Texas Children’s Overview

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Edward B. Singleton, MD

Thierry A.G.M. Huisman, MD, PD, FICIS, EDiNR, EDiPNR

Radiologist-in-Chief and

Edward B. Singleton Chair of Pediatric Radiology

Professor of Radiology, Pediatrics, Neurosurgery, Obstetrics and Gynecology

Imaging in cerebellar ataxia

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I have nothing to disclose

No relevant financial relations interfering with my presentation

No reference of any unlabeled or unapproved use of drugs

Disclosure

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For all I know about the cerebellum, I am very grateful to

Prof. Eugen Boltshauser and Prof. Andrea Poretti

Disclosure

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Ataxia: all cerebellar?

Ataxia: static, progressive, acute, intermittent, episodic?

Ataxia: Gait/truncal, limb, speech, eye movements?

Ataxia: Cognition?

Inherited/developmental versus acquired/disruptive?

Atrophy versus hypoplasia?

Introduction

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The word “ataxia,” comes from the Greek word “α-τάξις “ (a

taxis) meaning “lack of order”

www.ataxia.org:

• Ataxia is a rare neurological disease. It is progressive (?) –

affecting a person’s ability to walk, talk, and use fine motor skills

• These symptoms are caused by damage to the cerebellum (?)

Ataxia

www.ataxia.orgPage 5

Lack of coordination

Slurred speech

Trouble eating and swallowing

Impaired fine motor skills

Difficulty walking, gait abnormalities

Eye movement abnormalities

Tremors

Heart problems

Ataxia

www.ataxia.org

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If you can pronounce, write and recognize

Rhombencephalosynapsis

you most likely do not have cerebellar ataxia!!!

Ataxia, fun fact

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Cerebellar

Sensory

Vestibular

Optic

Epileptic pseudo-ataxia

Functional/psychogenic

Ataxia ~ affected systems

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Comprehensive history of patient and family

Complete interview

• Acute

• Non-progressive

• Progressive

• Intermittent

• Episodic

Ataxia ~ How to diagnose?

• Past medical history

• Family history

• Social history

• Toxin exposure

• Medication

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Complete interview

• Acute

• Subacute

• Non-progressive

• Chronic or progressive

• Intermittent

• Episodic

• Difficult to differentiate between static and slowly progressive


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Meticulous clinical examination

• Truncal ataxia

• Limb ataxia

• Dysartria (speech)

• Nystagmus

• Ocular motor apraxia

• Opsoclonus


Clinical presentation is often non-specific!!

Archimedes spiral, ladder test

Schmahmann JD. Brain 1998;121:561-579

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• Truncal ataxia

• Limb ataxia

• Dysartria (speech)

• Nystagmus

• Ocular motor apraxia

• Opsoclonus• c

• Cerebellar cognitive affective syndrome (dysmetria of thought)


Schmahmann JD. Brain 1998;121:561-579

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Targeted additional investigations

• Laboratory (blood and urine)

• Molecular genetics

• Anatomical and functional imaging (MRI)

of the CNS (not limited to the cerebellum)


Clinical presentation is often non-specific!!

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Neuroimaging normal in many cases!

Confusing terminology in neuroradiology

• Cerebellar hypoplasia

• Cerebellar agenesis

• Ponto-cerebellar hypoplasia

• Cerebellar dysplasia

• Cerebellar dysmorphia

• Cerebellar atrophy

• Atrophy versus hypoplasia requires follow up imaging

Ataxia ~ Neuroimaging

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• Atrophy versus hypoplasia requires follow up imaging

- Cerebellar atrophy: • Dilated interfoliar spaces, normal size of the posterior fossa, evolving, progressive

- Cerebellar hypoplasia: • Decreased size of the cerebellum, possibly small posterior fossa, no evidence of progression.

Increased prevalence of microcephaly, seizures, developmental delay, autism

Ataxia ~ Neuroimaging

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Classification based upon terminology

Cerebellar ataxia in Topics in Magnetic Resonance Imaging, 2018; 27(4): 275-302

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Classification based upon temporal evolution

Ataxia in handbook of Clinical Neurology 2013;112

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Acute cerebellar ataxia ~> e.g. Cerebellitis

Non-progressive cerebellar ataxia ~> e.g. Malformations, disruptions

Progressive cerebellar ataxia ~> e.g. Friedreich ataxia, Tumors

Intermittant cerebellar ataxia ~> e.g. Multiphasic ADEM

Episodic cerebellar ataxia ~> e.g. Migraine

Cerebellar ataxia: Boltshauser & Poretti

Pediatric age group!!

