Aims: Headaches have not been considered a typical symptom of multiple sclerosis (MS), although since 2000, almost every study showed high prevalence. We screened 50 MS patients at the time of first occurrence of neurological symptoms and found the highest prevalence of headache in MS that was ever recorded (78%). Postmortem histological analyses of MS patients’ brains revealed lymphoid follicle-like structures in the cerebral meninges and a pathophysiological link between headache, and high inflammatory activity especially in the initial phase of MS could be suspected. The aim of this study was to get insights into the persistence of headache in the further progress of the disease. Methods: In a prospective, multicenter study, 50 MS patients at the time of first symptom manifestation were screened for the presence of headache within the last 4 weeks and again 6 months later with help of the Rostock Headache Questionnaire (Rokoko) as well as using the evaluation of case history and clinical-neurological investigation. Results: We found a decrease of headache prevalence after 6 months from 78 to 61% (p = 0.01). We could also show a decrease of headache frequency, measured by days with headache in the last 4 weeks (9.5 vs. 5.9, p = 0.001). Migraine or probable migraine was the most frequent headache. In both investigations, the most frequent headache was recurrent pain with pulsating and throbbing character that lasted between 4 and 72 h. Conclusion: Headaches should be taken seriously as an important symptom in early MS. The decrease of headache 6 months after first symptom manifestation of MS could be a result of the immunomodulatory therapy. Young patients in whom migraine-like headaches occur should obligatory undergo an MRI of the head, and in the case of abnormal findings differential diagnosis should be initiated. This could reduce latency until final diagnosis of MS and enable early treatment.

Keywords:
Clinically isolated syndrome, Headache, Migraine, Multiple sclerosis, Radiologically isolated syndrome
1.
Skierlo S, Rommer PS, Zettl UK: Symptomatic treatment in multiple sclerosis-interim analysis of a nationwide registry. Acta Neurol Scand 2017; 135: 394–399.
2.
Cossburn M, Ingram G, Hirst C, Ben-Shlomo Y, Pickersgill TP, Robertson NP: Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis. Mult Scler 2012; 18: 45–54.
3.
Kalincik T, Buzzard K, Jokubaitis V, Trojano M, Duquette P, Izquierdo G, Girard M, Lugaresi A, Grammond P, Grand'Maison F, Oreja-Guevara C, Boz C, Hupperts R, Petersen T, Giuliani G, Iuliano G, Lechner-Scott J, Barnett M, Bergamaschi R, Van Pesch V, Amato MP, van Munster E, Fernandez-Bolanos R, Verheul F, Fiol M, Cristiano E, Slee M, Rio ME, Spitaleri D, Alroughani R, Gray O, Saladino ML, Flechter S, Herbert J, Cabrera-Gomez JA, Vella N, Paine M, Shaw C, Moore F, Vucic S, Savino A, Singhal B, Petkovska-Boskova T, Parratt J, Sirbu CA, Rozsa C, Liew D, Butzkueven H: Risk of relapse phenotype recurrence in multiple sclerosis. Mult Scler 2014; 20: 1511–1522.
4.
Stuke K, Flachenecker P, Zettl UK, Elias WG, Freidel M, Haas J, Pitschnau-Michel D, Schimrigk S, Rieckmann P: Symptomatology of MS: results from the German MS Registry. J Neurol 2009; 256: 1932–1935.
5.
Kister I, Caminero AB, Monteith TS, Soliman A, Bacon TE, Bacon JH, Kalina JT, Inglese M, Herbert J, Lipton RB: Migraine is comorbid with multiple sclerosis and associated with a more symptomatic MS course. J Headache Pain 2010; 11.5: 417–425.
6.
Villani V, Prosperini L, Ciuffoli A, Pizzolato R, Salvetti M, Pozzilli C, Sette G: Primary headache and multiple sclerosis: preliminary results of a prospective study. Neurol Sci 2008; 29:S146–S148.
7.
Möhrke J, Kropp P, Zettl UK: Headaches in multiple sclerosis patients might imply an inflammatorial process. PLoS One 2013; 8:e69570.
8.
Gebhardt M, Kropp P, Jürgens TP, Hoffmann F, Zettl UK: Headache in the first manifestation of multiple sclerosis – prospective, multicenter study. Brain Behav 2017; 7:e00852.
