Approach to ataxia

1. 1
PRESENTER-DR.VAIHBAVkr
SOMVANSHI
DMRESIDENT(NEUROLOGY)
GMC,KOTA
ApproachtoAtaxia

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Introduction
Ataxia=fromGreek-a-[lackof]+taxia[order]
Rate,rhythmandforceofcontractionofvoluntarymovements
Disorganized,poorlycoordinated,orclumsymovements
Traditionallyusedspecificallyforlesionsinvolving
Cerebellumorit’spathways
Proprioceptivesensorypathways

3. Localisation
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Cerebellum(mostcommon)
Sensorypathways(SensoryAtaxia)-posteriorcolumns,dorsalrootganglia,
peripheralnerves
Vestibulardysfunction

4. Localizationofcerebellarlesions
Gaitataxia
Limbataxia
Dysarthria
Titubation
Actiontremor
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Anteriorvermis
Lateralhemispheres
Posteriorlefthemispherevermis
Ant.Vermisassociateddeepnuclei
Dentatenuclei,orcerebellaroutflowto
ventralthalamus

5. Localizationofcerebellarlesions
Palataltremor
Saccadicdysmetria
Squarewavejerks
Gazeevokednystagmus
Highercognitivechanges
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Dentatenucleus,GuillainMollaret
triangle
Dorsalvermis
Cerebellaroutflow
Flocculusparaflocculus
Lateralhemispheres

6. Neuroanatomy
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7. SensoryAtaxia
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Lossofdistaljoint,positionsense
Absenceofcerebellarsignssuchasdysarthriaornystagmus
Lossoftendonreflexes
Correctiveeffectsofvisiononsensoryataxia
Rombergsign

8. VestibularDysfunction
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Vertigoisprominent
Consistentfalltooneside
Nystagmus
Limbataxiaisabsent
Speechisnormal
Jointpositionsenseisnormal

9. Approachtoataxicpatient
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MeticulousevaluationofHistory
AgeatOnset
Courseofdisease
Drugintake
FamilyHistory
PersonalSocialOccupationalinformation
Distributionofataxia
Historyofothersystemillness
Neurologicalevaluation
Ancillarytests
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10. History
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Ageatonset
Childhood(congenital,metabolic,infectious,posteriorfossatumors,
hereditaryataxias-morecommon)
Adult(sporadicataxias,hereditaryataxias)
Courseofillness/progression
Acute(metabolic/toxic,infectious,inflammatory,traumatic)
Subacute(metabolic/toxic,infectious,inflammatory,paraneoplastic,
tumor)
Chronic(morelikelygenetic,degenerative,tumor,paraneoplastic)
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Drugintake
Phenytoin,barbiturates,lithium,immunosuppressants
(methotrexate,cyclosporine),chemotherapy(fluorouracil,
cytarabine)
Familyhistory
Studyatleast3generations
Consanguinity
Ethnicity
Social/OccupationalHistory
Alcoholanddruguse,toxins(heavymetals,solvents,thallium),
smoking(Vascular)
History
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Distributionofataxia
Symmetric-Acquired,Hereditary,degenerativeataxias
Asymmetric-Vascular,Tumors,demyelinating,Infection,congenital
causes
Othersystemillness
Gastrointestinalsymptoms-glutenataxia
Masslesion-paraneoplasticataxias
History
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13. Children
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Refusaltowalkorwithawide-based,drunkengait.
Vertigo,dizzinessandvomiting
Personalityandbehavioralchanges.
Abnormalmentalstatus
Ahistoryofheadtrauma,necktrauma
Patientswitharecentinfectionorvaccination
Previoussimilarepisodesofacuteataxia.
Childrenwithfamilymemberswithataxia
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14. Examination
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Neurologicalexamination
Ataxia(appendicularoraxial)
Dysmetria
Dysdiadochokinesia
ReboundPhenomenon
Dysarthria
Tremor
Titubationandincreasedposturalsway
Hypotonia
Nystagmus
Othersystemevaluation
BreastLump,massper-abdomenetc. 14

