Top

Published in:

01-05-2017 | Original Paper

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

Authors: Anna Nigri, Elisa Visani, Nicola Bertolino, Lorenzo Nanetti, Caterina Mariotti, Marta Panzeri, Maria Grazia Bruzzone, Silvana Franceschetti, Laura Canafoglia

Published in: Brain Topography | Issue 3/2017

Abstract

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.

Available only for authorised users

Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38:95–113CrossRefPubMed

Bhatia KP, Brown P, Gregory R, Lennox GG, Manji H, Thompson PD, Ellison DW, Marsden CD (1995) Progressive myoclonic ataxia associated with coeliac disease. The myoclonus is of cortical origin, but the pathology is in the cerebellum. Brain 118:1087–1093CrossRefPubMed

Buijink AW, Caan MW, Tijssen MA, Hoogduin JM, Maurits NM, van Rootselaar AF (2013) Decreased cerebellar fiber density in cortical myoclonic tremor but not in essential tremor. Cerebellum 12:199–204CrossRefPubMed

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 1–9

Canafoglia L, Ciano C, Visani E, Anversa P, Panzica F, Viri M, Gennaro E, Zara F, Madia F, Franceschetti S (2010) Short and long interval cortical inhibition in patients with Unverricht-Lundborg and Lafora body disease. Epilepsy Res 89:232–237CrossRefPubMed

Chew NK, Mir P, Edwards MJ, Cordivari C, Martino D, Schneider SA, Kim HT, Quinn NP, Bhatia KP (2008) The natural history of Unverricht-Lundborg disease: a report of eight genetically proven cases. Mov Disord 23:107–113CrossRefPubMed

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 216:275–288CrossRefPubMed

Diedrichsen J (2006) A spatially unbiased atlas template of the human cerebellum. Neuroimage 33:127–138CrossRefPubMed

Diedrichsen J, Balsters JH, Flavell J, Cussans E, Ramnani N (2009) A probabilistic MR atlas of the human cerebellum. Neuroimage 46:39–46CrossRefPubMed

Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ (1983) ‘‘Baltic’’ myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet 2:838–842CrossRefPubMed

Friston KJ, Holmes AP, Poline JB, Grasby PJ, Williams SC, Frackowiak RS, Turner R (1995) Analysis of fMRI time-series revisited. Neuroimage 2:45–53CrossRefPubMed

Ganos C, Erro R, Edwards MJ, Rothwell J, Bhatia K (2014) The role of the cerebellum in the pathogenesis of cortical myoclonus. Mov Dis 29:438–443

Genton P (2010) Unverricht-Lundborg disease (EPM1). Epilepsia 51(suppl 1):37–39CrossRefPubMed

Haltia M, Kristensson K, Sourander P (1969) Neuropathological studies in three Scandinavian cases of progressive myoclonus epilepsy. Acta Neurol Scand 45:63–77CrossRefPubMed

Jayakumar PN, Desai S, Pal PK, Balivada S, Ellika S, Kalladka D (2008) Functional correlates of incoordination in patients with spinocerebellar ataxia 1: a preliminary fMRI study. J Clin Neurosci 15:269–277CrossRefPubMed

Kälviäinen R, Khyuppenen J, Koskenkorva P, Eriksson K, Vanninen R, Mervaala E (2008) Clinical picture of EPM1-Unverricht-Lundborg disease. Epilepsia 49:549–556CrossRefPubMed

Klockgether T, Wüllner U, Spauschus A, Evert B (2000) The molecular biology of the autosomal-dominant cerebellar ataxias. Mov dis 15:604–612CrossRef

Korja M, Kaasinen V, Lamusuo S, Parkkola R, Nagren K, Marttila RJ (2007) Substantial thalamostriatal dopaminergic defect in Unverricht-Lundborg disease. Epilepsia 48:1768–1773CrossRefPubMed

Koskenkorva P, Khyuppenen J, Niskanen E, Könönen M, Bendel P, Mervaala E, Lehesjoki AE, Kälviäinen R, Vanninen R (2009) Motor cortex and thalamic atrophy in Unverricht-Lundborg disease: voxelbased morphometric study. Neurology 73:606–611CrossRefPubMed

Koskenkorva P, Niskanen E, Hyppönen J, Könönen M, Mervaala E, Soininen H, Kälviäinen R, Vanninen R (2012) Sensorimotor, visual, and auditory cortical atrophy in Unverricht-Lundborg disease mapped with cortical thickness analysis. AJNR Am J Neuroradiol 33:878–883CrossRefPubMed

Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R (1974) Progressive myoclonus epilepsy. A clinical and histopathological study. Acta Neurol Scand 50:307–332CrossRefPubMed

Long L, Song Y, Zhang L, Hu C, Gong J, Xu L, Long H, Zhou L, Zhang Y, Zhang Y, Xiao B (2015) A case-control proton magnetic resonance spectroscopy study confirms cerebellar dysfunction in benign adult familial myoclonic epilepsy. Neuropsychiatr Dis Treat 11:485–491PubMedPubMedCentral

