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Trigeminal neuralgia and pain related to multiple sclerosis
PAINÒ 143 (2009) 186–191
www.elsevier.com/locate/pain
Trigeminal neuralgia and pain related to multiple sclerosis G. Cruccu a,b,*, A. Biasiotta b, S. Di Rezze c, M. Fiorelli d, F. Galeotti a,b, P. Innocenti e, S. Mameli f, E. Millefiorini c, A. Truini a,b,g a
Centro Dolore Neuropatico, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy Neurofisiologia Clinica, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy c Centro Sclerosi Multipla, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy d Neuroradiologia, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy e Neurofisiologia, Ospedale di Colleferro, Italy f Medicina del Dolore, Ospedale di Cagliari, Italy g IRCCS San Raffaele, Roma, Italy b
a r t i c l e
i n f o
Article history: Received 7 October 2008 Received in revised form 27 November 2008 Accepted 15 December 2008
Keywords: Trigeminal neuralgia Multiple sclerosis Trigeminal pain Trigeminal reflexes MRI
a b s t r a c t Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P < 0.0001) centred on the intrapontine trigeminal primary afferents. In the non-TN group, brainstem lesions were more scattered, with the highest probability for lesions (P < 0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS-related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second-order neurons in the spinal trigeminal complex. Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Trigeminal neuralgia (TN) consists of paroxysmal attacks of electric shock-like sensations that may develop spontaneously or be evoked by innocuous stimuli in specific facial or intraoral areas (trigger zones). By definition, typical TN is a pain syndrome that arises without a clinically manifested sensory deficit. TN is termed classic when investigation identifies no cause other than a neurovascular contact, or ‘‘symptomatic” when secondary to major neurological disease, such as multiple sclerosis (MS) or benign tumours in the posterior fossa [11,17,18]. About 15% of patients with typical TN are symptomatic [11,17]. Symptomatic TN is frequently related to MS, with MS patients having a 20-fold increased risk of developing trigeminal neuralgia [21]. About 1.9–4.9% of patients with MS have a typical TN [19,20,31,34,35].
* Corresponding author. Present address: Dipartimento Scienze Neurologiche, Università La Sapienza, viale Universita 30, 00185 Roma, Italy. Tel.: +39 06 49694209; fax: +39 06 49914758. E-mail address: [email protected] (G. Cruccu).
MS-related TN has for long been attributed to a demyelinating plaque in the pons, as indicated by a few postmortem specimens [20,24,30]. The plaque theory nevertheless contrasts with the frequent neuroimaging finding of a neurovascular contact with the trigeminal root in patients with TN and MS and the existence of patients with MS in whom TN is the sole clinical manifestation. Others therefore proposed that in most patients with MS, TN merely reflects the high frequency of neurovascular contacts in the normal population [2,4,15,27,28,37]. Indeed, histopathological studies of surgical specimens describe demyelination in the proximal, centrally myelinated part of the trigeminal root both in patients with MS-related TN and in those with classic TN [25,26]. Unfortunately, the question cannot be simply solved through an MRI screening for neurovascular contact because, according to the recent guidelines [10,16], there is no reliable, standardized technique that ensures the demonstration of neurovascular contacts, and because documenting a contact does not prove a causative relationship [1,10,16,18,23]. Because MS-related TN is often a complaint for which patients undergo various surgical procedures [3,4,33], having more infor-
0304-3959/$36.00 Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2008.12.026
G. Cruccu et al. / PAINÒ 143 (2009) 186–191
mation about the real cause of MS-related TN is important both for understanding the pathophysiology of this pain condition and for choosing therapy. Trying to clarify the causes and the mechanisms of MS-related trigeminal pain, in this study we enrolled 130 patients with MS, who underwent clinical examination, trigeminal reflex testing, MRI, and a voxel-based method of analysing MRI data that allow spatial statistics. 2. Materials and methods In a partly retrospective (June 2000–December 2005, 60 patients) and partly prospective study (January 2006–April 2008, 79 patients), we collected 139 consecutive patients from three Italian outpatient centres specializing in MS or neuropathic pain management. Patients included had to have a diagnosis of definite MS, according to Polman et al. [32], and one of these three conditions: typical trigeminal neuralgia for at least six months (group with TN) according to the latest definition of the International Headache Society [17], trigeminal sensory disturbances other than TN, (group without TN), or no symptom or history of trigeminal disturbances (control group). We excluded patients who had undergone surgical interventions for trigeminal neuralgia and patients who after the electric shock-like paroxysm had a long-lasting ‘‘after pain” because atypical [28,29]. All patients underwent a neurological examination. Regarding sensory disturbances, patients were examined for negative (tactile, thermal, and pricking hypoesthesia) and positive symptoms (paroxysmal pain, ongoing pain, dysesthesia, mechanical allodynia, and pinprick hyperalgesia) using standard bedside tools [7]. We also collected demographic and clinical variables, such as gender, age at onset of MS and trigeminal symptoms, side and trigeminal division involved. All patients had dedicated MRI scans. Most patients (115/139) underwent an electrophysiological recording of trigeminal reflexes: blink reflex after stimulation of the supraorbital nerve and masseter inhibitory reflex after stimulation of the infraorbital and mental nerves [8,11]. Methods of trigeminal reflex testing adhered to the Recommendations for Clinical Practice of the International Federation of Clinical Neurophysiology [12]. Responses were considered abnormal when absent or exceeding the normal limits previously calculated in one hundred normal subjects [9]. Neuroradiologists and neurophysiologists who examined prospective patients were aware of MS and blind to the kind and side of symptoms. All patients gave informed consent to the procedures according to the Declaration of Helsinki, and the study was approved by the local Ethical Committees. 2.1. Voxel-based brainstem analysis The brainstem model was subdivided into 5268 volume elements (‘‘voxels”) ranging from 2 2 2 mm to 2 2 4 mm. After MR images were imported and normalised into the brainstem model, each voxel of the model was assigned a value of 0, 0.5, or 1;
