Diagnostic Approach to the Ataxic Child

Home , Dysdiadochokinesia, Dysmetria, Scanning speech, Sensory ataxia, Truncal ataxia

9/9/2013

Diagnostic approach to Disclosure the ataxic child

Andrea Poretti, MD We have nothing to disclose and no financial Postdoctoral research fellow Division of Pediatric Radiology relations interfering with our presentation Alec Hoon, MD Johns Hopkins Hospital Hilary Gwynn, MD Associate Professor of Pediatrics Assistant Professor of Neurology Johns Hopkins School of Medicine Johns Hopkins School of Medicine Director, Phelps Center Phelps Center Kennedy Krieger Institute Kennedy Krieger Institute AACPDM 67th Annual Meeting Milwaukee, October 16‐19, 2013

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Take‐Home Messages Outline

 Ataxia: different systems and courses Cerebellum: embryology and anatomy  Cerebellar ataxia most prevalent in children Definition of ataxia and its clinical findings  History + examination: most important Examples of pediatric ataxia diagnostic tools Ataxia Rating Scales  Neuroimaging: key role in cerebellar ataxia Treatment  Cerebellar dysfunction: motor + cognitive

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Cerebellar Development Cerebellar Development

Very long: early embryonic period => first postnatal years Development of cerebellum and brain stem are closely linked Several genes involved => wide spectrum of malformations Protracted development => vulnerable to several developmental disorders

ten Donkelaar HJ et al, J Neurol, 2003 ©AP ©AP

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Cerebellar Development: Cerebellar Anatomy Selective Vulnerability

Poretti A et al, Eur J Paed Neurol, 2009 ©AP ©AP

Cerebellar Anatomy CerebellarCerebral Connections

Granziera C et al, PLoS One, 2009 Krienen FM and Buckner RL, Cortex, 2009 ©AP ©AP

CerebellarCerebral Connections

Volpe JJ, J Child Neurol, 2009

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Ataxia Ataxia: Classification

 Ataxia = lack of order Affected system Course  Medicine = imbalance, Cerebellar Acute incoordination Sensory Non‐progressive Vestibular Progressive  Common problem in Optic Intermittent child neurology, but broad differential Epileptic pseudoataxia Episodic diagnosis = challenging Functional/psychogenic

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Diagnostic Approach History

1. Basic (background) history 1. History 2. Examination 2. Neurological history: 3. Targeted additional . Family history investigations: . Past medical history . Laboratory . Social history . Neuroimaging . Toxin exposure, medication . Genetic . Patient‘s perception of problem 4. Diagnosis

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History Issues Examination

Not easy to differentiate static  slowly Neurological General progressing:  Test for cerebellar dysfunction  Involvement of other . Short‐term observation  Test for other system organs: . Clinical heterogeneity with variable course involvement: . Eye: retina, cataract, optic nerve . Abnormal eye movements: . Some examples: •Nystagmus Hearing . Cerebellar ataxia in CDG syndrome •Ocular motor apraxia . Skin . . Organomegaly . Cerebellar ataxia in coenzyme Q10 deficiency Polyneuropathy . Spasticity . Marinesco‐Sjögren syndrome . Encephalopathy Ataxia “pure” vs. Ataxia “plus”? ©AP © AP

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Cerebellar Motor Dysfunction Truncal Ataxia

Impaired coordination and motor control:  Sitting:  Stance: . Stance . Support needed . Broad based Trunk Ataxia . . Gait Tandem position, standing on one leg . Limb Dysmetria . Speech Dysarthria  Romberg test: Ask patient to . Swallowing Dysphagia 1. Stand 2. Close eyes . Eye movements Nystagmus  Negative (normal) = no change  Positive = loss of position sense ≠ cerebellar disease

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Truncal Ataxia: Gait Truncal Ataxia

Cerebellar dysfunction: . Wide‐based . Irregular rhythm, irregular steps . Truncal titubation . Unilateral lesion => stumble/fall towards affected side Influenced by additional abnormalities: . Proprioceptive loss . Vestibular deficit . Visual impairment . Spasticity

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Limb Ataxia Limb ataxia

Finger‐nose‐test: simple, boring Dysmetria: incoordination of a limb while performing a task Examination should be “fun”, include activities of daily life: Intenon tremor: amplitude ↑ as an . Drawing, writing, peg‐board, games, ….. extremity approaches the endpoint Dysdiadochokinesia: incoordination while performing alternating movements

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Limb Ataxia Limb Ataxia

Archimedes spiral Ladder Slow down: faster is easier ! Look for compensatory “tricks” ! . Arm support on table, arms pressed against trunk, pencil firmly pressed on paper

