Ataxia and Cerebellar DysfunctionAtaxia Rating Scales • ICARS International cooperative Ataxia...

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Ataxia and Cerebellar Dysfunction: Implications for Pediatric Neurology of Cerebellar Cognition Harvard Medical School Massachusetts General Hospital Postgraduate Course: Child Neurology 2017 September 7 th , 2017 Jeremy D. Schmahmann, M.D. Professor of Neurology, Harvard Medical School Director, Ataxia Unit; Cognitive/Behavioral Neurology Unit Laboratory for Neuroanatomy and Cerebellar Neurobiology Massachusetts General Hospital, Boston, MA [email protected]

Transcript of Ataxia and Cerebellar DysfunctionAtaxia Rating Scales • ICARS International cooperative Ataxia...

Page 1: Ataxia and Cerebellar DysfunctionAtaxia Rating Scales • ICARS International cooperative Ataxia Rating Scale • SARA Scale for the Assessment and Rating of Ataxia • BARS Brief

Ataxia and Cerebellar Dysfunction:Implications for Pediatric Neurology of

Cerebellar Cognition

Harvard Medical School Massachusetts General Hospital

Postgraduate Course: Child Neurology 2017September 7th, 2017

Jeremy D. Schmahmann, M.D.Professor of Neurology, Harvard Medical School

Director, Ataxia Unit; Cognitive/Behavioral Neurology UnitLaboratory for Neuroanatomy and Cerebellar Neurobiology

Massachusetts General Hospital, Boston, MA [email protected]

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Cerebellar motor syndrome

• Gait ataxia• Dysmetria of extremities• Oculomotor abnormalities• Dysarthria

From Dow and Moruzzi, 1958

Sir Gordon Morgan Holmes1876 – 1965The Croonian Lectures On The Clinical Symptoms Of Cerebellar Disease And Their Interpretation. Lecture I. 1922. Cerebellum. 2007;6(2):142-7.

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AtaxiaRatingScales• ICARS InternationalcooperativeAtaxiaRatingScale

• SARA ScalefortheAssessmentandRatingofAtaxia

• BARS BriefAtaxiaRatingScale

• FARS FriedreichAtaxiaRatingScale

• SCAFI SCAFunctionalIndex- 9HPBT,8mwalk,PATArate

• CCFS CompositeCbllarFunctionalScore- 9HPBT,clicktest

• INAS InventoryofNon-AtaxiaSymptoms

• ATScale QuantitativeAssessmentofAtaxiaTelangiectasia

• UMSARS UnifiedMSARatingofScale

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ADULTSWITHATAXIA- VIDEOS

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CHILDRENWITHATAXIA- VIDEOS

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Problems encountered using adult rating scales in children

• Age-dependence – young healthy children score in the abnormal range[Sival 2009]

• Some motor test items are not appropriate for young children

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Plots of total scores related to age.

• age-dependency until 12.5, 10, and 11 years of age (for ICARS, SARA, and BARS, respectively)

• 9-hole PEG-board test shows age-dependency until 11.5 years of age.

• Ataxia rating scaleranges from zero reflecting no ataxia, to 100, 40, and 30 representing maximum ataxia in ICARS, SARA, and BARS respectively.

(Brandsma et al., 2014)

N= 52 Controls (f=m), ages 4-16ys

Problem I: potential misinterpretation of therautic trial outcomes whenusing adult-based scales in children

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Subscales indicated for (a) ICARS and (b) SARA. Figures reveal that mature speech tends to develop earlier than gait, and gait earlier than kinetic function.