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value 1 stood for a voxel certainly involved in the area of MR abnormal signal, value 0 for a voxel certainly uninvolved, and value 0.5 for a voxel only partly involved or disagreed by two raters. For within-group, one-sample analysis the system used the Kolmogorov–Smirnov test. For each voxel, the statistical probabilities for finding an affected voxel in the population were calculated against a hypothetical mean value for the probability of finding a chance lesion, provided by the average number of affected voxels in our population. For two-sample statistical analysis between two groups of patients (those with and those without a given symptom), we used the Mann–Whitney U test. The significance of the results of statistical tests was colour-coded in each voxel, and displayed at its proper location in the brainstem model, creating a 3D statistical map. From the 3D visualization, 2D slices could be extracted along any of the three section planes and further elaborated to smooth the boundaries of the areas containing significantly affected voxels. Further details of the method can be found in the earlier studies [6,11]. 2.2. Other statistics Kolmogorov–Smirnov test was used to evaluate the normal distribution of samples. Fisher’s exact test or chi-square test was used to evaluate frequency differences in sex, side, abnormal trigeminal reflexes and abnormal brainstem MRI, and to compare frequency differences in affected trigeminal divisions. Mann–Whitney test and Kruskal–Wallis with Dunn’s comparisons were used to compare differences in onset age of trigeminal symptoms and multiple sclerosis. For all statistics and graphs, we used Prism 4.0 (GraphPad, Sorrento Valley, CA). All data are reported as mean ± SD. 3. Results 3.1. Clinical findings Of the 139 patients who met the inclusion criteria, nine were excluded because they had neuralgia and other sensory disturbances on the same side of the face. We identified 50 patients with typical TN (without any other sensory disturbance in the trigeminal territory), and 30 patients who had sensory trigeminal disturbances other than TN: 21 had hypoesthesia (4 having selective thermal-pain hypoesthesia), and 16 had neuropathic pain (6 ongoing pain, 8 dysesthesias, and 2 provoked pains). Four patients had bilateral trigeminal symptoms: two had typical TN on both sides, one had typical TN on one side and sensory disturbances on the other, and one had sensory disturbances on both sides. The female/male ratio was about 3/2 in both the groups. In the TN group (but not in the patients with non-TN sensory disturbances), the right/left ratio was again 3/2. In both groups, clinical examination showed that the first trigeminal division was significantly less often affected than the other divisions (P < 0.005). But the frequency of first division affected was the same (about 1/3) in the patients
Table 1 Data from 130 patients with multiple sclerosis with and without trigeminal symptoms (mean ± SD). Patients
TN n = 50 Non-TN n = 30 Controls n = 50 P
Sex (F/M)
32/18 21/9 37/13 >0.502
Affected side (R/L)
31/19 13/17 – = 0.113
MS onset (yrs)
38 ± 12 30 ± 9 30 ± 8 = 0.014
Trigeminal onset (yrs)
43 ± 11 33 ± 10 – <0.00015
Affected divisions (% of patients) V1
V2
V3
P1
17 (34) 10 (33) – >0.502
35 (70) 22 (73) –
37 (74) 19 (63) –
<0.001 <0.005 –
Reflexes (A/N)
MRI (A/N)
41/5 (89%) 23/4 (85%) 3/42 (7%) <0.00012
42/8 (84%) 29/1 (97%) 8/42 (16%) <0.00012
F, female; M, male; R, right; L, left; MS, multiple sclerosis; V1, ophthalmic; V2, maxillary; V3, mandibular; A, abnormal; N, normal; TN, trigeminal neuralgia. Non-TN: patients with trigeminal sensory disturbances other than neuralgia. 1, frequency difference between columns (chi-square) showing lower frequency of the V1 division. All the other statistics are between rows; 2, Chi-square test; 3: Fisher’s exact test; 4, Kruskal–Wallis with Dunn’s comparisons; 5: Mann–Whitney U test.
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bances. MS started later in the TN group than in the non-TN group and the control group (mean 38 vs 30 years and 30 years; P = 0.01), and even later in the sub-group of 15 patients in whom TN was the first symptom of MS (44 years). In the 80 patients with trigeminal symptoms, these started 4.2 years after MS, and at an older age in patients with TN than in those without (43 years vs 33 years); this difference was highly significant (P < 0.0001). Hence, TN began many years later than any other dysfunction. The normalised frequency histogram for onset age in patients without TN had a normal distribution (Kolmogorov–Smirnov test = 0.1285) (Fig. 1A). Although not really bimodal, the histogram for patients with TN showed two peaks, partly overlapped that of patients without TN, whereas the second peak largely exceeded the distribution of patients without TN and fell within the range of classic TN (Fig. 1B) [8,10,28]. 3.2. Trigeminal reflexes and MRI
Fig. 1. Histogram distribution of onset age of trigeminal symptoms. X-axis: years at onset. Y-axis: normalised frequency. (A) Patients with multiple sclerosis and either trigeminal neuralgia (TN, black bars; n = 50) or other trigeminal sensory disturbances (non-TN, white bars; n = 30). Whereas the onset age in non-TN patients has a Gaussian distribution, that in TN-patients shows a second peak (highlighted by the cubic spline curve) exceeding the maximum ages of the non-TN group and partly overlapping with that of patients in (B). (B) Patients with classic TN (CTN; n = 96). ((B) is modified from [9]). Note that the scale of X-axis is not the same in (A) and (B). One asterisk in (A) and one in (B) help to compare the second peak of the TN group with the corresponding position in the CTN histogram.
with TN and those with other sensory disturbances (P > 0.50) (Table 1). The clinical variable that most differentiated the patients with TN was age at onset of MS and age at onset of trigeminal distur-
Most patients in the TN group had abnormal trigeminal reflexes (Table 1) showing delayed latency of the early R1 and SP1 components (Fig. 2). Responses from the affected divisions had delayed mean latencies typical of patients with MS [9,22]: the mean latency of the R1 component of the blink reflex was 18.2 ± 3.9 ms on the symptomatic, and was 13.9 ± 2.9 ms on the healthy side (nine patients had abnormal responses also on the clinically asymptomatic side). The frequency of abnormality was 89%, consistent with the previous data about symptomatic TN [10,16]. In the non-TN group, we found a similar abnormality frequency (85%), only slightly higher than the rate reported in the previous studies assessing the blink reflex alone [22]. In contrast, the control group had a far lower abnormality frequency (7%; P < 0.0001). MRI more frequently detected brainstem areas with abnormal signal in patients with trigeminal disturbances (TN and non-TN) than in control patients (84% and 97% vs 16%; P < 0.0001) (Table 1). 3.3. Voxel-based brainstem analysis One-sample analyses, though yielding wider and less significant areas than two-sample analyses, showed that the brainstem location of the areas of lesion differed in patients with and without TN. In patients with TN, the highest probability of lesion was located in the ventrolateral midpons, whereas in those with sensory
Fig. 2. Trigeminal reflexes. (Left) Schematic drawing of the three trigeminal divisions, stimulation sites at the supraorbital (V1), infraorbital (V2), and mental (V3) nerves, and recording sites from the orbicularis oculi (A) and masseter (B) muscles. (Right) Recordings from a representative patient with trigeminal neuralgia and multiple sclerosis. Early (R1) and late (R2) blink reflex, and early (SP1) and late (SP2) masseter inhibitory reflex. The dashed vertical lines indicate normal latency. Calibration: 10 ms/200 lV. Note that the SP1 responses after V2 and V3 stimulation are strongly delayed on the affected side.