15. Neuro-ophthalmologicevaluationinataxia
Retinalpigmentosa Refsumdisease,mitochondrial
disorders
Retinal/Maculardegeneration SCA7,aceruloplasminemia
Opticatrophy/visualloss MS,FA
Squarewavejerks FA
Occulomotorapraxia AT,AOA1,AOA2
Slowsaccades
DownbeatNystagmus
SCA2,SCA7
SCA6,EA2,antiGADataxia
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16. OtherSpecificsigns
Focalandlateralizedbrainstem
deficits(hemiparesis,facialpalsy)
Posteriorcirculationstroke,tumour,MS
Paplidema,headache Posteriorfossatumours
INO Posteriorcirculationstroke,MS
Spasticity,UMNsigns SCA1,3,7,8,Strokes,tumour
compressingbrainstem
Basalgangliadeficits SCA1,2,12,17,MJD,MSA,Wilson
Tremor SCA12,15,FAXTS
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Deafness Mitochondrial,superficial
himosiderosis
Myoclonus Mitochondrial,ceroidlipofuschinosis,
SCA7(earlyonset),SCA14
Palatalmyoclonus Alexanderdisease,SCA20
Cognitivedecline Alcohol,MS,CJD,HIV,DRPLA,SCA12,13,
superficialsiderosis
Psychiatricfeatures SCA12,17,27
Autonomicfailure MSA,FXTAS
OtherSpecificsigns

18. AtaxiawithNeuropathy
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Friedreichataxia
AOA2
FragileXsyndrome
VitEdeficiencyataxia
Antigliadinataxia
SCA2,3,4,12,18,25,27
Refsumdisease
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19. AtaxiawithDementia
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Antigliadinataxia
FXTASsyndrme
SREAT
SCA17,19,21,2,1,6
HIV/AIDS
Mitochondrialdisease
Amylodosis
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20. Ataxiawithseizures
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AntiGAD
Antigliadin
Mitochondrialataxia
Episodicataxia2,4
DRPLA
SCA10,SCA17
CJD
SREAT
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21. Investigations
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Neuroimaging
Electrodiagnostictests
Ophthalmologicexamination-Pigmentaryretinopathy,maculardegeneration,
cataracts,Kayser-Fleischerrings

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Genetictests
Metabolic–Thyroidfunction,vitaminsB12,E,andB1,serumcholesterol
plasmalipoproteinprofile,phytanicacid,toxicologyscreen(mercury,bismuth,
lead,ethanol)
Immunefunction-Immunoglobulinlevels,Antigliadinantibodies,GAD
antibodies,paraneoplasticantibodies,AntiTPO.

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Laboratorystudies
Mitochondrial(Serumlactateandpyruvate)
Heavymetals,PBFforacanthocytes,VLCF,hexosaminidaseA/B,alpha
fetoproteinimmunoglobulins,serumceruloplasmin24hoururinary
copper
CSFstudies-Cellcount,glucoseandprotein,oligoclonalbands,14-3-3
protein,GADantibodies,paraneoplasticantibodies,lactate/pyruvate

24. • Diagnostic
workflow
Continuummovementdisorder2019pgno.161

25. prabhakar_sudesh_singh_gagandeep_eds_differential_diagnosischapter22pg.no.251

