References 1. van Schaik IN, Bossuyt PM, Brand A, Vermeulen M. Diagnostic value of GM1 antibodies in motor neuron disorders and neuropathies: a metaanalysis. Neurology 1995;45:1570 –1577. 2. Pestronk A, Chaudhry V, Feldman EL, et al. Lower motor neuron syndromes defined by patterns of weakness, nerve conduction abnormalities, and high titers of antiglycolipid antibodies. Ann Neurol 1990;27: 316 –326. 3. Corbo M, Quattrini A, Lugaresi A, Santoro M, Latov N, Hays AP. Patterns of reactivity of human anti-GM1 antibodies with spinal cord and motor neurons. Ann Neurol 1992;32:487– 493. 4. Dalakas MC, Stein DP, Otero C, Sekul E, Cupler EJ, McCrosky S. Effect CME of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and multifocal motor neuropathy. Arch Neurol 1994;51:861– 864. 5. van den Berg LH, Franssen H, Van Doorn PA, Wokke JH. Intravenous immunoglobulin treatment in lower motor neuron disease associated with highly raised anti-GM1 antibodies. J Neurol Neurosurg Psychiatry 1997;63:674 – 677. 6. Farbu E, Rekand T, Tysnes OB, Aarli JA, Gilhus NE, Vedeler CA. GM1 antibodies in post-polio syndrome and previous paralytic polio. J Neuroimmunol 2003;139:141–144. 7. Ravindranath RM, Ravindranath MH, Graves MC. Augmentation of natural antiganglioside IgM antibodies in lower motor neuron disease (LMND) and role of CD5⫹ B cells. Cell Mol Life Sci 1997;53: 750 –758. Volitional facial palsy after a vascular lesion of the supplementary motor area Ralf Jox, MD; Roland Bruning, MD; Gerhard Hamann, MD; and Adrian Danek, MD The concept of parallel cortical representation is well established in sensory systems and increasingly accepted for motor function.1,2 Dissociation of voluntary and emotional facial movements serves as an excellent example. While the primary motor cortex in the precentral gyrus (M1) is active during voluntary movements, the supplementary motor area (SMA) has been thought essential for emotional innervation.3 New anatomic studies in nonhuman primates, however, question the role of the SMA and attribute it to the cingulate cortex instead.4 Whether this new concept holds true also for humans has not yet been addressed. Case Report. A 62-year-old woman presented with a 2-week history of frontal headache, tingling of the right foot, and word finding difficulties. Upon examination, her face looked symmetric at rest (figure, A), but facial movements were reduced on the right side when she was asked to voluntarily show her teeth or quickly alternate between widening and pursing her lips (see figure, B). Yet, smiling and natural laughing were symmetric (see figure, C). There was some bucco-facial apraxia, but no aphasia on formal testing. In addition, there was a central sensorimotor deficit of the distal right leg with hypesthesia, mild paresis (Medical Research Council scale grade 4⫹), an increased ankle reflex, and extensor plantar response. MRI revealed a cerebral hemorrhage located in the left superior frontal gyrus and the adjoining medial wall (see figure, D through F). Venous thrombosis appeared to be the most likely cause, even though the superior sagittal sinus was patent both in venous magnetic resonance angiography and T2-weighted imaging. The patient improved considerably on IV heparin. Discussion. One-sided volitional paresis of the face in the presence of spared emotional innervation has been reported with a variety of lesion sites, ranging from the primary motor cortex and the pyramidal tract down to the pons.5 Conversely, impaired emotional innervation of the face has been associated with infratentorial lesions, but may also be found after thalamic or anterior capsular damage.6 Anatomic tract-tracing experiments in nonhuman primates have demonstrated that corticofacial projections arise from six distinct cortical motor areas: M1 (Brodmann area 4/F1), SMA (M2/6m/F3), rostral and caudal cingulate motor cortices (M3 and M4/24c and 23c), and dorsal and ventral lateral premotor cortices (6d and 6v/F2 and F4).4 These sites have counterparts in distinct cortical areas of the human brain with probably homologous functions.1,2 Our patient had a lesion that involved the cortical representation of the lower extremity, thus explaining her sensorimotor deficit of the right foot. Her facial palsy, however, is difficult to explain according to traditional concepts. The face representation of the precentral gyrus (M1) and its descending fibers were clearly spared, as was the lateral premotor cortex. Rather, the lesion was primarily located between the vertical lines through the anterior commissure (VCA) and posterior commissure (VCP), corresponding to the left SMA proper. This area contains a representation of the face.1,2 We hypothesize that the left SMA lesion was responsible for the right-sided facial motor impairment. In contrast to earlier observations of an emotional facial palsy after SMA resections,3 this lesion spared the patient’s emotional expressions. This is in accordance with recent data demonstrating that the cingu756 NEUROLOGY 63 August (2 of 2) Figure. (A) Face at rest; (B) When pronouncing “x,” right lower facial paresis becomes apparent; (C) A laugh produces symmetric facial contractions; (D) A cerebral hemorrhage is seen on the T2-weighted left parasagittal