Magaudda A, Ferlazzo E, Nguyen V-H, Genton P (2006) Unverricht-Lundborg disease, a condition with self-limited progression: long-term follow-up of 20 patients. Epilepsia 47(5):860–866CrossRefPubMed

Magaudda A, Gelisse P, Genton P (2004) Antimyoclonic effect of levetiracetam in 13 patients with Unverricht-Lundborg disease: clinical observations. Epilepsia 45:678–681CrossRefPubMed

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 269:232–239CrossRefPubMed

Marsden CD, Harding AE, Obeso JA, Lu CS (1990) Progressive myoclonic ataxia (the Ramsay Hunt syndrome). Arch Neurol 47:1121–1125CrossRefPubMed

Mascalchi M, Michelucci R, Cosottini M, Tessa C, Lolli F, Riguzzi P, Lehesjoki AE, Tosetti M, Villari N, Tassinari CA (2002) Brainstem involvement in Unverricht-Lundborg disease (EPM1): an MRI and 1H MRS study. Neurology 58:1686–1689CrossRefPubMed

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 47:39–46CrossRefPubMed

Panzica F, Canafoglia L, Franceschetti S (2014) EEG-EMG information flow in movement-activated myoclonus in patients with Unverricht-Lundborg disease. Clin Neurophysiol 125(9):1803–1808CrossRefPubMed

Pennacchio LA, Bouley DM, Higgins KM, Scott MP, Noebels JL, Myers RM (1998) Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet 20:251–258CrossRefPubMed

Santoshkumar B, Turnbull J, Minassian BA (2008) Unverricht-Lundborg progressive myoclonus epilepsy in Oman. Pediatr Neurol 38:252–255CrossRefPubMed

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;67:299CrossRefPubMed

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;50:1712CrossRefPubMed

Silén T, Forss N, Salenius S, Karjalainen T, Hari R (2002) Oscillatory cortical drive to isometrically contracting muscle in Unverricht-Lundborg type progressive myoclonus epilepsy (ULD). Clin Neurophysiol 113:1973–1979CrossRefPubMed

Stoodley CJ, Schmahmann JD (2009) Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 44:489–501CrossRefPubMed

Striano P, Caranci F, Di Benedetto R, Tortora F, Zara F, Striano S et al (2009) 1H-MR spectroscopy indicates prominent cerebellar dysfunction in benign adult familial myoclonic epilepsy. Epilepsia 50:1491–1497CrossRefPubMed

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:e69905CrossRefPubMedPubMedCentral

Tijssen MA, Thom M, Ellison DW, Wilkins P, Barnes D, Thompson PD, Brown P (2000) Cortical myoclonus and cerebellar pathology. Neurology 54:1350–1356CrossRefPubMed

Ugawa Y, Day BL, Rothwell JC, Thompson PD, Merton PA, Marsden CD (1991) Modulation of motor cortical excitability by electrical stimulation over the cerebellum in man. J Physiol 441:57–72CrossRefPubMedPubMedCentral

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 29:139–143CrossRefPubMed

van Rootselaar AF, Aronica E, Jansen Steur EN, Rozemuller- Kwakkel JM, de Vos RA, Tijssen MA (2004) Familial cortical tremor with epilepsy and cerebellar pathological findings. Mov Disord 19:213–21726CrossRefPubMed

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 22:2378–2385CrossRefPubMed

Visani E, Agazzi P, Canafoglia L, Panzica F, Ciano C, Scaioli V, Avanzini G (2006) Franceschetti. movement-related desynchronization-synchronization (ERD/ERS) in patients with Unverricht-Lundborg disease. Neuroimage 33:161–168CrossRefPubMed

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 164278

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 24:65–77CrossRefPubMed

Title: 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
Authors: Anna Nigri
Elisa Visani
Nicola Bertolino
Lorenzo Nanetti
Caterina Mariotti
Marta Panzeri
Maria Grazia Bruzzone
Silvana Franceschetti
Laura Canafoglia
Publication date: 01-05-2017
Publisher: Springer US
Published in: Brain Topography / Issue 3/2017
Print ISSN: 0896-0267
Electronic ISSN: 1573-6792
DOI: https://doi.org/10.1007/s10548-016-0534-y

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2017

Prior Visual Experience Modulates Learning of Sound Localization Among Blind Individuals

Whole-Brain High-Resolution Structural Connectome: Inter-Subject Validation and Application to the Anatomical Segmentation of the Striatum

Neurophysiological Correlates of Attentional Fluctuation in Attention-Deficit/Hyperactivity Disorder

Theta Burst Stimulation of the Precuneus Modulates Resting State Connectivity in the Left Temporal Pole

Higher Fasting Plasma Glucose is Associated with Increased Cortical Thinning Over 12 Years: The PATH Through Life Study

Missing the Target: the Neural Processing Underlying the Omission Error