26. GeneticTestingProtocolofataxias
Spinocerebellar
Ataxia
Aut.Dominant Aut.Recessive
Sporadic
LOCA(25)
EOCA
(25)
SCA1
SCA2
SAC3
SCA7
SCA12
FRDA
NO YES
YES NO
SCA6
SCA8
SCA17
DRPLA
YES NO
Raretypesof
SCAs(ADCA)
screening
Investigationfor
otherARCA
genes
Level20
Level10
Level30
featuressuggestiveof
SCA
LOCA-Lateonsetcerebellarataxia
EOCA-Earlyonsetcerebellarataxia
SCA2
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SCA2
8
Ageat
Onset(Yrs)
10-3
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3
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Variable
SCA11
SCA14
SCA2
3
SCA5
SCA13
SCA14
SCA15
SCA2
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27. SignsthatDistinguishesSCAsubtypes
Benigncourse SCA6
UMNsigns SCA1,7,8and3
Akineticrigidsyndrome SCA3,2,1712,21
Chorea SCA2,1,3
Actiontremor SCA12,16
Slowsaccades SCA27maybein1,3
Downbeatnystagmus SCA6
Hyporeflexia/Areflexia SCA2,4,319,21
Visionloss SCA7
Seizure SCA10
Myoclonus SCA14orSCA19
Cognitiveimpairment SCA2,14,19,21,23
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28. Disease Additionalfeaturesover
CerebellarAtaxia
Distinguishablefeatures Laboratory
findings
SensoryAxonalneuropathy
MRI-spinalatrophy
FA Pescavus,Amyotrpohy,
ExtensorPlantar,
Nystagmus
Cardiomyopathy,DM GAAexpansion
inFXN
AtaxiaVit
EDef.
PesCavus,ExtensorPlantar,
HeadTremor
RetinitisPigmentosa,
Cardiomyopathy
LowVitE
MRI-CerebellarAtrophy
Infantile
onsetSCA
Pescavus,Amyotorphy,
Ophthalmoplegia,Cognitive
Impairment,Chorea
Seizures,Hearingloss,
Hypogonadism
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MRI-Normal
Abetalipop Pescavus,Amyotrophy RetinitisPigmentosa, LowVitE,low
ClinicalapproachtoARCA
MRIfindingsandNerveconductionstudies
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29. Disease AdditionalfeaturesoverCerebellar
Ataxia
Distinguishablefeatures Laboratoryfindings
AtaxiawithsensorimotorAxonalneuropathy
MRI-CerebellarAtrophy
LateonsetTay
sachs
Amyotrophy,tremor,Myoclonus ProminentExtrapyramidal,
Seizures,PsychiatricImpairment
Hexoseaminidase
levels-
Ataxia
telengiectasi
a
OcculomotorApraxia,Amyotrophy,
TremorMyoclonus,Extrapyramidal,
BabinskiSign
Telengiectasia,Lymphoidcancer,
Radiosensitivity,Immunodeficiency,
DM
Highalpha-fetoprotein
andlowimmunoglobin
ATlike
disorders
OcculomotorApraxia,
Extrapyramidal
Radiosensitivity,Immunodeficiency lowimmunoglobin
Ataxiawith
OA1
Occulomotorapraxia,Pescavus,
Amyotrophy,tremor,Extrapyramidal,
cognitiveimpairment
Scoliosis Lowalbumin,High
Cholesterol
Aprataxingene
AtaxiawithOA2 OcculomotorApraxia,PesCavus,
amyotrophyTremors,Extrapyramidal,
cognitionImpairment
Scoliosis Highalpha-fetoprotein,
Highcholesterol
Senataxingene
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30. Disease AdditionalfeaturesoverCerebellar
Ataxia
Distinguishablefeatures Laboratoryfindings
MRI-Spinal+CerebellarAtrophy
ARataxia
Charlevoix-
Saguenay
PesCavus,Amyotrophy,Spasticity,
extensorPlantar,cogitive
Impairment
Chromosome13
MRI-CerebellarAtrophy+WMH
Cerebrotendin
ous
xanthomatosis
PesCausAmyotrophy,Spasticity,
myoclonus,Parkinsonism
PsychiatricImpairment,Tendon
Xanthomas,Seizures,Cataract,
Liverfailure
CYP27A1
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33. Sporadicataxias
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Multiplesystematrophy(MSA)
Toxins/metabolic
Paraneoplasticcerebellardegeneration
Immune-mediatedataxias(gluten,anti-GAD)
Infectiousetiology
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34. Antibody Condition
Anti-Yo(Purkinjecellantobodytype1) BreastandovarianCa
Anti-Hu(Antineuronalnuclearantibody
type1) SmallcelllungCa(SCLC)
Anti-Tr HodgkinLymphoma
Anti-mGluR1(metabotrpinglutamate
receptor) HodgkinLymphoma
Anti-CRMP5(Collapsinreceptor
mediatedprotein)/Anti-CV2 SCLC
Anti-ZIC4(zincfingerprotein) SCLC
Paraneoplasticataxiaassociatedantibodies