9.
Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F: Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130: 1089–1104.
10.
Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B, Aloisi F, Reynolds R: A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010; 68: 477–493.
11.
Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM, Serafini B, Aloisi F, Roncaroli F, Magliozzi R, Reynolds R: Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011; 134: 2755–2771.
12.
Moisset X, Ouchchane L, Guy N, Bayle DJ, Dallel R, Clavelou P: Migraine headaches and pain with neuropathic characteristics: comorbid conditions in patients with multiple sclerosis. Pain 2013; 154: 2691–2699.
13.
Straube A, Aicher B, Förderreuther S, Eggert T, Köppel J, Möller S, Schneider R, Haag G: Period prevalence of self-reported headache in the general population in Germany from 1995–2005 and 2009:results from annual nationwide population-based cross-sectional surveys. J Headache Pain 2013; 14; 14: 11.
14.
Müller B, Baum A, Holzhausen M, Grittner U, Hilgendorf I, Martus P, Altiner A, Evers S, Rolfs A, Zettl UK, Kropp P: [The Rostock Headache Questionnaire (“Rokoko”) – validation of a tool to screen and to qualify primary headaches]. Fortschr Neurol Psychiatr 2014; 82: 145–148.
15.
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS: Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.
16.
Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444–1452.
17.
Headache Classification Committee of the International Headache Society: The international classification of headache disorders, 3rd edition. Cephalalgia 2013; 33: 629–808.
18.
Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H: The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009; 132; 1175–1189.
19.
Klein M, Woehrl B, Zeller G, Straube A: Stabbing headache as a sign of relapses in multiple sclerosis. Headache 2013; 53: 1159–1161.
20.
Levy D: Migraine pain, meningeal inflammation, and mast cells. Curr Pain Headache Rep 2009; 13: 237–240.
21.
Fiesseler FW, Shih R, Szucs P, Silverman ME, Eskin B, Clement M, Saxena R, Allegra J, Riggs RL, Majlesi N: Steroids for migraine headaches: a randomized double-blind, two-armed, placebo-controlled trial. J Emerg Med 2011; 40: 463–468.
22.
Rozen TD: Migraine headache: immunosuppressant therapy. Curr Treat Options Neurol 2002; 4: 395–401.
23.
Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S: Radiologically isolated syndrome – incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler 2013; 19: 271–280.
24.
De Stefano N, Stromillo ML, Rossi F, Battaglini M, Giorgio A, Portaccio E, Hakiki B, Malentacchi G, Gasperini C, Santangelo M, Bartolozzi ML, Sormani MP, Federico A, Amato MP: Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One 2011; 6:e19452.
25.
Azevedo CJ, Overton E, Khadka S, Buckley J, Liu S, Sampat M, Kantarci O, Lebrun Frenay C, Siva A, Okuda DT, Pelletier D: Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm 2015; 2:e102.
26.
Absinta M, Rocca MA, Colombo B, Copetti M, De Feo D, Falini A, Comi G, Filippi M: Patients with migraine do not have MRI-visible cortical lesions. J Neurol 2012; 259: 2695–2698.
27.
Bevan CJ, Cree BA: Disease activity free status – a new endpoint for a new era in multiple sclerosis. JAMA Neurol 2014; 71: 269–270.
28.
Fox EJ, Rhoades RW: New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis. Curr Opin Neurol 2012; 25(suppl):S11–S19.
29.
Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J, King J, Komoly S, Lubetzki C, Montalban X, Myhr KM, Ravnborg M, Rieckmann P, Wynn D, Young C, Filippi M: Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (precise study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 1503–1511.
30.
Miller DH, Leary SM: Treatment of clinically isolated syndrome: to be PreCISe. Lancet 2009; 374: 1475–1476.
31.
Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R: Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67: 1242–1249.
32.
Solomon AJ, Bourdette DN, Cross AH, Applebee A, Skidd PM, Howard DB, Spain RI, Cameron MH, Kim E, Mass MK, Yadav V, Whitham RH, Longbrake EE, Naismith RT, Wu GF, Parks BJ, Wingerchuk DM, Rabin BL, Toledano M, Tobin WO, Kantarci OH, Carter JL, Keegan BM, Weinshenker BG: The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology 2016; 87: 1393–1399.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.