N= 52 Controls (f=m), ages 4-16ys

Problem 2: Population of children< 4 years not tested

Page 12: Ataxia and Cerebellar DysfunctionAtaxia Rating Scales • ICARS International cooperative Ataxia Rating Scale • SARA Scale for the Assessment and Rating of Ataxia • BARS Brief

Selectedcausesofataxiainchildren• Congenital/Genetic

– CNSMalformations• Cerebellarhypoplasia• Vermian aplasia/Joubert syndrome• Dandy-Walker• Chiarimalformation• Rhombencephalosynapsis

• Hereditary/Genetic– Autosomalrecessive

• Friedreich’s ataxia• Ataxia-telangiectasia• Ataxiaoculomotorapraxiatypes1,2• Abetalipoproteinemia• VitaminEdeficiency(AVED)• Pontocerebellarhypoplasia,types1-10• Refsum disease

– X-linkedrecessive• Sideroblastic anemiaandataxia• SCA-Xlinked,type1

– Autosomaldominant• Spinocerebellarataxiastypes1– 43• EpisodicAtaxias

– Mitochondrial• KearnsSayreSyndrome

• SensoryAtaxia• Guillain-Barre• Multiplesclerosis

• Acute/Sub-acute– Infectious/Immune-mediated

• InfectiousCerebellarAtaxia• Post-infectiousCerebellarAtaxia• Acutedisseminatedencephalomyelitis• Acutelabyrinthitis

– Drug/Toxin-related• Alcohol,BZDs,anticonvulsants,heavy

metals,carbonmonoxide– Masslesions

• Tumor• Vascularlesions(AVM)• Abscess

– Trauma• Hemorrhage• Vertebralarterydissection

– Paraneoplastic• Opsoclonus-myoclonus(neuroblastoma)

• Other• Basilarmigraine,benignparoxysmal

vertigo,non-convulsiveseizures

Boltshauser and Schmahmann. Cerebellar Disorders in Children. Mac Keith Press, 2012Bird TD. Hereditary Ataxia Overview. Updated 2016 Nov 3. GeneReviews®

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Age 14:Ruptured cerebellar AVM

Age 17: Persistent mutism - occasional high pitched soundsFollows instructions intermittentlyAggression, striking out, inability / refusal to eat Bed-ridden, mild dysmetria

Case Study

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Langerhans cell histiocytosisCerebellar involvement, age 6

MRI scans ages 10 though 27

At age 22:

Brief Ataxia Rating Scale 13/30

Neuropsychiatric features

Impetuous, impulsive, inappropriate Poor judgment, perseverativeAggression, agitation, depression

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• Distributed neural systems comprise anatomic regions, or nodes • Unique architectural properties• Geographically arranged throughout cortical and subcortical areas• Linked anatomically in a precise and unique manner

Mesulam, 2000

Courtesy MGH-CMABrodmann, 1905

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from The Sorcerer's Apprentice.Jonathan Leonard, Harvard Magazine, 1999

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Reticular influence - EEG Arousal, sleep wake cycleAutonomic phenomena Grooming, sham rage, predatory attackConditional associative learning (eyeblink)

Snider and Stowell, 1946Snider, 1950Snider and Eldred, 1951

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Schmahmann, Doyon, Toga, Petrides, Evans, 2000

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Santiago Ramon y Cajal,1911

www.vocesdelaciencia.com.ar

Eccles, Ito, Szentágothai, 1967

Cerebellar histology consistent throughout

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Voogd, 1965Voogd and Glickstein, 1998Leclerc et al, 1990

Corticonuclear microcomplexes; cerebello-olivary modules

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Cerebellar growth (by MRI) in the 3rd trimester

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Cerebellar ICC Volume BrainVolume

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Cerebro-cerebellar circuits: Feedforward limb

Schmahmann, 1994, 1996Schmahmann and Pandya, 1987, 1997

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Middleton and Strick. Science, 1994 Kelly and Strick. J Neurosci, 2003

M1 Area 46

Cerebro-cerebellar circuits: Feedback limb

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Stoodley, Valera, Schmahmann. Neuroimage. 2012;59:1560-70

Cerebellar functional topography. Case series task-fMRI

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Stoodley, Valera, Schmahmann. Neuroimage. 2012;59:1560-70

Cerebellar functional topography. Comparison task fMRI studies

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Buckner et al. J Neurophysiol, 2011Wang et al. J Neurophysiol, 2013

Functional topography of human cerebrocerebellar connectionsas determined by resting state fcMRI

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Blood supply of human cerebellumAdapted from Tatu et al., 1996