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disturbances other than TN lesions were scattered throughout the brainstem. Two-sample analysis between the TN group (n = 42) and the control group (n = 50) showed an area of very high probability of lesion (P < 0.0001) centred in the ventrolateral pons between the trigeminal root entry zone and the trigeminal nuclei, i.e. along the intrapontine part of the trigeminal primary afferents (Fig. 3A). Two-sample analysis between the non-TN group (n = 29) and the control group (n = 50) showed an area of high probability (P < 0.001) in a region still in the pons, but more caudal, medial, and dorsal, involving the subnucleus oralis of the spinal trigeminal complex (Fig. 3B).
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4. Discussion Unlike earlier studies, we enrolled a large cohort of patients with MS who had a trigeminal involvement, did dedicated neurophysiological and neuroimaging studies, and analysed the brainstem lesions with a voxel-based method that allows spatial statistics. We identified several features that bring information on MS-related trigeminal pain. Our findings suggest that in most patients with MS, the cause of TN is a demyelinating plaque along the intra-axial primary afferents. Although TN cannot be caused by a neurovascular contact alone, a neurovascular contact may concur
Fig. 3. Voxel-based analysis. Axial sections corresponding to the sections 120 and 160 of the Shaltenbrandt atlas. Areas of maximum probability of lesion for the TN group (A, n = 42) and non-TN group (B, n = 29) versus controls. The level of probability is colour-coded. Blue indicates non-significant areas, white the minimum level of significance (P < 0.05), and red the highest level of significance.
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to its development. The other kinds of pain are probably caused by plaques on the second-order neurons. The reason why we did not screen our patients for neurovascular contacts is that no reliable, standardized MRI technique exists to document neurovascular contacts (i.e. even if no contact is seen on MRI, neurosurgeons often find one at operation), and because documenting a contact does not prove a causative relationship (i.e. MRI scans often show and neurosurgeons find contacts with asymptomatic nerves) [10,16]. Bilateral neurovascular contacts are frequent in patients with unilateral TN (71% in the recent study) [1], as well as unilateral or bilateral contacts in subjects who do not have TN (75% in a recent study) [23]. In our MS patients, trigeminal neuralgia was strongly associated (P < 0.0001) with a lesion along the pathway of the presynaptic trigeminal afferents in the pons, and the neurophysiological studies showed severe abnormalities compatible with demyelination at this site. Most important, 89% of patients in our TN-group had abnormal trigeminal reflexes (Table 1), whereas these same reflexes are abnormal in only 3% of patients with classic TN [8,10,16], who presumably have a neurovascular contact alone. These findings argue against a neurovascular contact as a primary and unique cause of MS-related TN. Other findings in this study nevertheless show that the TNgroup differed from the other patients with MS, both those with other trigeminal symptoms and controls. The patients with TN showed the typical right–left asymmetry of classic TN, and had an onset age similar to patients with classic TN (Fig. 1). In patients with MS, TN must therefore develop through some other mechanism. We favour a neurovascular contact because this is acknowledged as the most frequent cause of classic TN [10,16,17]. Furthermore, these two mechanisms, MS and a neurovascular contact, would act on the same primary axons and both would produce demyelination [25,26]. A dual mechanism involving MS and a neurovascular contact receives support from neurosurgical studies on the outcome of microvascular decompression because patients with MS-related TN, despite experiencing a considerable pain relief, benefited less than patients with classic TN [4,15]. An interesting finding in this study was that the site of lesions differed in the two groups of patients with trigeminal symptoms. Whereas in patients with TN they involved the afferents from the first-order neurons, in patients with other sensory disturbances, including ongoing pain and dysaesthesia, they involved secondorder neurons (Fig. 3). In an earlier study using the same 3D brainstem model in patients with ischemic infarctions, we had a group of 25 patients with the same neurophysiological abnormalities and whose infarctions involved the same area found in this study in patients with MS-related TN (see Fig. 5 in [11]), although none of them had TN. We therefore confirm that the typical paroxysms of TN develop only in the presence of demyelination and favour the view that demyelination of the primary afferents, whether produced by MS or chronic compression exerted by a blood vessel or a benign tumor, increases nerve-fibre susceptibility to ectopic excitation and high-frequency discharges [5,13]. Naturally, although TN must necessarily arise from damage to the primary afferents, the pathophysiological mechanism may secondarily involve the central areas that process the nociceptive input [14,36]. In the non-TN group, our voxel-based model of the human brainstem identified the area of highest probability of lesion within the subnucleus oralis of the spinal trigeminal complex. Instead of producing the paroxysmal pain typical of TN, these demyelinating lesions produce sensory deficits or ongoing pain. Although we expect MS to affect myelinated axons rather than cell bodies, the spatial resolution of our system prevented us from distinguishing the two. Furthermore, we had too few patients in the non-TN group to
