Restless legs syndrome is common in patients with multiple sclerosis but has not been reported as occurring due to an acute, inflammatory, demyelinating attack.  Restless legs syndrome is known to be related to low brain iron levels.  Multiple sclerosis has been associated with the abnormal accumulation of iron in the chronic, progressive phase of axonal degeneration.  Iron deficiency may play a role in demyelination.  This suggests that restless legs syndrome may be caused by the inflammatory, demyelinating component of multiple sclerosis rather than axonal degeneration.  The author presents a case of self-limited restless legs syndrome occurring as an acute attack of multiple sclerosis, supporting the notion that inflammatory demyelination is the underlying pathophysiology of restless legs syndrome in multiple sclerosis

Bernheimer, James H.

English

PubMed

Restless legs syndrome is common in patients with multiple sclerosis but has not been reported as occurring due to an acute, inflammatory, demyelinating attack. Restless legs syndrome is known to be related to low brain iron levels. Multiple sclerosis has been associated with the abnormal accumulation of iron in the chronic, progressive phase of axonal degeneration. Iron deficiency may play a role in demyelination. This suggests that restless legs syndrome may be caused by the inflammatory, demyelinating component of multiple sclerosis rather than axonal degeneration. The author presents a case of self-limited restless legs syndrome occurring as an acute attack of multiple sclerosis, supporting the notion that inflammatory demyelination is the underlying pathophysiology of restless legs syndrome in multiple sclerosis.</jats:p