MRI (repetition time [TR] ⫽ 5,225 msec, echo time [TE] ⫽ 119 msec, slice thickness ⫽ 5 mm, distance from midline 14 mm). Damage to the supplementary motor area (SMA) can be inferred from the spatial relation to the vertical lines through the anterior and posterior commissures (VCA and VCP, Talairach stereotaxic system1); (E, F) The same lesion in coronal fluid-attenuated inversion recovery sequence images (TR ⫽ 5,000 msec, TE ⫽ 110 msec, slice thickness ⫽ 6 mm). The lesion does not extend to the cingulate sulcus and gyrus. late motor areas are crucially involved in laughter and other facial expression of emotions.4,7 Our patient’s lesion did not extend to the cingulate gyrus or sulcus (see figure E-F). Sparing of its motor areas (M3 and M4) may explain the patient’s intact emotional facial innervation. Clinico-radiologic observations of central facial palsy help to corroborate or refute experimental data concerning parallel motor pathways. Multiple representation is of major clinical interest because of the possible role of parallel motor areas for recovery of function after brain damage. Acknowledgments The authors thank Gisela Stenglein-Krapf and Susanne Stuiber for cognitive testing of the patient. From the Department of Neurology (Drs. Jox, Hamann, and Danek) and the Division of Neuroradiology (Dr. Bruning), University Hospital MunichGrosshadern, Ludwig-Maximilians-University Munich, Germany. Received February 16, 2004. Accepted in final form April 12, 2004. Address correspondence and reprint requests to Prof. Dr. Adrian Danek, Neurologische Klinik and Poliklinik, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, D-81377 München, Germany; e-mail: danek@lmu.de Copyright © 2004 by AAN Enterprises, Inc. References 1. Picard N, Strick PL. Motor areas of the medial wall: a review of their location and functional activation. Cereb Cortex 1996;6:342–353. 2. Rizzolatti G, Luppino G, Matelli M. The organization of the cortical motor system: new concepts. Electroencephalogr Clin Neurophysiol 1998; 106:283–296. 3. Laplane D, Talairach J, Meininger V, Bancaud J, Orgogozo JM. Clinical consequences of corticectomies involving the supplementary motor area in man. J Neurol Sci 1977;34:301–314. Melatonin, 3 mg, is effective for migraine prevention M.F.P. Peres, MD, PhD; E. Zukerman, MD; F. da Cunha Tanuri, MD; F.R. Moreira, BS; and J. Cipolla-Neto, MD, PhD There is increasing evidence that melatonin secretion and pineal function are related to headache disorders. Altered melatonin levels have been found in cluster headache, migraine with and without aura,1 menstrual migraine,2 and chronic migraine.3 A great variety of melatonin mechanisms may be linked to headache pathophysiology.3 Melatonin may have antiinflammatory effect, it scavenges toxic free radicals, reduces the up-regulation of proinflammatory cytokines, and inhibits nitric oxide synthase activity and dopamine release. It also interferes with membrane stabilization, ␥-aminobutyric acid and opioid analgesia potentiation, protection from glutamate neurotoxicity, neurovascular regulation, and serotonin modulation. Melatonin and indomethacin share similar chemical structure.4 Melatonin is then a possible candidate for migraine prevention. We tested the hypothesis of the potential effectiveness of melatonin for migraine prophylaxis. Methods. We performed an open-label trial of melatonin, 3 mg, for migraine prevention. Forty patients with episodic migraine with or without aura according to the International Headache Society (IHS) diagnostic criteria were screened for the baseline period. Three patients did not have headaches during the baseline period; three patients were lost to follow-up evaluation. Thirty-four patients (29 women, 5 men) started prophylactic treatment with melatonin, 3 mg, 30 minutes before bedtime. Thirtytwo patients completed the study. All patients signed an informed consent form. The local and federal ethics committees approved the study. Study participants experienced between two and eight migraine attacks per month. Chronic daily headache patients were excluded. Patients on preventive therapy 3 months before recruitment for the trial were excluded. Patients were examined, and an adequate headache history was ascertained. Patients with insomnia or considerable sleep hygiene problems were excluded. The total study length was 4 months, with a 1-month baseline period and 3-month therapy phase. A study diary was provided to each study participant. The primary endpoint was the percentage of patients with ⬎50% reduction in headache frequency comparing baseline vs month 3 after treatment. Headache intensity, duration, and analgesic consumption were also ascertained. Analgesic units were considered according to the IHS classification. Triptans, ergots, nonsteroidal anti-inflammatory drugs, and analgesics were taken. An intention-to-treat analysis was done; all patients who returned for at least one follow-up visit were included (34 patients); and the mean values were carried to month 3. One-way repeated-measures analysis of variance was used to compare values between the four periods. Tukey method was used for post hoc pairwise comparisons. All p values reported were two-tailed, and values ⬍0.05 were considered significant. Results. Thirty-two of 34 patients completed the study; 78.1% of patients (25/32) who completed the study had at least 50% reduction. No patients reported increase in headaches. Complete (100%) response was achieved in 8 patients (25%), ⬎75% reduction was found in 7 patients (21.8%), and 50 to 75% reduction was 4. Morecraft RJ, Louie JL, Herrick JL, Stilwell-Morecraft KS. Cortical innervation of the facial nucleus in the non-human primate: a new interpretation of the effects of stroke and related subtotal brain trauma on the muscles of facial expression. Brain 2001;124:176 –208. 