Speech Nystagmus

Involuntary eye movement alternating a Dysartria = scanning speech slow and a fast component in two directions Poorly modulated rate, rhythm and force

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Nystagmus Nystagmus

Horizontal nystagmus => unilateral lesion: Slow and coarse looking towards lesion Faster and finer looking away from lesion Vertical nystagmus => central (brain stem/ cerebellar lesion) Downbeat: craniocervical junction, toxic Upbeat: MS, ischemic, degenerative

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Nystagmus Ocular Motor Apraxia

Congenital or acquired impairment of voluntary horizontal saccades Compensatory jerky head movements to enable fixation Congenital: Joubert, Cogan disease Acquired: Ataxia telenagiectasia, AOA1, AOA2

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Ocular Motor Apraxia Ocular Motor Apraxia

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Opsoclonus Opsoclonus

Rapid Involuntary Multivectorial (horizontal + vertical) Chaotic/unpredictable Conjugate

Opsoclonus‐myoclonus syndrome (DD of acute ataxia)

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Cerebellar Cognitive Affective Cognitive Function + Behavior Syndrome

Executive function Spatial cognition Language deficits Personality change

Schmahmann JD and Sherman JC, Brain, 1998

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Dysmetria of Thought Hypothesis: Dysmetria of Thought Hypothesis Topography Anterior ‐ Posterior

Motor system = Ataxia  Sensorimotor : Ipsilateral . Predominantly anterior cerebellar Thought and Emotion = Cerebellar lobe (I –V) motor syndrome cognitive affective syndrome  Cognitive, affective : Cerebellum regulates speed, capacity, . Predominantly consistency and appropriateness of mental neocerebellum (vermal and cognitive processes + hemispheric No ataxia components of VI + VII)

©AP Schmahmann JD, Neuropsychol Rev, 2010 ©AP

Dysmetria of Thought Hypothesis: Cerebellar Cognitive Affective Topography Medial ‐ Lateral Syndrome Based on observations in adults with:  Vermis and fastigial . Cerebellar stroke nucleus: . Cerebellitis . Autonomic regulation, . Low‐grade cerebellar tumors affect, emotionally important memory Concept extended to children: .  Cerebellar hemispheres Low‐grade cerebellar tumors . and dentate nucleus: Cerebellitis . Congenital non‐progressive ataxia . Executive, visual‐spatial, linguistic, learning and . Cerebellar malformations memory . Cerebellar disruptions

Schmahmann JD, Neuropsychol Rev, 2010 ©AP ©AP

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Cerebellar Ataxia Progressive Cerebellar Ataxia

Acute Long list of rare diseases Progressive Heterogeneous group (clinical, genetic) Non‐progressive Focused diagnostic work‐up Only few are treatable 40‐50% without specific diagnosis Dominantly inherited spinocerebellar ataxias (SCA) = rare in childhood

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Friedreich Ataxia Friedreich Ataxia

Autosomal recessive Involved organs: CNS, myocardium, pancreas Presentation: “clumsiness”, ataxia Pes cavus and scoliosis = late signs Areflexia: already present in preclinical stage MRI: normal cerebellum, cervical cord atrophy DD: Charcot‐Marie‐Tooth polyneuropathy

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Non‐Progressive “Congenital” Ataxia Non‐Progressive Cerebellar Ataxia (NPCA) Non‐progressive “congenital” ataxia “Congenital” = early evidence of cerebellar Cerebellar malformations: ataxia, not really congenital . Joubert syndrome, rhombencephalosynapsis, Dandy‐Walker malformation No reliable data about prevalence, but Cerebellar disruptions: more common than any defined cerebellar malformation . Unilateral cerebellar hypoplasia, cerebellar disruption in preterm neonates

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NPCA: Early Presentation NPCA in Toddlers

Hypotonia (no weakness, normal reflexes) Situation dominated by impaired motor performance: Delayed motor + language milestones . Slow, careful; avoidance of difficult tasks Ataxia: not congenital, in the first year of life . Balance problems more evident on soft ground, DD: changing gait direction, gait initiation/deceleration . Variant (buttom shuffler) With age: . Neuromuscular disorder . Impaired coordination more obvious . Syndromic (e.g. neurofibromatosis type 1) . Delay in language milestones . Developmental delay . Concerns about cognitive abilities

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NPCA: Long‐Term Problems NPCA: Neuroimaging Spectrum

1. Normal: most prevalent Ataxia tends to improve 2. Cerebellar hypoplasia  Major limitation = intellectual disability 3. Mimicking cerebellar atrophy Increased prevalence of seizures Some patients: spastic‐dystonic component => Intrafamilial variability observed => No correlation imaging ‐ clinical ‐ outcome