James H. Bernheimer

Crossref

Hindawi Publishing CorporationMultiple Sclerosis InternationalVolume 2011, Article ID 872948, 3 pagesdoi:10.1155/2011/872948Case ReportRestless Legs Syndrome Presenting as an Acute Exacerbation ofMultiple SclerosisJames H. BernheimerMercy Medical Center, Baltimore, MD 21202, USACorrespondence should be addressed to James H. Bernheimer, jbernheimer@mdmercy.comReceived 18 March 2011; Accepted 16 May 2011Academic Editor: Oscar FernandezCopyright © 2011 James H. Bernheimer. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.Restless legs syndrome is common in patients with multiple sclerosis but has not been reported as occurring due to an acute,inflammatory, demyelinating attack. Restless legs syndrome is known to be related to low brain iron levels. Multiple sclerosis hasbeen associated with the abnormal accumulation of iron in the chronic, progressive phase of axonal degeneration. Iron deficiencymay play a role in demyelination. This suggests that restless legs syndrome may be caused by the inflammatory, demyelinatingcomponent of multiple sclerosis rather than axonal degeneration. The author presents a case of self-limited restless legs syndromeoccurring as an acute attack of multiple sclerosis, supporting the notion that inflammatory demyelination is the underlyingpathophysiology of restless legs syndrome in multiple sclerosis.1. Case ReportThe patient was a 25-year-old, right-handed woman whopresented two months after the sudden onset of lowerextremity paresthesias and sensory loss that extended intothe abdomen and lower chest and one episode of urinaryurgency and subsequent incontinence. Her examination wasnotable for brisk lower extremity deep tendon reflexes but noother abnormalities. MRI of the cervical and thoracic spinerevealed both cervical and midthoracic plaques consistentwith demyelination. A subsequent brain MRI revealed fivescattered, nonenhancing, white-matter lesions; including alarge (approximately 5mm in diameter) lesion involving thecorpus callosum and two lesions perpendicular to the leftlateral ventricle. Her B12 level, HTLV-1 antibodies, vitaminE level, RPR, ANA, and Lyme titre were all within normallimits She was started on glatiramer acetate following herclinically isolated syndrome of partial transverse myelitisand MRI findings confirming dissemination in space. Twoand a half years after her initial presentation, she developedright hemiparesis that resolved over a few days followingtreatment with intravenous steroids. She had a subsequentsimilar episode of left hemiparesis and hemisensory deficittwo months after that, confirming a diagnosis of clinicallydefinite multiple sclerosis.One year after her initial presentation, she developed asudden onset of discomfort in her legs associated with anurge to move that was worse at night and impaired sleep. Thesymptom resolved while walking and had been present foronly 3-4 days at the time of presentation. Her last menstrualperiod was two weeks prior to this presentation, and shewas faithfully using an oral contraceptive. Her iron levelwas 108mcg/dl, iron saturation was 28.6%, and ferritin was94 ng/ml. A brain MRI did not reveal any new lesions. Hersymptoms resolved a few days after a course of intravenousmethylprednisolone (1 g daily for three days), and she hadno recurrence over the next three years.2. DiscussionRestless legs syndrome is a movement disorder characterizedby distressing urge to move the legs (akathisia) associatedwith discomfort and that is brought on by rest, relieved bymovement or walking, and become worse at night or inthe evening [1]. The patient described above fulfilled all of2 Multiple Sclerosis Internationalthese diagnostic criteria. Her rather abrupt onset suggestedthe possibility of restless legs syndrome secondary to anunderlying cause, such as pregnancy or iron deficiency. How-ever, her diagnostic evaluation excluded these possibilities,and her clinical course and probable response to steroidssuggested that her restless legs syndrome was due to an acuteexacerbation of her multiple sclerosis.Several studies have reported an increased incidence ofrestless legs syndrome in patients with multiple sclerosis,have suggested both a role for restless legs syndrome in MS-related fatigue, and have suggested that multiple sclerosis isa cause of secondary restless legs syndrome [2–5]. However,none of these studies describe self-limited restless legssyndrome occurring as an acute exacerbation of multiplesclerosis as in this case. Manconi et al. demonstrated acorrelation between RLS and cervical cord lesion burden[6]. This patient had a known cervical cord plaque, and thiscorrelationmight also explain why no new intracranial lesionwas detected during her acute presentation with RLS.Restless legs syndrome is commonly idiopathic, but ithas been associated with a number of conditions otherthan multiple sclerosis, including pregnancy, renal failure,peripheral neuropathy, and iron deficiency [1, 7]. Irondeficiency has been recognized in several studies as a causefor secondary restless legs syndrome, particularly at serumferritin concentrations of less than 50 ng/ml [7–10]. Thepathophysiology of even idiopathic restless legs syndrome isprobably related to low brain iron levels [1]. MRI, CSF, andneuropathological studies have all implicated central nervoussystem iron deficiency in the pathophysiology of restless legssyndrome, even in the absence of systemic iron deficiency[11–16]. Recently, there has been interest in the role ofiron in MS and iron deposition because cerebral venousinsuﬃciency has been suggested as a proposed mechanismfor the disease [17]. Haacke et al. reported MRI evidenceof iron accumulation in the basal ganglia and thalamus ofMS patients [18]. However, CSF studies have demonstratednormal CSF ferritin levels in MS [19]. Furthermore, ironappears to