Cerebellar Involvement in Patients with Mild to Moderate Myoclonus Due to EPM1: Structural and Functional MRI Findings in Comparison with Healthy Controls and Ataxic Patients
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EPM1 (epilepsy, progressive myoclonic 1; Unverricht-Lundborg disease, OMIM #254800) is the most frequent form of progressive myoclonus epilepsy. Previous findings have suggested that its pathophysiology mainly involves the cerebellum, but the evaluation of cerebellar dysfunction is still unsatisfactory. The aim of this study was to assess the structural and functional involvement of the cerebellum in EPM1. We used voxel-based morphometry and spatially unbiased infra-tentorial template analyses of structural magnetic resonance imaging (MRI) scans, and functional MRI (fMRI) scans during block and event-related go/no-go motor tasks to study 13 EPM1 patients with mild to moderate myoclonus. We compared the results with those obtained in 12 age-matched healthy controls (HCs) and in 12 patients with hereditary spinocerebellar ataxia (SCA). Structural analyses revealed different patterns of atrophic changes in the EPM1 and SCA patients: in the former, they involved both cerebrum and cerebellum but, in the latter, only the cerebellum. During fMRI, block and event-related go/no-go tasks similarly activated the cerebellum and cerebrum in the EPM1 patients and HCs, whereas both tasks revealed much less cerebellar activation in the SCA patients than in the other two groups. Volumetric evaluation of the EPM1 patients showed that the cerebellum seemed to be marginally involved in a widespread atrophic process, and fMRI showed that it was not functionally impaired during motor tasks.
KeywordsProgressive myoclonus epilepsy EPM1 Unverricht-Lundborg disease Spinocerebellar ataxia Cerebellum Myoclonus
This study was partly supported by the Italian Ministry of Health, Grant RF-2011-02347420 (to CM).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Ethics Committee of C. Besta Neurological Institute Foundation and carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All of the persons gave their informed consent before being included in the study. Any details that might reveal the identity of the study subjects have been omitted.
- Buijink AW, Broersma M, van der Stouwe AM, Sharifi S, Tijssen MA, Speelman JD, Maurits NM, van Rootselaar AF (2015) Cerebellar atrophy in cortical myoclonic tremor and not in hereditary essential tremor—a voxel-based morphometry study. Cerebellum, pp 1–9Google Scholar
- D’Agata F, Caroppo P, Boghi A, Coriasco M, Caglio M, Baudino B, Sacco K, Cauda F, Geda E, Bergui M, Geminiani G, Bradac GB, Orsi L, Mortara P (2011) Linking coordinative and executive dysfunctions to atrophy in spinocerebellar ataxia 2 patients. Brain Struct Funct 216:275–288CrossRefPubMedGoogle Scholar
- Ganos C, Erro R, Edwards MJ, Rothwell J, Bhatia K (2014) The role of the cerebellum in the pathogenesis of cortical myoclonus. Mov Dis 29:438–443Google Scholar
- Manninen O, Koskenkorva P, Lehtimäki KK, Hyppönen J, Könönen M, Laitinen T, Kalimo H, Kopra O, Kälviäinen R, Gröhn O, Lehesjoki AE, Vanninen R (2013) White matter degeneration with Unverricht-Lundborg progressive myoclonus epilepsy: a translational diffusion-tensor imaging study in patients and cystatin B-deficient mice. Radiology 269:232–239CrossRefPubMedGoogle Scholar
- Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand MS, Andermann E, Andermann F, Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DM, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben-Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki AE (2015) A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet 47:39–46CrossRefPubMedGoogle Scholar
- Schmitz-Hübsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Schöls L, Szymanski S, van de Warrenburg BP, Dürr A, Klockgether T, Fancellu R (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720. Erratum in: Neurology;67:299CrossRefPubMedGoogle Scholar
- Schulz JB, Borkert J, Wolf S, Schmitz-Hübsch T, Rakowicz M, Mariotti C, Schöls L, Timmann D, van de Warrenburg B, Dürr A, Pandolfo M, Kang M, Kang JS, Mandly AG, Nägele T, Grisoli M, Boguslawska R, Bauer P, Klockgether T, Hauser TK (2010) Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6. Neuroimage 49:158–168. Erratum in Neuroimage. 2010;50:1712CrossRefPubMedGoogle Scholar
- Suoranta S, Holli-Helenius K, Koskenkorva P, Niskanen E, Könönen M, Äikiä M, Eskola H, Kälviäinen R, Vanninen R (2013) 3D texture analysis reveals imperceptible MRI textural alterations in the thalamus and putamen in progressive myoclonic epilepsy type 1, EPM1. PLoS ONE 8:e69905CrossRefPubMedPubMedCentralGoogle Scholar
- van Egmond ME, Verschuuren-Bemelmans CC, Nibbeling EA, Elting JW, Sival DA, Brouwer OF, de Vries JJ, Kremer HP, Sinke RJ, Tijssen MA, de Koning TJ (2014) Ramsay Hunt syndrome: clinical characterization of progressive myoclonus ataxia caused by GOSR2 mutation. Mov Disord 29:139–143CrossRefPubMedGoogle Scholar
- van Rootselaar AF, van der Salm SM, Bour LJ, Edwards MJ, Brown P, Aronica E, Rozemuller-Kwakkel JM, Koehler PJ, Koelman JH, Rothwell JC, Tijssen MA (2007) Decreased cortical inhibition and yet cerebellar pathology in “familial cortical myoclonic tremor with epilepsy”. Mov Disord 22:2378–2385CrossRefPubMedGoogle Scholar
- Visani E, Minati L, Canafoglia L, Gilioli I, Salvatoni L, Varotto G, Fazio P, Aquino D, Bruzzone MG, Franceschetti S, Panzica F (2010) Simultaneous EEG-fMRI in patients with Unverricht-Lundborg disease: event-related desynchronization/synchronization and hemodynamic response analysis. Comput Intell Neurosci, p 164278Google Scholar
- Visani E, Minati L, Canafoglia L, Gilioli I, Granvillano A, Varotto G, Aquino D, Fazio P, Bruzzone MG, Franceschetti S, Panzica F (2011) Abnormal ERD/ERS but unaffected BOLD response in patients with Unverricht-Lundborg disease during index extension: a simultaneous EEG-fMRI study. Brain Topogr 24:65–77CrossRefPubMedGoogle Scholar