run separate analyses for specific sensory symptoms. Our impression is that ongoing pain and dysaesthesia could arise from the same areas yielding sensory deficits, though sensory deficits were associated with larger lesions (statistically non-significant). Acknowledgements This study has been supported by grants from La Sapienza University of Rome. The authors do not have any conflict of interest. References [1] Anderson VC, Berryhill PC, Sandquist MA, Ciaverella DP, Nesbit GM, Burchiel KJ. High-resolution three-dimensional magnetic resonance angiography and three-dimensional spoiled gradient-recalled imaging in the evaluation of neurovascular compression in patients with trigeminal neuralgia: a doubleblind pilot study. Neurosurgery 2006;58:666–73. [2] Athanasiou TC, Patel NK, Renowden SA, Coakham HB. Some patients with multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and can be treated effectively with MVD: report of five cases. Br J Neurosurg 2005;19:463–8. [3] Berk C, Constantoyannis C, Honey CR. The treatment of trigeminal neuralgia in patients with multiple sclerosis using percutaneous radiofrequency rhizotomy. Can J Neurol Sci 2003;30:220–3. [4] Broggi G, Ferroli P, Franzini A, Nazzi V, Farina L, La Mantia L, Milanese C. Operative findings and outcomes of microvascular decompression for trigeminal neuralgia in 35 patients affected by multiple sclerosis. Neurosurgery 2004;55:830–9. [5] Burchiel KJ. Abnormal impulse generation in focally demyelinated trigeminal roots. J Neurosurg 1980;53:674–83. [6] Capozza M, Iannetti GD, Mostarda M, Cruccu G, Accornero N. Threedimensional mapping of brainstem functional lesions. Med Biol Eng Comput 2000;38:639–44. [7] Cruccu G, Anand P, Attal N, Garcia-Larrea L, Haanpää M, Jørum E, Serra J, Jensen TS. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11:153–62. [8] Cruccu G, Biasiotta A, Galeotti F, Truini A, Gronseth G. Diagnostic accuracy of trigeminal reflex testing in trigeminal neuralgia. Neurology 2006;66:139–41. [9] Cruccu G, Deuschl G. The clinical use of brainstem reflexes and hand-muscle reflexes. Clin Neurophysiol 2000;111:371–87. [10] Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol 2008;15:1013–28. [11] Cruccu G, Iannetti GD, Marx JJ, Thoemke F, Truini A, Fitzek S, Galeotti F, Urban PP, Romaniello A, Stoeter P, Manfredi M, Hopf HC. Brainstem reflex circuits revisited. Brain 2005;128:386–94. [12] Deuschl G, Eisen A. Recommendations for the practice of clinical neurophysiology. Electroenceph. Clin. Neurophysiol. 1999; Suppl. 52. [13] Devor M, Amir R, Rappaport ZH. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin J Pain 2002;18:4–13. [14] Dubner R, Sharav Y, Gracely RH, Price DD. Idiopathic trigeminal neuralgia: sensory features and pain mechanisms. Pain 1987;31:23–33. [15] Eldridge PR, Sinha AK, Javadpour M, Littlechild P, Varma TR. Microvascular decompression for trigeminal neuralgia in patients with multiple sclerosis. Stereotact Funct Neurosurg 2003;81:57–64. [16] Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology 2008;71:1183–90. [17] Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2nd ed. 2004;24(Suppl. 1):1–160. [18] Herweh C, Kress B, Rasche D, Tronnier V, Tröger J, Sartor K, Stippich C. Loss of anisotropy in trigeminal neuralgia revealed by diffusion tensor imaging. Neurology 2007;68:776–8. [19] Hooge JP, Redekop WK. Trigeminal neuralgia in multiple sclerosis. Neurology 1995;45:1294–6. [20] Jensen TS, Rasmussen P, Reske-Nielsen E. Association of trigeminal neuralgia with multiple sclerosis: clinical and pathological features. Acta Neurol Scand 1982;65:182–9. [21] Katusic S, Williams DB, Beard CM, Bergstralh EJ, Kurland LT. Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: similarities and differences, Rochester, Minnesota, 1945–1984. Neuroepidemiology 1991;10:276–81. [22] Kimura J. Electrically elicited blink reflex in diagnosis of multiple sclerosis. Review of 260 patients over a seven-year period. Brain 1975;98:413–26. [23] Kress B, Schindler M, Rasche D, Hähnel S, Tronnier V, Sartor K. Trigeminal neuralgia: how often are trigeminal nerve-vessel contacts found by MRI in normal volunteers. Rofo 2006;178:313–5. [24] Love S, Coakham HB. Trigeminal neuralgia: pathology and pathogenesis. Brain 2001;124:2347–60.
G. Cruccu et al. / PAINÒ 143 (2009) 186–191 [25] Love S, Gradidge T, Coakham HB. Trigeminal neuralgia due to multiple sclerosis: ultrastructural findings in trigeminal rhizotomy specimens. Neuropathol Appl Neurobiol 2001;27:238–44. [26] Love S, Hilton DA, Coakham HB. Central demyelination of the Vth nerve root in trigeminal neuralgia associated with vascular compression. Brain Pathol 1998;8:1–11. [27] Meaney JF, Eldridge PR, Dunn LT, Nixon TE, Whitehouse GH, Miles JB. Demonstration of neurovascular compression in trigeminal neuralgia with magnetic resonance imaging. Comparison with surgical findings in 52 consecutive operative cases. J Neurosurg 1995;83:799–805. [28] Nurmikko TJ, Eldridge PR. Trigeminal neuralgia-pathophysiology, diagnosis and current treatment. Br J Anaesth 2001;87:117–32. [29] Obermann M, Yoon MS, Ese D, Maschke M, Kaube H, Diener HC, Katsarava Z. Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia. Neurology 2007;69:835–41. [30] Olafson RA, Rushton JG, Sayre GP. Trigeminal neuralgia in a patient with multiple sclerosis: an autopsy report. J Neurosurg 1966;24:755–9. [31] Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis – prevalence and clinical characteristics. Eur J Pain 2005;9:531–42.
191
[32] Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘‘McDonald Criteria”. Ann Neurol 2005;58:840–6. [33] Rogers CL, Shetter AG, Ponce FA, Fiedler JA, Smith KA, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia associated with multiple sclerosis. J Neurosurg 2002;97:529–32. [34] Solaro C, Brichetto G, Amato MP, Cocco E, Colombo B, D’Aleo G, Gasperini C, Ghezzi A, Martinelli V, Milanese C, Patti F, Trojano M, Verdun E, Mancardi GL, and the PaIMS Study Group. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology 2004;63:919–21. [35] Svendsen KB, Jensen TS, Overvad K, Hansen HJ, Koch-Henriksen N, Bach FW. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol 2003;60:1089–94. [36] Watson JC. From paroxysmal to chronic pain in trigeminal neuralgia: implications of central sensitization. Neurology 2007;69:817–8. [37] Zaffaroni M, Baldini SM, Ghezzi A. Cranial nerve, brainstem and cerebellar syndromes in the differential diagnosis of multiple sclerosis. Neurol Sci 2001;22:S74–8.