be an important cofactor in CNSmyelination, andvan Toorn et al. have reported two cases of iron deficiencyassociated with tumefactive demyelination in children [20–22].The pathophysiology of MS consists of both an inflam-matory demyelinating component and an axonal degen-eration component [23]. LeVine et al. reported normalCSF ferritin, transferrin, and iron concentrations in MSpatients with stable or relapsing and remitting MS, butelevated levels in the CSF of patients with chronic progressiveMS [24]. Therefore, it is likely that the pathophysiologyof RLS in MS patients is related to the inflammatory,demyelinating component of the disease which may beassociated with low or normal CNS iron levels, rather thandue to axonal degeneration, which is associated with CNSiron accumulation. The observation that RLS is associatedwith spinal cord plaques would also suggest a relationship tothe inflammatory and demyelinating component of disease[6]. This patient, presenting with transient RLS due to anacute, inflammatory exacerbation of her multiple sclerosis,further supports the notion that the pathophysiology of RLSin multiple sclerosis is related to autoimmune inflammatorydemyelination.References[1] C. J. Earley, “Restless legs syndrome,” New England Journal ofMedicine, vol. 348, no. 21, pp. 2103–2109, 2003.[2] C. Auger, J. Montplaisir, and P. Duquette, “Increased fre-quency of restless legs syndrome in a French-Canadianpopulation with multiple sclerosis,” Neurology, vol. 65, no. 10,pp. 1652–1653, 2005.[3] M. Manconi, M. Fabbrini, E. Bonanni et al., “High prevalenceof restless legs syndrome in multiple sclerosis,” EuropeanJournal of Neurology, vol. 14, no. 5, pp. 534–539, 2007.[4] N. C. V. Moreira, R. S. Damasceno, C. A. M. Medeiros et al.,“Restless leg syndrome, sleep quality and fatigue in multiplesclerosis patients,” Brazilian Journal of Medical and BiologicalResearch, vol. 41, no. 10, pp. 932–937, 2008.[5] M. Manconi, L. Ferini-Strambi, M. Filippi et al., “Multicentercase-control study on restless legs syndrome in multiplesclerosis: The REMS Study,” Sleep, vol. 31, no. 7, pp. 944–952,2008.[6] M. Manconi, M. A. Rocca, L. Ferini-Strambi et al., “Restlesslegs syndrome is a common finding in multiple sclerosis andcorrelates with cervical cord damage,” Multiple Sclerosis, vol.14, no. 1, pp. 86–93, 2008.[7] K. A. Ekbom, “Restless legs syndrome,” Neurology, vol. 10, pp.868–873, 1960.[8] S. T. O’Keeﬀe, K. Gavin, and J. N. Lavan, “Iron status andrestless legs syndrome in the elderly,” Age and Ageing, vol. 23,no. 3, pp. 200–203, 1994.[9] E. R. Sun, C. A. Chen, G. Ho, C. J. Earley, and R. P. Allen, “Ironand the restless legs syndrome,” Sleep, vol. 21, no. 4, pp. 371–377, 1998.[10] M. H. Silber and J. W. Richardson, “Multiple blood donationsassociated with iron deficiency in patients with restless legssyndrome,” Mayo Clinic Proceedings, vol. 78, no. 1, pp. 52–54,2003.[11] R. P. Allen, P. B. Barker, F. Wehrl, H. K. Song, and C. J. Earley,“MRI measurement of brain iron in patients with restless legssyndrome,” Neurology, vol. 56, no. 2, pp. 263–265, 2001.[12] C. J. Earley, P. B. Barker, A. Horska´, and R. P. Allen, “MRI-determined regional brain iron concentrations in early- andlate-onset restless legs syndrome,” Sleep Medicine, vol. 7, no. 5,pp. 458–461, 2006.[13] L. G. Astrakas, S. Konitsiotis, P. Margariti, S. Tsouli, L.Tzarouhi, and M. I. Argyropoulou, “T2 relaxometry and fMRIof the brain in late-onset restless legs syndrome,” Neurology,vol. 71, no. 12, pp. 911–916, 2008.[14] C. J. Earley, J. R. Connor, J. L. Beard, E. A. Malecki, D. K.Epstein, and R. P. Allen, “Abnormalities in CSF concentrationsof ferritin and transferrin in restless legs syndrome,” Neurol-ogy, vol. 54, no. 8, pp. 1698–1700, 2000.[15] S.Mizuno, T.Mihara, T.Miyaoka, T. Inagaki, and J. Horiguchi,“CSF iron, ferritin and transferrin levels in restless legssyndrome,” Journal of Sleep Research, vol. 14, no. 1, pp. 43–47,2005.[16] J. R. Connor, P. J. Boyer, S. L. Menzies et al., “Neuropatholog-ical examination suggests impaired brain iron acquisition inrestless legs syndrome,” Neurology, vol. 61, no. 3, pp. 304–309,2003.[17] P. Zamboni, R. Galeotti, E. Menegatti et al., “Chroniccerebrospinal venous insuﬃciency in patients with multipleMultiple Sclerosis International 3sclerosis,” Journal of Neurology, Neurosurgery and Psychiatry,vol. 80, no. 4, pp. 392–399, 2009.[18] E. M. Haacke, J. Garbern, Y. Miao, C. Habib, and M. Liu,“Iron stores and cerebral veins in MS studied by susceptibilityweighted imaging,” International Angiology, vol. 29, no. 2, pp.149–157, 2010.[19] V. Worthington, J. Killestein, M. J. Eikelenboom et al.,“Normal CSF ferritin levels inMS suggest against etiologic roleof chronic venous insuﬃciency,” Neurology, vol. 75, no. 18, pp.1617–1622, 2010.[20] B. Todorich, J. M. Pasquini, C. I. Garcia, P. M. Paez, and J. R.Connor, “Oligodendrocytes and myelination: the role of iron,”GLIA, vol. 57, no. 5, pp. 467–478, 2009.[21] S. J. van Rensburg, M. J. Kotze, D. Hon et al., “Ironand the folate-vitamin B12-methylation pathway in multiplesclerosis,” Metabolic brain disease, vol. 21, no. 2-3, pp. 121–137,2006.[22] R. Van Toorn, J. F. Schoeman, R. Solomons, M. A. Rensburg,and S. J. Van Rensburg, “Iron status in children with recurrentepisodes of tumefactive cerebral demyelination,” Journal ofChild Neurology, vol. 25, no. 11, pp. 1401–1407, 2010.[23] J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G.Weinshenker, “Multiple sclerosis,” New England Journal ofMedicine, vol. 343, no. 13, pp. 938–952, 2000.[24] S. M. LeVine, S. G. Lynch, C. N. Ou, M. J. Wulser, E. Tam,and N. Boo, “Ferritin, transferrin and iron concentrations inthe cerebrospinal fluid of multiple sclerosis patients,” BrainResearch, vol. 821, no. 2, pp. 511–515, 1999.Submit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Multiple Sclerosis International