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For the purpose of the image based classification/presentation

1. Acquired/disruptive cerebellar ataxia

2. Inherited (genetic) and developmental cerebellar ataxia

Cerebellar ataxia

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Congenital/perinatal onset

- Global hypoxic ischemic injury to the supratentorial brain~> Abnormal cerebellar development

- Intra-uterine cerebellar hemorrhage~> Prenatal cerebellar disruption

~> Unilateral cerebellar hypo-/dysplasia ~ complete aplasia

~> Not genetic in origin, low recurrence risk

1. Acquired cerebellar ataxia

Cerebellar injury in global hypoxic ischemic injury


Cerebellar hemorrhage


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Childhood acute cerebellar ataxia

• Relatively common, symptoms evolving over hrs to 2 days• Infection

• Post-infection

• Intoxication

• Trauma

• Stroke


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Acute post-infectious cerebellar ataxia

• Most common cause of acute/subacute cerebellar ataxia (40%)• Acute onset after viral or bacterial infection or vaccination

• Likely auto-immune mediated inflammatory cerebellitis

• MRI • Usually negative in acute phase

• Occasionally parenchymal swelling, T2/FLAIR hyperintensity, faint enhancement,

elevated ADC values

• Acute obstructive hydrocephalus may develop

• On follow-up, cerebellar volume loss may be see


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Infectious cerebellitis

• Varicella-zoster virus (neurotropic) most frequent

• Epstein-Barr virus, influenza, Mycoplasmam Listeria monocytogenes less frequent• d

Toxic “cerebellitis”

• Metronidazole, Vigabatrin, Benzodiazepines

• Chemotherapeutics: 5FU, cystosine arabinoside

• Supra-therapeutic levels of anti-epilepsy drugs (phenytoin)

• Recreational drugs (alcohol, heroin, cocaine)



Herniation/obstruction!!T2 underestimates



+1d +2dAcute

Severe herniation -> global brain injury despite decompression


Vigabatrin (anti-convulsant)

F/U


Opioid intoxication


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Subacute and chronic cerebellar ataxia

- Inflammatory and auto-immune diseases

- Infectious and toxic disorders

- Nutritional and endocrine abnormalities• Vit B12, Vit E, folate and copper deficiencies

• Hypothyroidism and diabetes

- Neoplastic lesions (JPA, medulloblastoma, ependymoma, DIPG)

- Paraneoplastic disorders (neuroblastoma)

- Hemosiderosis


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Neoplastic


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Paraneoplastic cerebellar degeneration

• Immune-mediated cortical cerebellar degeneration

• Seen with multiple tumors but in children typically with neuroblastoma

• Opsoclonus-myoclonus-ataxia syndrome (children <3y)


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Superficial hemosiderosis

• Hemosiderin and free iron along pial and subpial surfaces injures

cerebellar/cerebral cortex, cranial nerves (hearing loss) and spinal cord

• Repeated subarachnoid hemorrhage from tumor, vascular

malformations, neurosurgery, germinal matrix hemorrhage

~> SWI!!!


Hemosiderosis


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For the purpose of the image based classification/presentation

1. Acquired/disruptive cerebellar ataxia

2. Inherited (genetic) and developmental cerebellar ataxia

Cerebellar ataxia

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Developmental cerebellar ataxia

- “Should” be diagnosed prenatally by US and/or MRI

- Impacting early development: Cerebellum + brainstem

- Impacting later development: Predominantly cerebellum

- May involve multiple systems outside of posterior fossa

• Apnea, feeding difficulties, aspiration, spasticity, seizures, delayed neuro-

cognitive development (cerebellum is involved in neuro-cognitive and

emotional progress!!)

2. Inherited and developmental cerebellar ataxia

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Genetic malformations

• Predominantly cerebellar• Dandy-Walker Malformation, Rhombencephalosynapsis

• Cerebellar dysplasia + cysts: Poretti-Boltshauser syndrome (LAMA1), Alpha-

dystroglycanopathies

• Cerebellum and Brainstem• Ponto-cerebellar hypoplasia (PCH)

• Dystroglycanopathies (Walker Warburg, Muscle-Eye Brain, Fukuyama muscular

dystrophy)

• Ciliopathies (Joubert Syndrome) and Tubulinopathies


Predominant cerebellar

• Cerebellar ataxia is NOT a feature of Chiari 1 or

posterior fossa arachnoid cysts!!!!



