Ataxia

    Definitions. 1

Clinical manifesations. 1

DDX Quick List 2

Full DDX: 3

Symmetrical 3

Focal 3

Specific Entities. 3

General Diagnosis of Ataxia. 4

Inherited diseases: 4

Spinocerebellar Ataxias. 5

SCA1. 5

Other SCA’s. 6

Friedreich’s ataxia. 6

Clinical Manifestations. 6

Diagnosis. 7

Treatment 7

Prognosis. 7

 

Definitions

•   Ataxia – failure of muscle co-ordination

•   Cerebellar ataxia – due to disease of cerebellum or its afferent or efferent pathways.

o    Vestibulocerebellum

o    Spinocerebellum

o    Cerebrocerebellum

•   Sensory ataxia

o    Similar symptoms to ‘true’ ataxia but due to defect in sensory input

o    Musch worse when eyes are closed

•   Vestibular ataxia

o    Due to dysfunction of vestibular apparatus

 

•   Dysmetria – inaccuracy of movement – desired target is either under-reached or over-reached (“distrurbance of rate, range and force of movement”)

•   Dysdiadochokinesia – irregularity of the rhythm and amplitude of rapid alternating movements

•   Intention (Kinetic) tremor – worsens on movement to target

o    Action tremor – postural tremor initiated by sustained action.

Clinical manifesations

·         Lateralized lesions cause symptoms on ipsilateral side

·         Some correlation with anatomy

    • Vestibulocerebellum – disequilibrium and ataxic gait
    • Vermis/Spinocerebellum – truncal and gait ataxia with sparing of the limbs

o    Cerebrocerebellum – appendicular ataxia

·          

Examination

·         Gait impairment

    • Broad based, irregular, staggering
    • Increased body sway
    • Stagger to side of unilateral lesion.
    • Problems with tandem gait (may detect more subtle lesions)
    • Rhomberg’s
      1. positive often in cerebellar ataxia (although this is not ‘designed’ to test this)
      2. Grossly positive in sensory ataxia
  • Truncal ataxia
    • Fold arms and sit up
    • Rhythmic osscilations of the trunk and head – titubation
    • Difficulty sitting upright unsupported
  • Strength
    • Should be normal
  • Co-ordination
    • Finger-nose/ chase – intention tremor, dysmetria
    • Hold fingers pointing at each other with outstretched arms – action tremor
    • Rapid alternating movements – d
    • Rebound
      1. Test rebound rapidly raise arms and stop OR hold arm straight and avoid being pushed out of position OR get patient to push against hands and quickly let go
      2. Due to inco-ordination of agoinst and antagonist muscles
    • Heel-shin-finger test in lower limb
    • Foot tapping
  • Sensory
    • Test proprioception in particular to exclude ‘sensory ataxia’
  • Occular
    • Test EOM movements – look at pursuit and nystagmus
    • Test saccades
    • Pursuit – ratchety
    • Saccades – normal velocity however ‘dysmetria’ – miss target followed by corrective saccade.
      1. Opsoclonus – continuous saccades in all directions in a chaotic fashion.
    • Nystagmus
      1. Gaze evoked nystagmus, worse on looking to side of lesion.  Slow drift back to centre with rapid phase outwards towards side of lesion.
    • Vestibulo-ocular reflex – normal patient can suppress VOR and watch a object attached to spinning chair, cerebellar disease prevents VOR suppression.
  • Speech
    • “Scanning dysarthria”
    • Assess with “British constitution” or “West register street”
    • Slow, jerky, explosive, inappropriate variation in tone and pitch.

 

DDX Quick List

  • Drugs
  • Alcohol
  • Wernicke’s
  • Hypothyroidism
  • Vascular
  • Neoplastic/ Paraneoplastic
  • Inherited disorders
  • MS
  • Infection – Abscess, Syphilis  

Full DDX:

Symmetrical

Acute:

  • Toxic –EtOH, Li, barbiturates, diphenylhydantoin, Chemotherapy (5FU and Cytarabine)
  • Viral cerebellitis
  • Postinfection syndrome

Subacute:

  • Intoxication – Mercury, solvents, petrol, glue, cytotoxic drugs
  • Alcoholic-nutritional (B1 and B12 def)
  • Lyme disease

Chronic:

  • Inherited diseases (see below)
  • Paraneoplastic cerebellar degeneration
  • Antigiladin antibody syndrome
  • Hypothyroidism
  • Infections
    • Tertiary syphilis
    • CJD
  • Toxic
    • Phenytoin use (controversial)
  • “Sporadic”

Midline (truncal ataxia and dysarthria)

  • Paraneoplastic syndrome
  • Midline tumour

Rostral vermis (lower limbs symmetrically affected with uppersparing)

  • Alcohol

Focal

Acute:

  • Vascular
    • Cerebellar haemorrhage
    • Vertebrobasillar ischaemia
  • Infection - abscess

Subacute:

  • Neoplastic
  • Demyelinating – MS
  • AIDS related leukoencephalopathy

Chronic:

  • Gliosis
  • Congenital – Chiari or Dandy-Walker malformations

 

Specific Entities

Alcohol

·         Midline cerebellar atrophy with gait disturbance

·         Hemisphere’s relatively spared – hence upperlimb, eye signs etc. more rare.

·         Acute intoxication also results in ataxia

Post-infectious

·         Observed post many viral illnesses including varicella, EBV

·         MRI often reveals signal change in cerebellum

·         Acute swelling can occur

·         Prognosis is usually good

·         Bickerstaff’s/Miller-Fisher Syndrome should be considered if other signs present

Infection

·         HIV – 30% of patients with HIV dementia develop ataxia

·         CJD - ~17% of patients have ataxia as an early feature of disease

Autoimmune

·         Paraneoplastic Cerelellar Degeneration (See Paraneoplastic syndromes)

o    Rapidly progressive pancerebellar syndrome that reaches its nadir within a few months

o    Other neurological signs common

o    CSF shows a mononuclear pleocytosis

·         Ataxia with Gluten Sensitivity

o    High prevalence of anti-giladin antibodies in patients with undefined ataxia (controversial/disputed finding)

o    Some patients anecdotally better with gluten free diet

·         Anti-GAD antibodies

o    Ataxia, peripheral neuropathy, and ‘stiff-person’ syndrome all observed.

Sporadic Ataxia

·         Really a diagnosis of exclusion

·         Defines a group with generally slowly progressive disease

 

 

General Diagnosis of Ataxia

·         CSF

o    Monocytic pleocytosis – Postinfectious, paraneoplastic

 

Diagnosis

Test

Hypothyroidism

TFTs

Infections – HIV

HIV serology

Paraneoplastic

Paraneoplastic antibody screen

Gluten sensitivity

Anti-giladin, anti-endomysial antibodies

GAD antibody mediated

GAD antibody

B12 (sensory ataxia)

Vitamin B12

Inherited diseases

 

Abetalipoproteinemia

 Low vitamin E levels, abnormal lipoprotein electrophoresis

Adrenoleukodystrophy

 MRI, serum long-chain fatty acids

Ataxia with CoQ defi ciency

 Low CoQ in muscle biopsy

AOA 1

 High serum cholesterol, low albumin

AOA 2

 High alpha fetoprotein

Ataxia-telangiectasia

High alpha fetoprotein, low immunoglobulin

Carbohydrate-deficient glycoprotein syndromes

 Transferrin isoelectric focusing

Cerebrotendinous xanthomatosis

 Tendon xanthoma, serum cholestanol

GM2 gangliosidosis (late onset)

Hexosaminidase levels, preferably in cultured fi broblasts

Maple syrup urine disease

Urine amino acids

Organic acidurias

Urine organic acids, ketone bodies

Pyruvate dehydrogenase defi ciency

 Plasma and CSF lactate

Sialidosis

Neuraminidase

Urea cycle defects

Plasma ammonia

Vanishing white matter disease

MRI and MRS

Wilson’s disease

Serum copper, ceruloplasmin

Inherited diseases:

  • Spinocerebellar ataxia’s
  • Friedreich’s ataxia
  • Mitochondrial Disorders
    • MELAS
    • MERRF
    • Kearns-Sayre syndrome
    • POLG
  • Episodic ataxia
  • Ataxia Telangiectasia  
  • Leigh’s disease
  • Abetalipoproteinaemia
  • Cayman ataxia
  • Ataxia  with isolated vitamin E deficiency
  • Ataxia with occulomotor apraxia
  • Wilson’s disease
  • Vanishing White Matter Disease
  • Maple syrup urine disease
  • Organic acidurias
  • Urea cycle disorders