Schmahmann, MacMore, Vangel. Neuroscience, 2009; 162:852-61

SCA infarctionMICARS = 20

PICA infarctionMICARS = 1

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23-yr woman s/p resection, cerebellar gangioglioma

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Clinical impairments in patients with cerebellar lesions

Schmahmann and Sherman. Brain, 1998

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Schmahmann and Sherman. Brain, 1998

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Cerebellar Cognitive Affective Syndrome (CCAS)

• Executive Function Planning, set-shifting, verbal fluency, abstract reasoning, working memory

• Spatial Cognition Visual spatial organization and memory

• Language Deficits Agrammatism, aprosodia, anomia

• Personality ChangeBlunting of affect, disinhibited and inappropriate behavior

Schmahmann and Sherman. Brain, 1998

Mario Manto and Peter Mariën. Cerebellum and Ataxias 2015;2:2

1997

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Post-infectious (EBV) cerebellitis

Rey copy during illness Taylor copy after recovery

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25 cerebellar patients, 25 healthy controls.Deficits in the ability to:

• Resolve ambiguity: “I don’t know about you, but visiting relatives can be a nuisance.”

• Make inferences: “The sun was shining, when the Robertsons started out for the picnic.Unfortunately, they had the picnic in the living room.”

• Use and interpret metaphor: “He is as transparent as we thought.”

• Formulate propositions in grammatically complete sentences:

Guell, Hoche, Schmahmann. Cerebellum 2015;14:50-8

Metalinguistic functions in cerebellar patientsTest of Language Competence – Expanded (TLC-E)

Wolff, 6/14/2011. http://prezi.com/jqpvhxgzcteu/the-test-of-language-competence-expanded-edition-tlc-e/

P20: I never thought I would meet you here, nor did I, because everything seems so fresh here to buy

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Theory of MindMental processes required to understand, generate, and regulate social behavior 57 cerebellar patients tested on the RMET (Baron-Cohen et al., 2001):

31 complex (cerebrocerebellar)26 isolated (cerebellar)

Cerebellum. 2016;15:732-743.

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Rey figure.6-yr- old boy.Left cerebellar cystic astrocytoma

5-yr-old boy. Medulloblastoma

CCAS following tumor resection in children

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• Problem-solvingFailure to organize verbal or visual-spatial material

• Visual-spatial Impaired planning and organization

• Expressive language Latency, initiation, elaboration, word finding, anomia

• MemoryImpaired for stories; better with multiple-choice

• Regulation of affect (vermis lesions)Irritable, impulsive, disinhibited, labile affect

Levisohn, Cronin-Golomb, Schmahmann, 2000

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Post-operative Pediatric Cerebellar Mutism Syndrome

"Post-operative Pediatric CMS is characterized by delayed onset mutism/reducedspeech and emotional lability after cerebellar or 4th ventricle tumor surgery inchildren. Additional common features include hypotonia and oropharyngealdysfunction/dysphagia. It may frequently be accompanied by the cerebellar motorsyndrome, cerebellar cognitive affective syndrome and brain stem dysfunctionincluding long tract signs and cranial neuropathies. The mutism is always transient,but recovery from CMS may be prolonged. Speech and language may not return tonormal, and other deficits of cognitive, affective and motor function often persist."

Gudrunardottir et al. Consensus Statement on Pediatric Post-operative Cerebellar Mutism Syndrome: Iceland Delphi Results. In review

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FSIQ VIQ PIQ BNT PPVT-III Rey VMI WRAML Visual Learning FAS Semantic Trails A-B

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Cerebellar agenesis: Developmental CCAS

Chheda, Schmahmann, et al., 2002

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Cerebellar AgenesisBehavioral observations (n=6)

• Executive impairments Perseveration, disinhibition, impaired abstract reasoning, working memory and verbal fluency

• Spatial cognition Poor perceptual organization, copying and recall

• LanguageExpressive language delay – requiring sign language in two. Impaired prosody. Over-regularization of past tense verbs

• Psychiatric/affectiveAutistic-like stereotypical performance, obsessive rituals, difficulty understanding social cues. Tactile defensiveness