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Hypoplasia  Atrophy NPCA: Neuroimaging Spectrum

Hypoplasia Atrophy  Decreased size/volume of  Dilated interfoliar spaces cerebellum  Evolving, progressive  Not filling normally  Normal size of posterior configurated post.fossa or fossa small posterior fossa  But: increased interfoliar spaces possible  No evidence of progression Child with „static“ Normal MRI in girl with NPCA, Cerebellar hypoplasia cerebellar ataxia over years 2 sisters similarly affected in boy with NPCA MRI: Dilated interfolial Poretti A et al, Eur J Paeditr Neurol, 2008 spaces mimicking atrophy

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NPCA: Genetics NPCA: Differential Diagnosis

Autosomal recessive inheritance: Cerebellar malformations . Many familial observations Metabolic disorders: L2HGA, GA1, CDG, Glut1 . Some gene loci/genes (e.g. VLDLR, CA8, deficiency, CoQ10 deficiency ZNF592, WDR81) identified in isolated NPCA or NPCA “plus” (e.g. deafness, optic atrophy, Posterior fossa midline tumor short stature) Infantile onset progressive ataxias: AT, GM2, INAD Few publications on families with dominant Cogan ocular motor apraxia or X‐linked inheritance, no genes identified Hereditary sensory neuropathies

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NPCA: Diagnostic Approach Joubert syndrome (JS): Epidemiology

1. Brain MRI Estimated prevalence ~ 1:80‘000 2. α‐Fetoprotein (to exclude AT) Probably underestimated 3. Metabolic: . Organic acids (GA1, L2HGA) Male ≥ female . Transferrin electrophoresis (CDG) . Autosomal recessive with exception of rare cases following X‐linked recessive 4. Genetic testing Reported in almost all countries

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JS: Neurology JS: Cognitive Function

Normal cognitive function => very rare Neonatal breathing dysregulation: common Intellectual disability, variable degree Muscular hypotonia: always Prominent impairment in visuo‐spatial Ocular motor apraxia: very common organization, executive functions and Ataxia: always expressive language Intellectual disability: almost always Marked intrafamilial variability

Steinlin M et al, Neuropediatrics, 1997; Poretti A et al, Neuropediatrics, 2009 ©AP ©AP

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JS: Behavior

No systematic studies, mostly based on observations and reports by parents Variability, spectrum

Sensitivity to noise Usually “easy“ to handle, happy child Minority with behavioral difficulties (hyperactivity, aggression, self‐injury)

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JS: Systemic Involvement Molar Tooth Sign (MTS) Eyes: MTS = diagnostic criterion . Retinal dystrophy (~30%) . Colobomas (~19%) Kidneys: . Nephronophthisis (~25%) Liver: . Congenital hepatic fibrosis (~15%) Other: . Polydactyly (~20%)

JS: Neuroimaging JS: Neuroimaging

Beyond MTS and vermian hypoplasia Spectrum of additional posterior fossa and supratentorial findings Supratentorial findings common No neuroimaging‐genotype correlation Intrafamilial variability

Joubert syndrome Normal anatomy

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JS: Diffusion Tensor Imaging JS: Diffusion tensor imaging

Joubert Syndrome Control Joubert Syndrome Control

JS: Genetics JS: Primary Cilia

All JS‐genes encode for proteins of the primary cilium/centrosome => Ciliopathy  Key role in development and function of: 21 genes account for ~ 50% of patients . Retinal photoreceptors, neurons, kidney tubules, bile ducts Marked genetic heterogeneity  In developing cerebellum and Weak genotype‐phenotype correlation brainstem: . Are implicated in neuronal cell proliferation and axonal migration

Messerschmidt A et al, AJNR, 2005 Disruptive Development of the Disruptive Development of the Cerebellum Cerebellum: Neuroimaging  Symmetric volume reduction of the cerebellar hemispheres Cerebellar underdevelopment without  Small vermis with preserved shape direct injury of the cerebellum  Small brain stem with flattened anterior curvature of the pons Probably most frequent type of cerebellar abnormality in preterms Mean gestational age: 26‐28 weeks

