberating circuits, ephaptic connections, and changes in central connectivity (Loeser, 1989). The most recent and detailed theory was proposed by Rappaport and Devor (1994) to account for almost all clinical features of TN. They hypothesized that compression-induced damage to the trigeminal root leads to hyperexcitability of a small cluster of trigeminal ganglion neurons, which, in turn, forms an ‘ignition focus’ that spreads to more regions of the ganglion. What is unanswered, however, is how any compression-induced excitability would enable activity in low-threshold sensory fibers to induce paroxysmal pain that would normally only be evoked by a massive barrage of activity in high threshold C-fiber nociceptors. This paradox lies at the heart of the pathophysiology of TN: how does a normally innocuous input activate severe paroxysmal pain? There is certainly good evidence that the tactile allodynia (brush-evoked pain) in other neuropathic pain is mediated by low-threshold mechanoreceptors (A-beta fibers) (Woolf and Mannion, 1999), but there is no comparable situation where light touch provokes paroxysmal pain.
Attempts are underway to identify abnormal electrophysiological changes in single trigeminal ganglion neurons through microneurographic recordings in TN patients at the time of surgery (Baumann and Burchiel, 1997). Electrophysiological studies are imperative to pinpoint which sensory fibers initiate and which fibers generate the paroxsymal pain of TN. Even though pain triggering is inferred to be mediated by A-beta fibers by virtue of the non-noxious nature of triggering stimuli and the latency of activation (Kugelberg and Lindblom, 1959; Dubner et al., 1987), direct evidence in a large patient population is lacking. Pharmacological agents like capsaicin, which activates nociceptors selectively, may also be useful in parsing out the roles of A-beta fibers and nociceptors in pain triggering versus paroxysmal pain discharge. Other pharmacological agents as well as functional imaging may also help to disentangle central and peripheral pathophysiology. The problem is essentially whether low threshold A-beta fiber trigger input activates peripheral hyperexcitable C-fibers or does the A-beta fiber input activate hyperexcitable neurons in the spinal trigeminal nucleus in the medulla?
Mechanistic studies are also needed to account for TN's higher prevalence with increasing age and its possibly higher prevalence in women. Women also are at greater risk for recurrence of the condition after a first decompression surgery (Barker et al., 1996). Finally, virtually nothing is known about the role of genes in the pathophysiology of TN. Genetic contributions to complex pain traits are beginning to be studied through quantitative trait locus analysis and other forms of genetic analysis (Mogil, 1999).
4.1. Opportunities for research on pain mechanisms
The pathophysiology of TN warrants more research. Electrophysiological, morphological, biochemical, and genetic abnormalities in both the peripheral and central nervous systems should be explored through human, animal, and tissue studies. Studies need to tease apart which sensory fibers carry signals for pain triggering versus paroxsymal pain discharge. Studies need to examine variation in age, gender, and chronobiology in relation to pathophysiology. Studies also should be conducted on the potential contributions of non-neuronal cells, such as Schwann cells, vascular cells, and cells of the immune system. The development of model systems is essential to confirm vascular compression in the etiology of TN and to probe pathophysiology, yet model systems depend on access to human tissue for determining their fidelity. To foster the full range of investigations, a human tissue bank needs to be established to ensure access to tissue, both post-mortem and surgical specimens.
5. Treatment
Drug therapy is considered the first line of treatment for TN (Fields, 1996; Zakrzewska, 1997). The anticonvulsant carbamazepine has been used since the 1960s for its effectiveness in about 60–80% of patients (Campbell et al., 1966; Rockliff and Davis, 1966). Its effectiveness is so great that a response to carbamazepine is considered diagnostic for TN. However, side effects and eventual loss of efficacy have stimulated the search for other pharmacotherapies. Although several are used, only baclofen (Fromm et al., 1984), pimozide (Lechin et al., 1989), and lamotrigine (Zakrzewska et al., 1997) have been subjected to controlled clinical trials. Clinical trials also are underway for the NMDA receptor antagonist dextromethorphan in order to block central sensitization (I. Gilron, pers. commun.). Other new molecular targets have emerged for other chronic pain conditions with recent advances in understanding mechanisms of neuroplasticity (Woolf and Mannion, 1999). However, the applicability of these targets to the paroxysmal pain of TN awaits understanding of its pathophysiological mechanisms.
The design of clinical trials is hampered by the low incidence of TN, the difficulty of diagnosis (especially with atypical cases), the possibility of spontaneous remission, and the inability to use a placebo-only control group because of the severity of the pain (Zakrzewska et al., 1997). Other limitations relate to the selection of outcome measures. The use of mean pain intensity ratings and global pain relief measures, validated largely for other pain conditions, is complicated by the paroxysmal and episodic nature of TN. Furthermore, the relative merits of medical and surgical treatments are unstudied, despite the fact that up to half of all patients become surgical candidates because they do not respond initially to medication or eventually become refractory (Taylor, 1981).
Several surgical options are available to patients, but there are no randomized controlled trials to guide comparisons of their relative safety and efficacy (Zakrzewska, 1997). In the absence of randomized comparisons, the relative advantages and disadvantages of the various surgical procedures have been debated (Taha and Tew, 1996; Apfelbaum, 1999). Surgical intervention may generate a very powerful placebo response that ethically cannot be controlled for. Other major questions surrounding surgery are which patients are likely to benefit most from which procedure and at what point over the course of their disease. For example, the major predictors of recurrence in a large case series receiving microvascular decompression included female sex, symptoms lasting more than 8 years, and venous compression of the trigeminal root entry zone (Barker et al., 1996). What this suggests is the need for greater research on the mechanisms of TN, including gender-related mechanisms, research on more advanced preoperative imaging technology, and research on matching patients with treatment, including the timing of the procedure relative to the duration of symptoms.
5.1. Opportunities for treatment research
Several lines of research need to be pursued to improve drug and surgical treatments for TN. New molecular targets, carefully chosen from mechanism studies, need to be identified for drug development, and similarities or differences with other paroxysmal non-trigeminal neuropathic pain, such as the lancinating pain typically experienced by patients with brachial plexus avulsion injuries, need to be explored. A potentially rich source of molecular targets are the new classes of voltage-gated ion channels, including several sensory neuron-specific sodium channels. Pilot clinical trials are encouraged because they offer the best prospects for initial testing of pharmacotherapies, especially for a rare condition with difficulty in patient accrual and diagnosis. A funding mechanism for pilot clinical trials is available through the National Institutes of Health (http://www.ninds.nih.gov/scientists/grntcn/pa-97-103.htm). Comparisons of drug and surgical treatments of different types are also critical to enable patients to make informed decisions about treatment. Studies are needed to determine the best match between patients (e.g. age, gender, clinical subtype, duration of symptoms, etc.) and treatments. The development and validation of outcome measures, as well as their consistent use across studies, are especially important for the conduct of treatment research. Neuroimaging may also hold promise for studying treatment efficacy.
6. Conclusion
The workshop uncovered profound gaps in our understanding of TN. The participants highlighted numerous new opportunities for research on epidemiology, diagnosis and assessment, pain mechanisms, and treatment. The time is ripe for basic and clinical researchers to capitalize on advances in pain research in order to demystify trigeminal neuralgia. Collaborative research is destined to yield new targets for drug treatment and, more broadly, new knowledge of pain mechanisms.
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Keywords:
Trigeminal neuralgia; Epidemiology; Diagnosis and assessment; Etiology; Treatment
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