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Trigeminal neuralgia and pain related to multiple sclerosis G. Cruccu a,b,*, A. Biasiotta b, S. Di Rezze c, M. Fiorelli d, F. Galeotti a,b, P. Innocenti e, S. Mameli f, E. Millefiorini c, A. Truini a,b,g a
Centro Dolore Neuropatico, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy Neurofisiologia Clinica, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy c Centro Sclerosi Multipla, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy d Neuroradiologia, Dipartimento Scienze Neurologiche, Università La Sapienza, Roma, Italy e Neurofisiologia, Ospedale di Colleferro, Italy f Medicina del Dolore, Ospedale di Cagliari, Italy g IRCCS San Raffaele, Roma, Italy b
a r t i c l e
i n f o
Article history: Received 7 October 2008 Received in revised form 27 November 2008 Accepted 15 December 2008
Keywords: Trigeminal neuralgia Multiple sclerosis Trigeminal pain Trigeminal reflexes MRI
a b s t r a c t Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P < 0.0001) centred on the intrapontine trigeminal primary afferents. In the non-TN group, brainstem lesions were more scattered, with the highest probability for lesions (P < 0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS-related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second-order neurons in the spinal trigeminal complex. Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Trigeminal neuralgia (TN) consists of paroxysmal attacks of electric shock-like sensations that may develop spontaneously or be evoked by innocuous stimuli in specific facial or intraoral areas (trigger zones). By definition, typical TN is a pain syndrome that arises without a clinically manifested sensory deficit. TN is termed classic when investigation identifies no cause other than a neurovascular contact, or ‘‘symptomatic” when secondary to major neurological disease, such as multiple sclerosis (MS) or benign tumours in the posterior fossa [11,17,18]. About 15% of patients with typical TN are symptomatic [11,17]. Symptomatic TN is frequently related to MS, with MS patients having a 20-fold increased risk of developing trigeminal neuralgia [21]. About 1.9–4.9% of patients with MS have a typical TN [19,20,31,34,35].
* Corresponding author. Present address: Dipartimento Scienze Neurologiche, Università La Sapienza, viale Universita 30, 00185 Roma, Italy. Tel.: +39 06 49694209; fax: +39 06 49914758. E-mail address: [email protected] (G. Cruccu).
MS-related TN has for long been attributed to a demyelinating plaque in the pons, as indicated by a few postmortem specimens [20,24,30]. The plaque theory nevertheless contrasts with the frequent neuroimaging finding of a neurovascular contact with the trigeminal root in patients with TN and MS and the existence of patients with MS in whom TN is the sole clinical manifestation. Others therefore proposed that in most patients with MS, TN merely reflects the high frequency of neurovascular contacts in the normal population [2,4,15,27,28,37]. Indeed, histopathological studies of surgical specimens describe demyelination in the proximal, centrally myelinated part of the trigeminal root both in patients with MS-related TN and in those with classic TN [25,26]. Unfortunately, the question cannot be simply solved through an MRI screening for neurovascular contact because, according to the recent guidelines [10,16], there is no reliable, standardized technique that ensures the demonstration of neurovascular contacts, and because documenting a contact does not prove a causative relationship [1,10,16,18,23]. Because MS-related TN is often a complaint for which patients undergo various surgical procedures [3,4,33], having more infor-
0304-3959/$36.00 Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2008.12.026
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mation about the real cause of MS-related TN is important both for understanding the pathophysiology of this pain condition and for choosing therapy. Trying to clarify the causes and the mechanisms of MS-related trigeminal pain, in this study we enrolled 130 patients with MS, who underwent clinical examination, trigeminal reflex testing, MRI, and a voxel-based method of analysing MRI data that allow spatial statistics. 2. Materials and methods In a partly retrospective (June 2000–December 2005, 60 patients) and partly prospective study (January 2006–April 2008, 79 patients), we collected 139 consecutive patients from three Italian outpatient centres specializing in MS or neuropathic pain management. Patients included had to have a diagnosis of definite MS, according to Polman et al. [32], and one of these three conditions: typical trigeminal neuralgia for at least six months (group with TN) according to the latest definition of the International Headache Society [17], trigeminal sensory disturbances other than TN, (group without TN), or no symptom or history of trigeminal disturbances (control group). We excluded patients who had undergone surgical interventions for trigeminal neuralgia and patients who after the electric shock-like paroxysm had a long-lasting ‘‘after pain” because atypical [28,29]. All patients underwent a neurological examination. Regarding sensory disturbances, patients were examined for negative (tactile, thermal, and pricking hypoesthesia) and positive symptoms (paroxysmal pain, ongoing pain, dysesthesia, mechanical allodynia, and pinprick hyperalgesia) using standard bedside tools [7]. We also collected demographic and clinical variables, such as gender, age at onset of MS and trigeminal symptoms, side and trigeminal division involved. All patients had dedicated MRI scans. Most patients (115/139) underwent an electrophysiological recording of trigeminal reflexes: blink reflex after stimulation of the supraorbital nerve and masseter inhibitory reflex after stimulation of the infraorbital and mental nerves [8,11]. Methods of trigeminal reflex testing adhered to the Recommendations for Clinical Practice of the International Federation of Clinical Neurophysiology [12]. Responses were considered abnormal when absent or exceeding the normal limits previously calculated in one hundred normal subjects [9]. Neuroradiologists and neurophysiologists who examined prospective patients were aware of MS and blind to the kind and side of symptoms. All patients gave informed consent to the procedures according to the Declaration of Helsinki, and the study was approved by the local Ethical Committees. 2.1. Voxel-based brainstem analysis The brainstem model was subdivided into 5268 volume elements (‘‘voxels”) ranging from 2 2 2 mm to 2 2 4 mm. After MR images were imported and normalised into the brainstem model, each voxel of the model was assigned a value of 0, 0.5, or 1;