5. Hopf HC, Muller-Forell W, Hopf NJ. Localization of emotional and volitional facial paresis. Neurology 1992;42:1918 –1923. 6. Ross RT, Mathiesen R. Images in clinical medicine. Volitional and emotional supranuclear facial weakness. N Engl J Med 1998;338:1515. 7. Wild B, Rodden FA, Grodd W, Ruch W. Neural correlates of laughter and humour. Brain 2003;126:2121–2138. seen in 10 patients (31.3%) after 3 months of therapy. Melatonin decreased headache frequency (7.6 ⫾ 3.2 headaches/month at baseline, 4.4 ⫾ 2.5 at month 1, and 3.0 ⫾ 3.1 at month 3; p ⬍ 0.001), headache intensity on a 0 to 10 scale (7.4 ⫾ 1.3 at baseline, 5.5 ⫾ 1.9 at month 1, and 3.6 ⫾ 2.7 at month 3; p ⬍ 0.001), and duration in hours (19.8 ⫾ 19.8 at baseline, 10.2 ⫾ 13.4 at month 1, and 8.8 ⫾ 12.4 at month 3; p ⬍ 0.001). Significant clinical improvement was already achieved at month 1. Overall analgesic and triptan consumption also decreased (p ⬍ 0.001). Menstrually associated migraines equally decreased in frequency. Two patients withdrew from the study, one because of excessive sleepiness and the other because of alopecia. Three patients spontaneously reported increase in libido. No changes in body weight occurred (baseline 62.5 ⫾ 10.0 kg vs month 3 62.5 ⫾ 10.2 kg). Discussion. Melatonin and migraine are linked in several ways. A circadian attack predilection has been reported in episodic (55%) and chronic (62.5%) migraineurs.5 A distribution of attacks according to the estrous cycle is evident in menstrual migraine. True menstrual migraine occurs in 14%; menstrually associated migraine can occur in up to 55% of cases.6 A circannual variation can be observed in cyclic migraine or in the cluster migraine association. Only small studies reported benefit in migraine patients from melatonin treatment. One showed relief after melatonin infusion in status migrainous. A patient with delayed sleep phase syndrome and migraine had a dramatic decrease in headaches after beginning melatonin treatment.7 This is the first study to assess melatonin efficacy in migraine prevention. In our small series of migraine patients, melatonin was effective in reducing the number of headache days per month. A controlled study may be worthwhile. From the Hospital Israelita Albert Einstein (Drs. Peres, Zukerman, da Cunha Tanuri, and Moreira), São Paulo, Brazil; and Instituto de Ciências Biomédicas (Dr. Cipolla-Neto), Universidade de São Paulo, Brazil. Received January 31, 2004. Accepted in final form April 14, 2004. Address correspondence and reprint requests to Dr. Mario F.P. Peres, Al. Joaquim Eugenio de Lima, 881 cj 708, 01403-001 São Paulo SP, Brazil; e-mail: marioperes@yahoo.com Copyright © 2004 by AAN Enterprises, Inc. References 1. Claustrat B, Loisy C, Brun J, et al. Nocturnal plasma melatonin levels in migraine: a preliminary report. Headache 1989;29:242–245. 2. Murialdo G, Fonzi S, Costelli P, et al. Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine. Cephalalgia 1994;14:205–209. 3. Peres MF, Sanchez del Rio M, Seabra ML, et al. Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry 2001;71:747– 751. 4. Peres MF, Stiles MA, Oshinsky M, Rozen TD. Remitting form of hemicrania continua with seasonal pattern. Headache 2001;41:592–594. 5. Galego JC, Cipullo JP, Cordeiro JA, Tognola WA. Clinical features of episodic migraine and transformed migraine: a comparative study. Arq Neuropsiquiatr 2002;60:912–916. 6. Silberstein SD. The role of sex hormones in headache. Neurology 1992; 42(suppl 2):37– 42. 7. Claustrat B, Brun J, Geoffriau M, Zaidan R, Mallo C, Chazot G. Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus. Cephalalgia 1997;17:511–517. August (2 of 2) 2004 NEUROLOGY 63 757 Volitional facial palsy after a vascular lesion of the supplementary motor area Ralf Jox, Roland Bruning, Gerhard Hamann, et al. Neurology 2004;63;756-757 DOI 10.1212/01.WNL.0000135023.68233.56 This information is current as of August 23, 2004 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/63/4/756.full.html References This article cites 7 articles, 4 of which you can access for free at: http://www.neurology.org/content/63/4/756.full.html##ref-list-1 Citations This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/63/4/756.full.html##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Cerebrovascular disease/Stroke http://www.neurology.org//cgi/collection/all_cerebrovascular_disease_ stroke Cranial neuropathy http://www.neurology.org//cgi/collection/cranial_neuropathy Infarction http://www.neurology.org//cgi/collection/infarction Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. 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