Restless Legs Syndrome Presenting as an Acute Exacerbation of Multiple Sclerosis

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A l l e n ,P .B .B a r k e r ,F .W e h r l ,H .K .S o n g ,a n dC .J .E a r l e y , “MRI measurement of brain iron in patients with restless legs syndrome,”

a nT o o r n ,J .F .S c h o e m a n ,R .S o l o m o n s ,M .A .R e n s b u r g

Chronic cerebrospinal venous insuﬃciency in patients with multipleMultiple

E.R.Sun,C.A.Chen,G.Ho,C.J.Earley,andR.P.Allen,“Iron and the restless legs syndrome,”

Eikelenboom et al., “NormalCSFferritinlevelsinMSsuggestagainstetiologicrole of chronic venous insuﬃciency,”

ferritin and transferrin levels in restless legs syndrome,”

H a a c k e ,J .G a r b e r n ,Y .M i a o ,C .H a b i b ,a n dM .L i u , “Iron stores and cerebral veins in MS studied by susceptibility weighted imaging,”

High prevalence of restless legs syndrome in multiple sclerosis,”

Increased frequency of restless legs syndrome in a French-Canadian population with multiple sclerosis,”

Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis,”Metabolicbraindisease,vol.21,no.2-3,pp.121–137,

Iron status and restless legs syndrome in the elderly,”

L e V i n e ,S .G .L y n c h

MRIdetermined regional brain iron concentrations in early- and late-onset restless legs syndrome,”

Multicenter case-control study on restless legs syndrome in multiple sclerosis:

Multiple blood donations associated with iron deﬁciency in patients with restless legs syndrome,”

Multiple sclerosis,”

Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome,”

o r e i r a ,R .S .D a m a s c e n o

Oligodendrocytes and myelination: the role of iron,”

relaxometry and fMRI of the brain in late-onset restless legs syndrome,”

Restless legs syndrome is a common ﬁnding in multiple sclerosis and correlates with cervical cord damage,”

Restless legs syndrome,”

Restless legs syndrome,” New England

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Restless Legs Syndrome Presenting as an Acute Exacerbation of Multiple Sclerosis

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