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value 1 stood for a voxel certainly involved in the area of MR abnormal signal, value 0 for a voxel certainly uninvolved, and value 0.5 for a voxel only partly involved or disagreed by two raters. For within-group, one-sample analysis the system used the Kolmogorov–Smirnov test. For each voxel, the statistical probabilities for finding an affected voxel in the population were calculated against a hypothetical mean value for the probability of finding a chance lesion, provided by the average number of affected voxels in our population. For two-sample statistical analysis between two groups of patients (those with and those without a given symptom), we used the Mann–Whitney U test. The significance of the results of statistical tests was colour-coded in each voxel, and displayed at its proper location in the brainstem model, creating a 3D statistical map. From the 3D visualization, 2D slices could be extracted along any of the three section planes and further elaborated to smooth the boundaries of the areas containing significantly affected voxels. Further details of the method can be found in the earlier studies [6,11]. 2.2. Other statistics Kolmogorov–Smirnov test was used to evaluate the normal distribution of samples. Fisher’s exact test or chi-square test was used to evaluate frequency differences in sex, side, abnormal trigeminal reflexes and abnormal brainstem MRI, and to compare frequency differences in affected trigeminal divisions. Mann–Whitney test and Kruskal–Wallis with Dunn’s comparisons were used to compare differences in onset age of trigeminal symptoms and multiple sclerosis. For all statistics and graphs, we used Prism 4.0 (GraphPad, Sorrento Valley, CA). All data are reported as mean ± SD. 3. Results 3.1. Clinical findings Of the 139 patients who met the inclusion criteria, nine were excluded because they had neuralgia and other sensory disturbances on the same side of the face. We identified 50 patients with typical TN (without any other sensory disturbance in the trigeminal territory), and 30 patients who had sensory trigeminal disturbances other than TN: 21 had hypoesthesia (4 having selective thermal-pain hypoesthesia), and 16 had neuropathic pain (6 ongoing pain, 8 dysesthesias, and 2 provoked pains). Four patients had bilateral trigeminal symptoms: two had typical TN on both sides, one had typical TN on one side and sensory disturbances on the other, and one had sensory disturbances on both sides. The female/male ratio was about 3/2 in both the groups. In the TN group (but not in the patients with non-TN sensory disturbances), the right/left ratio was again 3/2. In both groups, clinical examination showed that the first trigeminal division was significantly less often affected than the other divisions (P < 0.005). But the frequency of first division affected was the same (about 1/3) in the patients
Table 1 Data from 130 patients with multiple sclerosis with and without trigeminal symptoms (mean ± SD). Patients
TN n = 50 Non-TN n = 30 Controls n = 50 P
Sex (F/M)
32/18 21/9 37/13 >0.502
Affected side (R/L)
31/19 13/17 – = 0.113
MS onset (yrs)
38 ± 12 30 ± 9 30 ± 8 = 0.014
Trigeminal onset (yrs)
43 ± 11 33 ± 10 – <0.00015
Affected divisions (% of patients) V1
V2
V3
P1
17 (34) 10 (33) – >0.502
35 (70) 22 (73) –
37 (74) 19 (63) –
<0.001 <0.005 –
Reflexes (A/N)
MRI (A/N)
41/5 (89%) 23/4 (85%) 3/42 (7%) <0.00012
42/8 (84%) 29/1 (97%) 8/42 (16%) <0.00012
F, female; M, male; R, right; L, left; MS, multiple sclerosis; V1, ophthalmic; V2, maxillary; V3, mandibular; A, abnormal; N, normal; TN, trigeminal neuralgia. Non-TN: patients with trigeminal sensory disturbances other than neuralgia. 1, frequency difference between columns (chi-square) showing lower frequency of the V1 division. All the other statistics are between rows; 2, Chi-square test; 3: Fisher’s exact test; 4, Kruskal–Wallis with Dunn’s comparisons; 5: Mann–Whitney U test.
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bances. MS started later in the TN group than in the non-TN group and the control group (mean 38 vs 30 years and 30 years; P = 0.01), and even later in the sub-group of 15 patients in whom TN was the first symptom of MS (44 years). In the 80 patients with trigeminal symptoms, these started 4.2 years after MS, and at an older age in patients with TN than in those without (43 years vs 33 years); this difference was highly significant (P < 0.0001). Hence, TN began many years later than any other dysfunction. The normalised frequency histogram for onset age in patients without TN had a normal distribution (Kolmogorov–Smirnov test = 0.1285) (Fig. 1A). Although not really bimodal, the histogram for patients with TN showed two peaks, partly overlapped that of patients without TN, whereas the second peak largely exceeded the distribution of patients without TN and fell within the range of classic TN (Fig. 1B) [8,10,28]. 3.2. Trigeminal reflexes and MRI
Fig. 1. Histogram distribution of onset age of trigeminal symptoms. X-axis: years at onset. Y-axis: normalised frequency. (A) Patients with multiple sclerosis and either trigeminal neuralgia (TN, black bars; n = 50) or other trigeminal sensory disturbances (non-TN, white bars; n = 30). Whereas the onset age in non-TN patients has a Gaussian distribution, that in TN-patients shows a second peak (highlighted by the cubic spline curve) exceeding the maximum ages of the non-TN group and partly overlapping with that of patients in (B). (B) Patients with classic TN (CTN; n = 96). ((B) is modified from [9]). Note that the scale of X-axis is not the same in (A) and (B). One asterisk in (A) and one in (B) help to compare the second peak of the TN group with the corresponding position in the CTN histogram.
with TN and those with other sensory disturbances (P > 0.50) (Table 1). The clinical variable that most differentiated the patients with TN was age at onset of MS and age at onset of trigeminal distur-
Most patients in the TN group had abnormal trigeminal reflexes (Table 1) showing delayed latency of the early R1 and SP1 components (Fig. 2). Responses from the affected divisions had delayed mean latencies typical of patients with MS [9,22]: the mean latency of the R1 component of the blink reflex was 18.2 ± 3.9 ms on the symptomatic, and was 13.9 ± 2.9 ms on the healthy side (nine patients had abnormal responses also on the clinically asymptomatic side). The frequency of abnormality was 89%, consistent with the previous data about symptomatic TN [10,16]. In the non-TN group, we found a similar abnormality frequency (85%), only slightly higher than the rate reported in the previous studies assessing the blink reflex alone [22]. In contrast, the control group had a far lower abnormality frequency (7%; P < 0.0001). MRI more frequently detected brainstem areas with abnormal signal in patients with trigeminal disturbances (TN and non-TN) than in control patients (84% and 97% vs 16%; P < 0.0001) (Table 1). 3.3. Voxel-based brainstem analysis One-sample analyses, though yielding wider and less significant areas than two-sample analyses, showed that the brainstem location of the areas of lesion differed in patients with and without TN. In patients with TN, the highest probability of lesion was located in the ventrolateral midpons, whereas in those with sensory
Fig. 2. Trigeminal reflexes. (Left) Schematic drawing of the three trigeminal divisions, stimulation sites at the supraorbital (V1), infraorbital (V2), and mental (V3) nerves, and recording sites from the orbicularis oculi (A) and masseter (B) muscles. (Right) Recordings from a representative patient with trigeminal neuralgia and multiple sclerosis. Early (R1) and late (R2) blink reflex, and early (SP1) and late (SP2) masseter inhibitory reflex. The dashed vertical lines indicate normal latency. Calibration: 10 ms/200 lV. Note that the SP1 responses after V2 and V3 stimulation are strongly delayed on the affected side.