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Disruptive Development of the Blood Products Cerebellum: Pathomechanisms Infratentorial hemosiderin in preterms Direct effects on cerebellum: without cerebellar injuries, but . Hemosiderin (blood products) supratentorial hemorrhages . Infection‐inflammation Continuous decline of cerebellar volume . Hypoxia‐ischemia over several weeks without any typical . Glucocorticoids vascular injury pattern . Undernutrition Remote effects on cerebellum (impaired

trans‐synaptic trophic effects) Messerschmidt A et al, AJNR, 2005

Tam EW et al, SciTranslMed, 2011 Glucocorticoids Exposure Remote Effects

Postnatal exposure to clinically routine doses Transsynaptic cerebro‐cerebellar diaschisis of hydrocortisone or dexamethasone => impaired cerebellar, but not cerebral growth involving neuronal connections between cerebrum and cerebellum Diaschisis = reduction of function of a part of the brain following the interruption of an afferent pathway at a remote site Association with supratentorial unilateral or bilateral injuries

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Motor + Cognitive Functions + Remote Effects Behavior Motor disturbances: . Ataxia to mixed CP: ~ 50% Cognitive deficits: . Deficits in visual‐spatial abilities, verbal fluency, reading, memory, learning: ~ 40% . Attentional deficits Cerebro => cerebellar diaschisis Behavioral deficits: Cerebellar => cerebro diaschisis Socialization deficits Autistic behavior: ~ 40%

Limperopoulos C et al, Pediatrics, 2005; Volpe JJ, J Child Neurol, 2009 Limperopoulos C et al, Pediatrics, 2007; Messerschimidt A et al, Eur J Pediatr, 2008 ©AP ©AP

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Sensory Ataxia Sensory Ataxia

Less common than cerebellar ataxia Hereditary sensory neuropathies: Loss of sensory afferents (proprioceptive) = . Areflexia worse with eyes closed => positive . Abnormal nerve conduction Romberg test Posterior column dysfunction: Areflexia or decreased reflexes . Friedreich ataxia: symptoms not congenital . Vitamine B12 deficiency: very rare in children

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Vestibular Ataxia Head‐Impulse Test Injury of the peripheral vestibular system => nystagmus suppressed by visual fixation Examination with Frenzel’s goggles: . No visual fixation => Visually depressed Vestibular injury nystagmus more obvious ↓ VOR deficit

Head‐Impulse Test Bilateral Vestibular Dysfunction

Stance + gait unsteadiness, darkness and on uneven ground ↑ Usually NO vertigo Examination: . Head impulse test bilaterally abnormal . Romberg positive Causes: . Toxic (gentamycin vestibulotoxicity) . Meningitis

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Functional Ataxia Ataxia Rating Scales Usually easy to recognize Limited value in daily work Inconsistent “performance” Important for: Abasia, astasia . Natural history documentation Good achievements despite “greatest . Interventional (therapeutic) studies difficulties” Problems: Often better if “distracted” = engaged with . Time‐consuming additional task (e.g. balancing + calculating) . Training for assessment needed If dissociate disorder assumed => restraint . Limited validation in pediatric age group with additional investigations Edward MJ and Bhatia KP, Lancet Neurol, 2012 ©AP ©AP

Ataxia Rating Scales Ataxia Rating Scales in children

Brief Ataxia Rating Scale (BARS): 30‐point Not yet sufficiently studied in children total / 5 “items” Effect of gender and age (below 10 years of Scale for the Assessment and Rating of age) Ataxia (SARA): 40‐point total / 8 “items” BARS least reliable International Comparative Ataxia Rating SARA and ICARS reliable, applicable > 6 Scale (ICARS): 100‐point total / 19 “items” years Modified ICARS (MICARS): 120‐point total / 16 “items” Sival DA and Brunt ER, Dev Med Child Neurol, 2009; Sival DA et al, Dev Med Child Neurol, 2011 ©AP ©AP

Treatment Treatment

Opsoclonus‐myoclonus syndrome = immunomodulatory therapy . Should be started as soon as possible after onset of symptoms, don’t wait for surgery . No standard protocol . Most common: Prednisolone 1‐2 mg/kg/d for weeks‐months until symptoms improvement

Poretti A and Boltshauser E, Checklists in Cerebellar Disorders in Children, MacKeith Press, 2012 Poretti A et al, Neuropediatrics, 2013 ©AP ©AP

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Treatment Take‐Home Messages Can rehabilitation help? No data for children, scarce data for adults  Ataxia: different systems and courses Adults with progressive cerebellar ataxia =>  Cerebellar ataxia most prevalent in children coordination training focused on balance +  History + examination: most important walking => improvement after 12 weeks = diagnostic tools individuals with cerebellar damage can  Neuroimaging: key role in cerebellar ataxia learn to improve their movements  Cerebellar dysfunction: motor + cognitive Transcranial magnetic stimulation? Deep brain stimulation? Ilg W et al, Neurology, 2009; Groiss SJ and Ugawa Y, Cerebellum, 2012 ©AP ©AP