Chheda, Sherman, Schmahmann, 2002

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Cerebral lesions with secondary cerebellar growth impairment

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Transtentorial diaschisis

Limperopoulos et al, Pediatrics 2005

Ipsilateral Contralateral10.4 cc 7.1 cc

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Preterm infants with isolated cerebellar hemorrhagic infarction (n = 51)

• Neurological abnormality 66% – Hypotonia, abnormal DTRs, gait, ocular alignment, visual

field defects, microcephaly, lethargy/irritability, motor asymmetry

• Motor delay – gross (40%), fine (54%) • Severe functional limitations 40%

– Communication deficits (34%); socialization difficulties (26%)• Visual receptive defects 40%• Expressive language defects 43%• Receptive language defects 37%• Behavioral and social outcomes

– Withdrawn 40%, decreased attention 37%, affective problems 29%, pervasive difficulties 34%

• Autism scores 43%

Limperopoulos et al, Pediatrics 2007

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Behaviorally Defined Disorders with Cerebellar Anomalies

•Attention Deficit Hyperactivity Disorder Berquin et al. Neurology, 1998; 50: 1087-93Mostofsky et al. J. Child Neurol, 1998; 13: 434-9Castellanos et al. Arch Gen Psychaitry, 2001; 58: 289-95

• DyslexiaNicolson et al. Lancet, 1999; 353: 1662-7

•Cognitive deficits in infants born very pre-termAllin et al. Brain, 2001; 124: 60-66

• AutismBauman and Kemper, 1984, 1997Tsai et al. Nature 2012;488:647-51

Loss of Tsc1 in mouse PCs, autistic-like, abnormal social interaction, repetitive behaviors

• SchizophreniaLevitt et al. Am J Psychiatry, 1999; 156:1105-7Nopoulos et al. Biol Psychiatry, 1991; 46: 703-11Loeber et al. Am J Psychiatry, 2001; 158: 952-4Krystal Parker et al. Mol Psychiatry. 2017;22:647-655. Cerebellofrontal interactionTorgeir Moberget et al, Mol Psychiatry, 2017 May 16. Smaller cerebellum

Bauman and Kemper, 1984

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Schmahmann, Weilburg, Sherman. Cerebellum. 2007;6:254-267

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• Attentional Control• Emotional Control• Autism Spectrum Disorders• Psychosis Spectrum Disorders• Social Skill Set

Positive (exaggerated) symptomsNegative (diminished) symptoms

in each domainreflecting cognitive / emotional dysmetria

Neuropsychiatry of the cerebellum

Schmahmann, Weilburg, Sherman. Cerebellum. 2007;6:254-267

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We have ataxia rating scalesICARS, SARA, BARS, others

BUT:

How do we assess cognition and neuropsychiatric features in patients with cerebellar disorders?

• The cerebellar cognitive affective / Schmahmann syndrome scale (CCAS-scale)

• Cerebellar neuropsychiatric rating scale (CNRS)

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CCAS / Schmahmann ScaleHoche, Guell, Sherman, Vangel, Schmahmannn. Under review

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Daly, Sherman, Schmahmann. In progress

Cerebellar Neuropsychiatric Rating Scale

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CNRS in Chiari malformation – (association vs cause)

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Age 18: One week of cerebellar vermal iTBS]Age 20: Aspects of CCAS, walking with a walker, Dean’s list at school

Improvement sustained for 2 years so far

Case Study

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In the same way that cerebellum regulates rate, rhythm, force, andaccuracy of movements, so does it regulate the speed, consistency,capacity, and appropriateness of mental or cognitive processes.

Dysmetria of movement is matched by unpredictability and illogic tosocial and societal interaction.

Inability in the motor system to check parameters of movement isequated with a mismatch between reality and perceived reality, anderratic attempts to correct errors of thought or behavior.