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disturbances other than TN lesions were scattered throughout the brainstem. Two-sample analysis between the TN group (n = 42) and the control group (n = 50) showed an area of very high probability of lesion (P < 0.0001) centred in the ventrolateral pons between the trigeminal root entry zone and the trigeminal nuclei, i.e. along the intrapontine part of the trigeminal primary afferents (Fig. 3A). Two-sample analysis between the non-TN group (n = 29) and the control group (n = 50) showed an area of high probability (P < 0.001) in a region still in the pons, but more caudal, medial, and dorsal, involving the subnucleus oralis of the spinal trigeminal complex (Fig. 3B).
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4. Discussion Unlike earlier studies, we enrolled a large cohort of patients with MS who had a trigeminal involvement, did dedicated neurophysiological and neuroimaging studies, and analysed the brainstem lesions with a voxel-based method that allows spatial statistics. We identified several features that bring information on MS-related trigeminal pain. Our findings suggest that in most patients with MS, the cause of TN is a demyelinating plaque along the intra-axial primary afferents. Although TN cannot be caused by a neurovascular contact alone, a neurovascular contact may concur
Fig. 3. Voxel-based analysis. Axial sections corresponding to the sections 120 and 160 of the Shaltenbrandt atlas. Areas of maximum probability of lesion for the TN group (A, n = 42) and non-TN group (B, n = 29) versus controls. The level of probability is colour-coded. Blue indicates non-significant areas, white the minimum level of significance (P < 0.05), and red the highest level of significance.
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to its development. The other kinds of pain are probably caused by plaques on the second-order neurons. The reason why we did not screen our patients for neurovascular contacts is that no reliable, standardized MRI technique exists to document neurovascular contacts (i.e. even if no contact is seen on MRI, neurosurgeons often find one at operation), and because documenting a contact does not prove a causative relationship (i.e. MRI scans often show and neurosurgeons find contacts with asymptomatic nerves) [10,16]. Bilateral neurovascular contacts are frequent in patients with unilateral TN (71% in the recent study) [1], as well as unilateral or bilateral contacts in subjects who do not have TN (75% in a recent study) [23]. In our MS patients, trigeminal neuralgia was strongly associated (P < 0.0001) with a lesion along the pathway of the presynaptic trigeminal afferents in the pons, and the neurophysiological studies showed severe abnormalities compatible with demyelination at this site. Most important, 89% of patients in our TN-group had abnormal trigeminal reflexes (Table 1), whereas these same reflexes are abnormal in only 3% of patients with classic TN [8,10,16], who presumably have a neurovascular contact alone. These findings argue against a neurovascular contact as a primary and unique cause of MS-related TN. Other findings in this study nevertheless show that the TNgroup differed from the other patients with MS, both those with other trigeminal symptoms and controls. The patients with TN showed the typical right–left asymmetry of classic TN, and had an onset age similar to patients with classic TN (Fig. 1). In patients with MS, TN must therefore develop through some other mechanism. We favour a neurovascular contact because this is acknowledged as the most frequent cause of classic TN [10,16,17]. Furthermore, these two mechanisms, MS and a neurovascular contact, would act on the same primary axons and both would produce demyelination [25,26]. A dual mechanism involving MS and a neurovascular contact receives support from neurosurgical studies on the outcome of microvascular decompression because patients with MS-related TN, despite experiencing a considerable pain relief, benefited less than patients with classic TN [4,15]. An interesting finding in this study was that the site of lesions differed in the two groups of patients with trigeminal symptoms. Whereas in patients with TN they involved the afferents from the first-order neurons, in patients with other sensory disturbances, including ongoing pain and dysaesthesia, they involved secondorder neurons (Fig. 3). In an earlier study using the same 3D brainstem model in patients with ischemic infarctions, we had a group of 25 patients with the same neurophysiological abnormalities and whose infarctions involved the same area found in this study in patients with MS-related TN (see Fig. 5 in [11]), although none of them had TN. We therefore confirm that the typical paroxysms of TN develop only in the presence of demyelination and favour the view that demyelination of the primary afferents, whether produced by MS or chronic compression exerted by a blood vessel or a benign tumor, increases nerve-fibre susceptibility to ectopic excitation and high-frequency discharges [5,13]. Naturally, although TN must necessarily arise from damage to the primary afferents, the pathophysiological mechanism may secondarily involve the central areas that process the nociceptive input [14,36]. In the non-TN group, our voxel-based model of the human brainstem identified the area of highest probability of lesion within the subnucleus oralis of the spinal trigeminal complex. Instead of producing the paroxysmal pain typical of TN, these demyelinating lesions produce sensory deficits or ongoing pain. Although we expect MS to affect myelinated axons rather than cell bodies, the spatial resolution of our system prevented us from distinguishing the two. Furthermore, we had too few patients in the non-TN group to