35. Causesofsensoryataxia
Polyneuropathy
Paraneoplasticsensoryneuronopathy
Sjogren’ssyndome
MillerFisherSyndrome
Dysproteinemia
Cisplatin
Pyridoxineexcess
Acutesensoryneuronopathy
Chronicataxicneuropathy
Myelopathy
Multiplesclerosis
Tumourorcordcompression
Vascularmalformation
Vacuolarmyelopathy
Myeloneuropathy
Freidriech’sAtaxia
VitaminB12deficiency
VitaminEdeficiency
Tabesdorsalis 35

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Cerebral Sensory frontal
Baseofsupport
Widebase Looksdown Widebase
Velocity Variable Slow Veryslow
Initiation Normal Normal Hesitant
Turns Unsteady Unstaedy Hesitant,multiple
steps
Posturalinstability + + +++++
Falls Lateevent Moreinnight Frequent
Heelshin Abnormal Abnormal,difficultyin
pointofinitiation
Normal
TypesofAtaxia

38. Management
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Correctivemeasuresfordeficiencies–VitaminE,Thiamine
Specificdiet–Glutenfreediet,ketogenicdiet
Immunologicdisorder–IVIG,Plasmapharesis
Miglustatforniemannpickdisease
Riluzole–hereditaryanddegenerativeataxiaanddysarthria
Varenicline–SCA3
4-aminopyridine,Acetazolamide–Episodicataxiatype2
Nicotinamide,deferiprone,idebenon–friedreichataxia,mitochondrialataxia
Rehabilitation,exercisehelpinSCAtype1
ZincsupplementationandDBSalsohelpinSCA2
Actimmune–IFN-γanaloguemorbiditybenefitforfriedreichataxia
AntisenseoigonuceotideshowntoknockdowntoxicproteinlevelinSCA2and3mouse
model
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39. CaseScenario
55-year-oldmanpresentedwithprogressivegaitdifficulty.Hehadinitiallynoted
difficultywalkingdownstairs,upstairsandrunningattheageof47.Hisimbalance
problemsbecameprogressivelyworseovertheyears,andhedevelopedslurredspeech,
transientdoublevisionwhileturninghisheadquickly,andlossofhanddexterity.Hehad
frequentfallsandneededtouseawalker.Hehadanextensivefamilyhistoryof
cerebellarataxia,affectinghismotherandbrother.Onexamination,hehadslurred
speechandslowsaccadiceyemovementswithoutnystagmusorhypermetricor
hypometricsaccades.Hehaddysmetriaonfinger-nose-fingertestsandovershootin
fingerchasetests.Healsohadimpairedrapidalternatingmovementswithabsent
reflexesinupperlimbandhyporelexiainlowerlimb.Hehadahypomimicfacial
expressionandbradykinesialeftsidewithretropusiontestpositive.Hisgaitshowed
variablestridelengthandwaswidebased.
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40. PatientVideo
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41. Genetictests-38repeatsCAGexpansionsoftheATXN2gene(normal
32),
DiagnosedasSCA2
Thepatienttreatedwithriluzole50mg2timesadaywhich
providedmodestbenefitsforhisspeech.Physicaltherapyhelpedwith
hisbalance.Carbidopa/levodopa25mg/100mg,3timesaday,improved
hisparkinsonismbyincreasingthespeedofhermovements.
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42. Conclusion
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Anapproachtoataxiaisbasedonknowledgeofitssymptomsandcauses
Knowledgeofdifferentiatingclinicalfeaturestakescliniciansclosertothe
etiologicaldiagnosiswhichhelpininvestigationaldecisions.
Treatablecausesmustbeidentifiedandruledout
Genetictestingisprudentforprovidingbetterinsightintothemanagement.
Ongoingclinicaltrialsformanagementofhereditaryanddegenerative
ataxiaswillhelpinbettermorbidityoutcomeofthesediseases.
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43. ThankYou
ThankYou
ThankYou