Spinocerebellar Ataxias 

·         SCA1 to SCA28 based on genotyping

  • Phenotypes frequently overlap

Pathogenesis

·         28 different mutations

  • 6 of these are due to CTG (glutamaine) repeats
  • The resulting proteins with poly-glutamine motifs are called ataxins
  • Result in a toxic gain of function mutation – hence autosomal dominant 

SCA1

·         Most common

  • Previously referred to as olivopontocerebellar atrophy – however this phenotype probably encompases other mutations
  • SCA1 gene encoding ataxin-1
  • Presents in early or middle life (20-30years)
  • Clinical
    • Progressive cerebellar ataxia
      • Ataxia of trunk and limbs with gait disturbance
      • Slowness of voluntary movements
      • Scanning speech
      • Nystagmus
      • Oscillatory tremor of head and trunk. 
      • Dysarthria and dysphagia can occur
    • EPS symptoms
      1. Akinetic syndromes, hypomimetic facies, dystonia, chorea, athetosis
    • UMN signs
      1. Hyperreflexia, increased tone, extensor plantar responses
    • LMN
      1. Neuropathy can occur which masks UMN signs and may result in wasting and fasciculations.
      2. Bulbar dysfunction can occur
      3. Sensory neuropathy usually does not occur
    • Mild dementia may occur
    • Incontinence
  • Cerebellar and brainstem atrophy on MRI

Other SCA’s

·         Similar symptoms to SCA1 but with varying proportions

·         Other symptoms that occur in various types include:

o    Opthalmoparesis

o    Visual loss

o    Sensory changes (generally mixed and usually not the dominant feature)

Friedreich’s ataxia

·         Most common inherited ataxia – accounts for ~50%

  • Two forms
    • Frataxin gene – expanded GAA repeat
      1. Results in loss of function
      2. Protein processes iron in mitochondria, loss of function results in excess oxidised iron and cell death
    • VitaminE-VLDL interaction – disturbances (relatively rare)
  • Degeneration in
    • Spinocerebellar tracts
    • Lateral corticospinal
    • Dorsal columns
  • Some atrophy of cerebellum noted
  • Presents before 25years of age
  • Median age of death is 35yrs, women have better prognosis

 Clinical Manifestations

  • Summary
    • Cerebellar dysfunction
    • Posterior column sensory loss
    • UMN signs but with loss of reflexes
  • Cerebellar dysfunction
    • Ataxia in all four limbs - Lower limbs > upper limbs
    • Other cerebellar signs – nystagmus etc.
    • Truncal titubation
    • Cerebellar dysarthria can occur
  • Ataxic Gait (and subsequent falls)
  • Posterior column loss
    • Loss of vibration and proprioception
  • Pyramidal tracts affected (variable)
    • UMN signs and weakness
    • Flexor spasm
  • Reflexes are however often absent due to sensory loss (especially as disease progresses)
  • Occular
    • Loss of smooth pursuit
    • Optic atrophy
  • Brainstem
    • Difficulty swallowing can occur
  • Cardiac involvement – 50-90%
    • Hypertrophy
    • Conduction defects 
  • Kyphoscoliosis
  • Pes cavus
  • Cocking of toes
  • Wasting of small muscles of the hand
  • Endocrine
    • DM occurs in 10-30%
  • Cognition - Normal

  Diagnosis

 

  • NCS
    • Shows axonal peripheral sensory neuropathy
  • ECG – abnormal in majority
  • MRI
    • may show spinal atrophy in cervical cord and change in signal in the posterior columns
    • cerebellar atrophy may occur but is usually normal
  • Genetic testing
    • Autosomal recessive – both copies of the gene need to be either expanded or defective
    • Expanded GAA repeat
      1. 10 or less is ‘normal’ – 80% of population
      2. Affected genes usually have >66 repeats
      3. Between 10-66 is a group of asymptomatic ‘carriers’

 Treatment

•   Idebenone (Coenzyme Q analog) has shown some promise in treating the hypertrophic cardiomyopathy

•   Coenzyme Q and vitamin E have been proposed

•   Rehabilitation

•   Diagnose and treat co-morbidities (such as DM)

Prognosis

•   Usually loose ability to walk 9-15yrs after onset

•   Life expectancy ~30-50yrs

•   Main cause of death is cardiac abnormalities and bulbar dysfunction

•