run separate analyses for specific sensory symptoms. Our impression is that ongoing pain and dysaesthesia could arise from the same areas yielding sensory deficits, though sensory deficits were associated with larger lesions (statistically non-significant). Acknowledgements This study has been supported by grants from La Sapienza University of Rome. The authors do not have any conflict of interest. References [1] Anderson VC, Berryhill PC, Sandquist MA, Ciaverella DP, Nesbit GM, Burchiel KJ. High-resolution three-dimensional magnetic resonance angiography and three-dimensional spoiled gradient-recalled imaging in the evaluation of neurovascular compression in patients with trigeminal neuralgia: a doubleblind pilot study. Neurosurgery 2006;58:666–73. [2] Athanasiou TC, Patel NK, Renowden SA, Coakham HB. Some patients with multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and can be treated effectively with MVD: report of five cases. Br J Neurosurg 2005;19:463–8. [3] Berk C, Constantoyannis C, Honey CR. The treatment of trigeminal neuralgia in patients with multiple sclerosis using percutaneous radiofrequency rhizotomy. Can J Neurol Sci 2003;30:220–3. [4] Broggi G, Ferroli P, Franzini A, Nazzi V, Farina L, La Mantia L, Milanese C. Operative findings and outcomes of microvascular decompression for trigeminal neuralgia in 35 patients affected by multiple sclerosis. Neurosurgery 2004;55:830–9. [5] Burchiel KJ. Abnormal impulse generation in focally demyelinated trigeminal roots. J Neurosurg 1980;53:674–83. [6] Capozza M, Iannetti GD, Mostarda M, Cruccu G, Accornero N. Threedimensional mapping of brainstem functional lesions. Med Biol Eng Comput 2000;38:639–44. [7] Cruccu G, Anand P, Attal N, Garcia-Larrea L, Haanpää M, Jørum E, Serra J, Jensen TS. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11:153–62. [8] Cruccu G, Biasiotta A, Galeotti F, Truini A, Gronseth G. Diagnostic accuracy of trigeminal reflex testing in trigeminal neuralgia. Neurology 2006;66:139–41. [9] Cruccu G, Deuschl G. The clinical use of brainstem reflexes and hand-muscle reflexes. Clin Neurophysiol 2000;111:371–87. [10] Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol 2008;15:1013–28. [11] Cruccu G, Iannetti GD, Marx JJ, Thoemke F, Truini A, Fitzek S, Galeotti F, Urban PP, Romaniello A, Stoeter P, Manfredi M, Hopf HC. Brainstem reflex circuits revisited. Brain 2005;128:386–94. [12] Deuschl G, Eisen A. Recommendations for the practice of clinical neurophysiology. Electroenceph. Clin. Neurophysiol. 1999; Suppl. 52. [13] Devor M, Amir R, Rappaport ZH. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin J Pain 2002;18:4–13. [14] Dubner R, Sharav Y, Gracely RH, Price DD. Idiopathic trigeminal neuralgia: sensory features and pain mechanisms. Pain 1987;31:23–33. [15] Eldridge PR, Sinha AK, Javadpour M, Littlechild P, Varma TR. Microvascular decompression for trigeminal neuralgia in patients with multiple sclerosis. Stereotact Funct Neurosurg 2003;81:57–64. [16] Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology 2008;71:1183–90. [17] Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2nd ed. 2004;24(Suppl. 1):1–160. [18] Herweh C, Kress B, Rasche D, Tronnier V, Tröger J, Sartor K, Stippich C. Loss of anisotropy in trigeminal neuralgia revealed by diffusion tensor imaging. Neurology 2007;68:776–8. [19] Hooge JP, Redekop WK. Trigeminal neuralgia in multiple sclerosis. Neurology 1995;45:1294–6. [20] Jensen TS, Rasmussen P, Reske-Nielsen E. Association of trigeminal neuralgia with multiple sclerosis: clinical and pathological features. Acta Neurol Scand 1982;65:182–9. [21] Katusic S, Williams DB, Beard CM, Bergstralh EJ, Kurland LT. Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: similarities and differences, Rochester, Minnesota, 1945–1984. Neuroepidemiology 1991;10:276–81. [22] Kimura J. Electrically elicited blink reflex in diagnosis of multiple sclerosis. Review of 260 patients over a seven-year period. Brain 1975;98:413–26. [23] Kress B, Schindler M, Rasche D, Hähnel S, Tronnier V, Sartor K. Trigeminal neuralgia: how often are trigeminal nerve-vessel contacts found by MRI in normal volunteers. Rofo 2006;178:313–5. [24] Love S, Coakham HB. Trigeminal neuralgia: pathology and pathogenesis. Brain 2001;124:2347–60.
G. Cruccu et al. / PAINÒ 143 (2009) 186–191 [25] Love S, Gradidge T, Coakham HB. Trigeminal neuralgia due to multiple sclerosis: ultrastructural findings in trigeminal rhizotomy specimens. Neuropathol Appl Neurobiol 2001;27:238–44. [26] Love S, Hilton DA, Coakham HB. Central demyelination of the Vth nerve root in trigeminal neuralgia associated with vascular compression. Brain Pathol 1998;8:1–11. [27] Meaney JF, Eldridge PR, Dunn LT, Nixon TE, Whitehouse GH, Miles JB. Demonstration of neurovascular compression in trigeminal neuralgia with magnetic resonance imaging. Comparison with surgical findings in 52 consecutive operative cases. J Neurosurg 1995;83:799–805. [28] Nurmikko TJ, Eldridge PR. Trigeminal neuralgia-pathophysiology, diagnosis and current treatment. Br J Anaesth 2001;87:117–32. [29] Obermann M, Yoon MS, Ese D, Maschke M, Kaube H, Diener HC, Katsarava Z. Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia. Neurology 2007;69:835–41. [30] Olafson RA, Rushton JG, Sayre GP. Trigeminal neuralgia in a patient with multiple sclerosis: an autopsy report. J Neurosurg 1966;24:755–9. [31] Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis – prevalence and clinical characteristics. Eur J Pain 2005;9:531–42.
191
[32] Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘‘McDonald Criteria”. Ann Neurol 2005;58:840–6. [33] Rogers CL, Shetter AG, Ponce FA, Fiedler JA, Smith KA, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia associated with multiple sclerosis. J Neurosurg 2002;97:529–32. [34] Solaro C, Brichetto G, Amato MP, Cocco E, Colombo B, D’Aleo G, Gasperini C, Ghezzi A, Martinelli V, Milanese C, Patti F, Trojano M, Verdun E, Mancardi GL, and the PaIMS Study Group. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology 2004;63:919–21. [35] Svendsen KB, Jensen TS, Overvad K, Hansen HJ, Koch-Henriksen N, Bach FW. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol 2003;60:1089–94. [36] Watson JC. From paroxysmal to chronic pain in trigeminal neuralgia: implications of central sensitization. Neurology 2007;69:817–8. [37] Zaffaroni M, Baldini SM, Ghezzi A. Cranial nerve, brainstem and cerebellar syndromes in the differential diagnosis of multiple sclerosis. Neurol Sci 2001;22:S74–8.