Trigeminal Neuralgia

I would like to continue with my theme of questioning established dictums by discussing the evolution of my thinking about an important pain condition: trigeminal neuralgia (TN). The discovery by Gardner and Miklos1 and later Jannetta and colleagues2-6 that TN is often associated with vascular compression of the trigeminal nerve led to one of the most important operations in neurological surgery: microvascular decompression (MVD). There is a strong international consensus that MVD represents the gold-standard surgical procedure for TN and that, the patient's condition allowing, MVD is the procedure of choice for medically intractable TN. MVD is important because it is one of the most elegant and satisfying operations we do, satisfying to both the patient and the surgeon because it provides sustained pain relief from this horrific condition. MVD is also about as elegant a procedure as we do in neurological surgery, exemplified by the liberation of the trigeminal nerve from compression by the superior cerebellar artery shown in the video (see Video, Supplemental Digital Content 1, https://links.lww.com/NEU/A860, which shows MVD performed in a patient with TN type 1 [TN1] with a right trigeminal nerve with compression from the superior cerebellar artery). I will discuss MVD more tomorrow, but suffice it to say that this operation represents a major bright spot in the otherwise difficult world of pain surgery. Now we come to the question of what we know about TN and what we think we know. I, like most of you, was taught that neurovascular compression (NVC) is essential to the development of TN. However, multiple lines of evidence now convince me that this is not necessarily the case. I will review this evidence, which consists of the following: high-resolution 3-dimensional magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) images, cases of bilateral TN, population studies of TN, post-MVD recurrence of TN, and age and the influences on the onset of TN. During my residency training, I was taught that there were 3 facial pain diagnoses: TN, atypical TN, and atypical facial pain. The problem with this scheme is that there are no objective boundaries to these categories, which makes the scientific study of the natural history of facial pain with these definitions virtually impossible. It is akin to studying head injury before the Glasgow Coma Score. Many organizations and societies have put forth comprehensive, detailed, and structured classification schemes for facial pain, but unfortunately, none of these resulted in meaningful natural history or outcome studies, and there has been little consensus on the best classification system. Our goal was to develop a system that would be straightforward and that would be driven by the patient's history and symptoms.7 Facial pains that were completely spontaneous in onset were considered to be TN: TN1 for pains that were predominantly (> 50%) episodic, lancinating, “electric,” triggerable, subject to pain-free intervals, and generally responsive to anticonvulsant therapy; and type 2 (TN2) for more constant (> 50%), dull, aching, burning pain without pain-free intervals and fundamentally not responsive to anticonvulsants. Trigeminal neuropathic pain was the pain that followed inadvertent injury to the trigeminal system (facial injury or dental/oral surgical procedures with injury to a trigeminal branch). Trigeminal deafferentation pain was pain that occurred after intentional injury to the trigeminal system such as trigeminal neurectomy or rhizotomy and can be thought of as variations on anesthesia dolorosa. Symptomatic TN was that which occurred in patients with multiple sclerosis, and post-herpetic neuralgia occurred after the outbreak of ophthalmic zoster (shingles). Atypical facial pain was reserved for the rare patient with predominantly psychogenic pain, proven by neuropsychological testing. TN1 is probably the most important of the 6 diagnoses in our scheme because it largely represents what has been called classic TN, a condition for which we have numerous effective medical and surgical options. Our classification system has been implemented for more than a decade as part of a free, anonymous, online, autodiagnostic Web site using a neural network expert system to allow patients to gain insight into the nature of their pains, to establish their diagnosis, and to avoid ineffective or ill-advised therapy.8 The classification system has proven to have a high specificity and sensitivity for all 6 diagnostic categories9 and prognostic implications for the outcome of MVD for TN.10 Starting in 2007, we developed a routine imaging paradigm that allowed direct visualization of the trigeminal nerve and any offending vessel before surgery with high-resolution T2 MRI (balanced fast-field echo) fused with an MRA. The image (Figure 1) shows the left trigeminal nerve and a looping superior cerebellar artery emerging from the superior root entry zone. We found that imaging had a high sensitivity (0.96) and specificity (0.90) for the detection of trigeminal NVC or lack thereof.11,12FIGURE 1: Visualization of the trigeminal nerve and the offending vessel, before surgery, with high-resolution T2 magnetic resonance imaging (balanced fast field echo) fused with a magnetic resonance angiography. The image shows the left trigeminal nerve and a looping superior cerebellar artery emerging from the superior root entry zone.As we acquired more MRIs and MRA images, we began to discover that a substantial number of patients with TN1 did not seem to have any imaging evidence of NVC (Figure 2). Furthermore, if MRI/MRA did not suggest NVC, then it was virtually certain that none would be found intraoperatively, as shown in the video (see Video, Supplemental Digital Content 2, https://links.lww.com/NEU/A861, which shows the right trigeminal nerve of a patient with TN1 demonstrating no vascular compression). This encouraged us to look more comprehensively at our population of TN patients with imaging. What we found surprised us: In 1 series of 219 TN1 patients, fully 28.3% had no demonstrable NVC on imaging. This was also true of TN2, a condition similar to TN1 but in which constant pains predominate, as mentioned earlier.13FIGURE 2: Magnetic resonance imaging/angiography fused images showing no neurovascular compression of the left trigeminal root in a patient with trigeminal neuralgia type 1.We also began to examine our patients with recurrent pain after MVD and found that in patients who had undergone their original MVD at Oregon Health and Science University, there was no evidence of recurrent NVC either by imaging or at the time of surgical re-exploration (see Video, Supplemental Digital Content 3, https://links.lww.com/NEU/A862, which shows the