Dysmetria of Thought

Schmahmann. Arch Neurol,1991

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Cerebellum is an integral node in the distributed neural circuits subserving sensorimotor, cognitive, autonomic and affective processing

The cerebellar cortex is anatomically homogeneous, but different cerebellar regions modulate different functional domains i.e., functional topography

• Sensorimotor• Cognitive • Limbic

Makris et al., 2005

Dysmetria of Thought

Schmahmann. Arch Neurol,1991

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Topography anterior lobe – posterior lobe

Sensorimotor –

anterior lobe (I - V), encroaches on VI“secondary” representation in VIIIvestibulocerebellum in lobules X

Cognitive, affective –predominantly posterior lobe (vermal and hemispheric components of lobules VI and VII, likely including IX and X)

Makris et al., 2005

Dysmetria of Thought

Schmahmann. Arch Neurol, 1991; Hum Bran Mapp, 1996; J Neurolinguistics, 2000; J Neuropsych Clin Neurosc, 2004

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Vermis and fastigial nucleus -

autonomic regulation, affect, emotionally emotionally important memory

Cerebellar hemispheres and dentate nucleus -

Executive (including working memory), visual-spatial, linguistic, learning

Topography medial - lateral

Makris et al., 2005

Dysmetria of Thought

Schmahmann. Arch Neurol, 1991; Hum Bran Mapp, 1996; J Neurolinguistics, 2000; J Neuropsych Clin Neurosc, 2004

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Universal Cerebellar Transform

Cerebellum optimizes performance by modulating behavior

around a homeostatic baseline automatically, implicitly, and according to context

Anatomic specificity in cerebrocerebellar loops permits cerebellum to contribute to multiple domains

Dysmetria of Thought

Schmahmann. Arch Neurol, 1991; Hum Bran Mapp, 1996; J Neurolinguistics, 2000; J Neuropsych Clin Neurosc, 2004

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Universal Cerebellar Impairment

= Dysmetria

Lesions of sensorimotor cerebellumDysmetria of movement

The cerebellar motor syndrome

Lesions of cognitive – limbic cerebellumDysmetria of thought and emotion

The cerebellar cognitive affective syndrome

Dysmetria of Thought

Schmahmann. Arch Neurol, 1991; Hum Bran Mapp, 1996; J Neurolinguistics, 2000; J Neuropsych Clin Neurosc, 2004

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In patients with overt cerebellar lesions:

• The need to know imperative (CCAS is not “in their head, it is in their brain”)

• Recognition leads to intervention

• Window for cognitive rehabilitation and cross modal therapies

In patients with primary neuropsychiatric or behavioral neurology disorders:

• Evolving role of cerebellum in pathophysiology of these disorders

• Potential for novel treatment strategies in psychiatric illness

Cerebellum modulates cognition and emotion: Implications for patient care

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Collaborators

Funding:NIMH, National Ataxia Foundation, Harvard CTSC, AT Children’s ProjectBirmingham, MINDLink, and Sidney R. Baer Jr. Foundations

NeuroanatomyDeepak Pandya

Clinical studiesLouis CaplanMilan ChhedaAlice Cronin-Golomb Maureen DalyXavier GuëllFranziska Hoche Stefanie FreemanMatthew FroschWinthrop HarveyTessa Hedley-WhyteKatherine HermannRaquel GardnerLaura HortonRichard LewisLisi Levisohn David LinJason MacMoreMarygrace NealJanet ShermanChristopher StephenMark VangelJeffrey Weilburg

fMRI, morphometryLino BecerraDavid BorsookNikos MakrisEric MoultonCatherine StoodleyEve Valera

Diffusion ImagingGeorge Dai Ellen Grant Cristina Granziera Emi TakahashiRuopeng WangVan Wedeen

Photo by Jinny Sagorin

Cerebellar TMSJennifer CromerAsli Demirtas-TatlidedeFaranak FarzanCatarina FreitasIrene GonsalvesMark HalkoDost OngurAlvaro Pascual LeoneLaura SafarLarry SeidmanWilliam Stone

Cerebellar AtlasJulien Doyon Alan EvansDavid McDonaldMichael PetridesArthur Toga Primate behavior

Ronald KillianyTara Moore Mark MossDouglas Rosene

Clinical ConsortiaCerebellar Research Consortium for the Study of Spinocerebellar Ataxias (CRC-SCA)

Posterior Fossa Society

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