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Bradley’sNeurologyinclinicalPractice,eighthedition
HandbookofClinicalNeurology,Vol.103(3rdseries),AtaxicDisorders
http://www.ataxia.org-NationalAtaxiaFoundationwebsite
http://www.ncbi.nlm.nih.gov/books/NBK1138/Detailedinformationaboutataxias
http://www.clinicaltrials.gov–clinicaltrialsinformation
Pubmed-withthesearchterms“spinocerebellarataxia”,“Friedreich’sataxia”,“sporadicataxia”,
“sensoryataxia”,“approachtoataxia”,“ataxiadiagnosis”
TheCochraneLibrary
Continuummovementdisorder2016
Continuummovementdisorder2019
prabhakar_sudesh_singh_gagandeep_eds_differential_diagnosischapter22pg.no.251
References
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45. Genotype-PhenotypecorrelationsinSCA2
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Higherrepeatsareassociatedwithearlieronset
Homozygousexpansion-noincreaseinseverity
AllelicvariationsofRAI1andCACNA1Ainfluencesageatonset
DiseasedurationXCAGlengthaffectsoccurrenceofslowsaccades,
Fasciculation,Amyotrophy, AreflexiaandVibrationsenses
Smalldiseasealleles(32-37):PosturalTremorsandParkinsonism,lateonsetdisease
MediumSizealleles(38-44):Ataxia,areflexiaandslowingofsaccades
LargeSizeAlleles(45) :Onset20years,Choreaanddementia

46. Genotype-Phenotypecorrelationsin
SCA1
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Higherrepeatsareassociatedwithearlieronsetandseveredisease
Homozygousexpansion-noincreaseinseverity
Smalldiseasealleles(39-44)interrupted:MildPhenotype,Ataxic/nonataxic
features
MediumSizealleles(39-50)PureCAG: AtaxiaandPyramidalsyndrome
LargeSizeAlleles(50)Pure
CAG:
AtaxiaandPyramidal
syndrome
AmytrophicLateralsclerosis
HigherSizeAlleles(91)
:
Juvenile
disease

47. Genotype-Phenotypecorrelationsin
SCA3
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EarlieronsetwithHigherrepeatsandinverse
correlation
Homozygousexpansion-confersincreasing
severity
Smalldiseasealleles(52-73):AxonalNeuropathyandParkinsonism(Type-IIIMJD)
MediumSizealleles(73-80):AtaxiaandDiplopia(Type-IIMJD)
LargeSizeAlleles(80-86) :Ataxia,Dystoniaandspasticity(Type-IMJD)
HigherSizeAlleles(86) :RarecasespredominantDystonia(Type-IV)

48. Genotype-Phenotypecorrelationsin
SCA7
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Earlieronsetwithhigherrepeatsandanticipation
Greaterexpandabilityduringtransmissionofalleles
Recurrentdenovoexpansions
Smalldiseasealleles(36-41):CerebellarataxiawithoutRetinalinvolvement
MediumSizealleles(42-49):AtaxiapreceedesVisiondiminutionLargeSizeAlleles(49-60):Vision
losspreceedesAtaxiaHigherSizeAlleles(80) :JuvenileOnset
ExtremeHighLengthAlleles:InfantileOnset,Developmentalfailure,Multisysteminvolvement(200)