left trigeminal nerve of a patient with recurrent TN1 at 10 years after a successful MVD with long-term complete relief of their trigeminal neuralgia; the nerve remains fully decompressed with Teflon fibers interposed between the nerve and the superior cerebellar artery). We, like most centers that see large numbers of patients with TN, also found a small number of patients with bilateral TN1, essentially always occurring at different time periods in their lives. These cases presented an extraordinary opportunity to study the role of NVC in TN. What we found was again somewhat surprising in that in cases of bilateral TN, both TN1 and TN2, < 50% of the nerves had NVC. This was a puzzling finding that demonstrated to us that NVC was not necessarily required for the development of TN in these patients, despite the fact that they all had classic TN1 bilaterally at some point in their lives.13 Perhaps one of our most interesting imaging findings was that 17% of an age-matched asymptomatic patient population demonstrated NVC on MRI/MRA.10 When that frequency of baseline NVC in the general population is combined with the prevalence of TN, an extraordinary result is obtained: 99.94% of NVC is asymptomatic. Or to put it another way, in the general population, the association of TN1 with NVC is insignificant. These population results inspired us to look at our population of TN patients from other perspectives. In doing so, we found that the presence of NVC was clearly related to the age of onset of TN1; that is, patients without NVC were significantly (P = .007) younger (mean age = 42.92 years) than patients with NVC (mean age = 49.65 years; Figure 3).14 In short, it appears that patients with age of TN1 onset between 20 and 40 years are much less likely to have NVC than more typical older patients. Effectively, patients with TN1 without NVC present themselves at a younger age than do TN patients with NVC, as shown in the graph. Perhaps more interesting is the male:female ratio in the population of TN1 patients without NVC. It appears that women dominate this population by a margin of almost 3:1. This suggests that female sex is a risk factor for the development of TN1 at a younger age and without NVC (Figure 4).FIGURE 3: The presence of trigeminal neurovascular compression (NVC) was clearly related to the age of onset of trigeminal neuralgia type 1 (TN1); that is, patients without NVC were significantly (P = .007) younger (mean age = 42.92 years) than patients with NVC (mean age = 49.65 years). It appears that patients with age of TN1 onset between 20 and 40 years are much less likely to have NVC than more typical older patients.14 Reproduced from Figure 1 in Ko AL, Lee A, Raslan AM, et al. Trigeminal neuralgia without neurovascular compression presents earlier than trigeminal neuralgia with neurovascular compression. J Neurosurg. 2015;123(6):1519-1527. With permission from Journal of Neurosurgery.FIGURE 4: Comparison of the male:female ratio in the population of patients with trigeminal neuralgia type 1 (TN1) with and without trigeminal neurovascular compression (NVC). It appears that women dominate the population with no NVC by a margin of almost 3:1. This suggests that female sex is a risk factor for development of TN1 without NVC.14 Reproduced from Figure 2 in Ko AL, Lee A, Raslan AM, et al. Trigeminal neuralgia without neurovascular compression presents earlier than trigeminal neuralgia with neurovascular compression. J Neurosurg. 2015;123(6):1519-1527. With permission from Journal of Neurosurgery.Despite my appreciation and respect for MVD as a treatment of TN1, it has always bothered me that after MVD there seems to be a relentless rate of recurrence of TN, despite what appeared to have been a successful MVD previously. If NVC is the cause of TN, why does it ever recur after the NVC is relieved? A Cochrane analysis15 demonstrates the recurrence rates for several surgical procedures used to treat TN1. Despite the fact that MVD produces the most durable pain relief, recurrence of TN after MVD is both persistent and predictable. We showed much the same natural history in a study published in 1988, with an average TN recurrence rate of 4%/y after MVD (Figure 5).16 The question is not if TN reoccurs after MVD but rather why pain ever recurs. I will talk more about MVD tomorrow, as well as a different surgical approach to patients with TN and no NVC or patients who have experienced recurrent TN1 after MVD.FIGURE 5: Kaplan-Meier analysis of the recurrence of trigeminal neuralgia after microvascular decompression (MVD) over time, demonstrating an average trigeminal neuralgia recurrence rate of 4%/y.16 Adapted from Figure 1 in Burchiel KJ, Clarke H, Haglund M, Loeser JD. Long-term efficacy of microvascular decompression in trigeminal neuralgia. J Neurosurg. 1988;69(1):35-38. With permission from Journal of Neurosurgery.Currently, my hypothesis on the origins of TN1 is that the risk of development of TN1 is in large part determined genetically. NVC clearly plays a role in some TN cases. However, NVC is not essential for the development of TN. Tomorrow I will discuss my conclusion that MVD works by acute and chronic compression injury to the trigeminal nerve. I would like to conclude by mentioning an ongoing study directed at finding the genes that predispose individuals to the development of TN. Under the auspices of the Facial Pain Research Foundation, a group of international investigators from 9 centers in the United States, Canada, and Britain are now studying a well-described and -phenotyped group of patients with TN1 using a comprehensive DNA sequencing approach. It is unlikely that a single gene will be found that reliably results in TN1; more likely, we will uncover a cluster of genes that predispose individuals to the development of this disorder. Several candidate genes have already been identified, and our ultimate plan is to perform this genome-wide association study in 1000 patients with TN. Results for the first 500 patients should be available by the end of 2015. In conclusion, multiple lines of evidence argue that NVC is not required for the development of TN. This conclusion is supported by data from our patient population with TN: 28% of TN1 patients did not have NVC; < 50% of patients with bilateral TN1 have bilateral NVC; younger and female patients tend to develop TN without NVC; TN reoccurs after MVD without demonstrable recurrent NVC; and in the general population, trigeminal NVC is essentially never associated with TN. Again, I thank you for your attention, and it has been a pleasure to talk to you about TN this morning. Thank you all very much! Disclosure The author has no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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