Dandy Walker Malformation (+)



Rhombencephalosynapsis


Ciliopathy: Joubert Syndrome

Cerebellar and brainstem


Tubulinopathy

Cerebellar and brainstem


http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=m39O2ZQ71DuUpM&tbnid=3uDrxo6Kl5UtOM:&ved=0CAUQjRw&url=http://depositphotos.com/6053826/stock-illustration-Molar-Tooth.html&ei=EjIaU9XgCcLf0QGkqIG4Bw&bvm=bv.62578216,d.dmQ&psig=AFQjCNFzWJQNFStiQGKnr-3iye4jZ0xPRw&ust=1394312031307477

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=m39O2ZQ71DuUpM&tbnid=3uDrxo6Kl5UtOM:&ved=0CAUQjRw&url=http://depositphotos.com/6053826/stock-illustration-Molar-Tooth.html&ei=EjIaU9XgCcLf0QGkqIG4Bw&bvm=bv.62578216,d.dmQ&psig=AFQjCNFzWJQNFStiQGKnr-3iye4jZ0xPRw&ust=1394312031307477

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Autosomal metabolic and recessive inherited ataxias

• Most common causes of genetic ataxias in children

• Typically slowly progressive with gait and limb ataxia + sensori-motor

polyneuropathy

• Additional organs may be affected (myocardium, pancreas)

• Friedreich ataxia

• Louis-Bar syndromeMost frequent etiologies


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• MRI in Friedreich ataxia: Cerebellum usually normal or atrophic, cervical spinal

cord typically atrophic/thinned (posterior/lateral columns)

• Heart (hypertrophic cardiomyopathy) + pancreas (diabetes)


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• Louis-Bar syndrome or Ataxia Telangietasia• Progresssive cerebellar ataxia, immuno-deficiency, sino-pulmonary infections,

occulocutaneous telangiectasias and elevated α-fetoprotein

• Increased risk for cancer, genome instability syndrome (mutation of ATM gene)

• MRI: Superior cerebellar/vermian atrophy, inferior vermis hypoplasia, enlarged IV ventricle

and cisterna magna, multiple punctuate hemosiderin depositions


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• Mitochondrial disorders: • Most common cause of cerebellar atrophy in hereditary cerebellar ataxia

• Cerebellar atrophy is typical, additional findings include symmetrical involvement of

central gray matter in cerebrum/cerebellum, elevated lactate

• White matter is less frequently involved but may occur, e.g. in Kearns Sayre syndrome

• Strokes in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes

(MELAS)

• Co-enzyme Q10 deficiency: Isolated cerebellar atrophy, cerebellar cortical T2/FLAIR-

hyperintensity


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MELAS


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MELAS

F/U


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• Lysosomal storage disorders• GM2-gangliosidosis ~> severe, isolated cerebello-vermian atrophy

• Congenital disorders of glycosylation type 1a (CDG Type 1a)• Isolated cerebellar atrophy

• Marinesco Sjogren syndrome• Cerebellar ataxia with bilateral cataracts, developmental delay

• Autosomal recessive spastic ataxia of Charlevoix-Saguenay• Atrophy of anterior vermis and superior cerebellar peduncles and tigroid pons

• Sjogren-Larsson syndrome• Neurocutaneous syndrome with congenital ichthyosis, spastic di/tetraplegia

and mental retardation


Prodi E, et al. Eur J Radiol 2013;20:138-146

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T2 T1


• Hypomyelinating leukodystrophies

- Genetic white matter disorder with permanent deficit in amount of myelin

- Neurological (cerebellar ataxia), developmental and systemic findings

- MRI: high T2-sigal intensity, mild T1-hypointensity• Vanishing white matter

• H-ABC

• PMD

• 4H leukodystrophy

• Salla disease

• Cockayne syndrome


2y 8mo

8y 2mo

T2wT1w

T1w T2w

Hypomyelinating leukodystrophy with atrophy of Cerebellum and Basal Ganglia : H-ABC


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Hypomyelination with Hypodontia and Hypogonadotropic Hypogonadism (4H)

MRI: Hypomyelination of WM, progressive cerebellar atrophy and T2-

hypointensity of thalami and/or pallidum

T2w T1w


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Ponto-cerebellar hypoplasia (PCH)

- Heterogeneous group, descriptive term

- Fetal growth arrest with resulting cerebellar and

pontine degeneration/atrophy

- PCH1-10, CASK, RELN, VLDLR, PTF1A subtypes

- PCH2 and 4 (mutation in TSEN54 gene) mimic a

dragonfly

- MRI: Severe cerebellar volume loss, preserved

vermis, enlarged fourth ventricle and cisterna

magna

Bosemani, Huisman, Poretti. Radiographics2015;35(1)


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Finally

Research Review

Cerebellum—small brain but large confusion

Eugen Boltshauser

11 February 2004

Much more work to be done

https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Boltshauser,+Eugen

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Texas Children’s Overview