Differential Diagnosis in Neurology

13.4. Ataxias from other Etiologies

Mitochondrial Ataxias NARP

• General characteristics:
  • 8993T > G NARP mutation in the ATPase 6 gene
  • Also causes a portion of Leigh's syndrome
• Clinical features:
  • Neuropathy
  • Ataxia
  • Retinitis pigmentosa

Leigh's Disease

• General characteristics:
  • Defects of mitochondrial respiratory chain enzymes:
    • Cytochrome oxidase (COX) complex I/II
    • Deficiency of pyruvate dehydrogenase (PDH) complex
    • SURF 1 mutation leads to COX deficiency; AR inheritance in Leigh's syndrome
    • Maternal inheritance noted in 20% of patients (mutation of the 8993 nucleotide of mitochondrial ATP 6 gene (encodes a component of complex V)
• Clinical features:
  • Infantile fatal form with necrotizing encephalopathy
  • Late childhood adolescent form:
    • Optic atrophy
    • Recurrent exacerbations
    • Ataxia

Congenital Defects of the Cerebellum

• General characteristics:
  • Extended ontogenesis; neuroblast migration from the external granular layer takes one year
  • Development occurs from 32 days of gestation to one year
  • Cerebellar cortex is susceptible to toxic effects of drugs, chemicals, viral infections, ischemia and hypoxia
• Clinical features:
  • Hypoplasia or aplasia of the vermis with intact lateral ventricles
    • Associated with midline defects such as agenesis of the corpus callosum or holoprosencephaly
    • Joubert's syndrome
      • AR
      • Episodic hyperpnea
      • Abnormal eye movements
      • Ataxia
      • Mental retardation

Dandy–Walker

• General characteristics:
  • Large posterior one half of the IVth ventricle associated with atretic foramen of Magendie
  • Heterotopia of the inferior olivary nuclei
  • Pachygria of the cerebral cortex
  • Hydrocephalus
  • Large posterior fossa
• Clinical features:
  • Spastic diplegia
  • Mental retardation

Chiari Malformation

• General characteristics:
  • Chiari I
    • Vermis of the cerebellum protrudes through the foramen manganum. The tonsils are usually pointed and fibrotic.
  • Chiari II
    • Vermis herniation
    • Downward displacement of the medulla with nuclear dysplasia
    • Occurs with meningomyelocele
    • Associated syringomyelia
  • Chiari III
    • Cervical spina bifida
    • Cerebellar encephalocele
    • Elongated medulla
    • "Beaked" collicular plate of the midbrain
    • Widening of the angles of the petrous pyramid
  • Chiari IV
    • Above Chiari malformations with additional absence of the cerebellum
• Clinical Features of Chiari 1 and 2 (adults):
  • Associated syringomyelia of Chiari II with expected signs and symptoms
  • Sudden ataxia after age of 30
  • Shallow posterior fossa; low hairline
  • Increased reflexes

Selective Agenesis of the Cerebellar Hemispheres

• General characteristics:
  • Less common than aplasia of the vermis alone

Global Cerebellar Hypoplasia

• Differential Diagnosis:
  • Tay–Sachs disease
  • Menkes (kinky hair) disease
  • Rare spinal muscular atrophy
  • Sporadic and genetic causes
• Clinical features of cerebellar hypoplasia:
  • Developmental delay
  • Muscular hypotonia
  • Truncal titubation and ataxia
  • Nystagmus and intention tremor

Focal Cerebellar Dysplasia

• Differential Diagnosis
  • Migrational disorder
  • Exposure to cytotoxic drugs
  • Viral infection

Seminal Features of Some Named Cerebellar Syndromes

• Marie Sanger Brown (cranial nerve)
• Marinesco–Sjögren (cataracts)
• Friedreich's ataxia (scoliosis) dilated cardiomyopathy
• Marie's (pure cerebellar cortical atrophy)
• Gordon Holmes (cortex-hypogonadism)
• Ramsay Hunt (progressive with myoclonus)
• Madame Lewy Barr (ataxia telangiectasias)
• Fahr's disease (calcification dentate, BG)
• Menzel's variant OPCA (posterior column)
• Fick Hamacher variant of OPCA (cranial nerve)
• Leigh's disease (mt 8993); optic atrophy
• Gerstmann Straüssler Schenker (variant of CJ with late dementia)
• Pelizaeus Merzbacher (nystagmus)
• DRPLA (SCA 7) Russell's syndrome (myoclonus; basal ganglia)
• Adult Krabbe's (increased protein in CSF; peripheral neuropathy)
• Behr's disease (optic atrophy)
• SCA/Machado Joseph (amyotrophy)
• Spastic ataxias – HSP 4; (spastin)
• Paine's (X-linked recessive mental retardation, spasticity)
• Gillespie syndrome (congenital ataxia, mental retardation, aniridia)
• Granule cell hypoplasia (congenital ataxia and mental retardation)
• Tay-Sach's (cherry red spot)
• Fabry's (angiokeratoma diffusum universale)
• Wilson's Disease (flapping postural kinetic tremor)
• Refsum (cataracts, hearing loss, ichthyosis)
• Bassen Kornsweig's Disease (Abetalipoproteinemia and neuropathy)
• Hartnup's Disease (rash on extensor surfaces)
• Joubert's (episodic hyperpnea)

Chediak–Higashi Disease

• General considerations:
  • AR; gene is CHS1; encodes a lysosomal transport protein
  • Increased infections (primarily bacterial)
  • Lymphoma like illness
  • 50% have neurologic symptoms
• Clinical features:
  • Cerebellar ataxia
  • Progressive motor sensory neuropathy
  • Parkinsonism
  • Mental retardation
  • Partial albinism

Metabolic Ataxias

Intermittent

• General considerations:
  • Onset in infancy or childhood
  • Urea cycle defects
  • Aminoacidurias
  • Pyruvate and lactate metabolic abnormalities
  • Most have AR inheritance

Hyperammonia

• General considerations:
  • Defects of urea cycle enzymes:
    • Ornithine transcarbamylase (X-Linked)
    • Arginosuccinate synthetase
    • Arginase deficiency
    • Hyperornithemia (not a urea acid cycle enzyme)
• Clinical features:
  • Intermittent ataxia
  • Dysarthria
  • Vomiting
  • Headache
  • Ptosis
  • Seizures
  • Confusion
• Intermittent episodes precipitated by:
  • Intercurrent illness
  • High protein diet

Ornithine Transcarbamylase

• General considerations:
  • X-linked; affected males die in the neonatal period
  • Clinical symptomatology varies widely in females

Aminoacidurias with Intermittent Ataxia

• General considerations:
  • Conditions to be considered are:
    • Branch chain ketoaciduria
    • Isovaleric acidemia
    • Hartnup disease

Hartnup Disease

• General considerations:
  • AR
  • Defect of intestinal transport of monoaminomonocarboxylic acids
• Clinical features:
  • Intermittent ataxia
  • Rash on extensor surfaces (similar to pellagra)
  • Tremor
  • Chorea
  • Psychiatric symptomatology
  • Mental retardation

Pyruvate Dehydrogenase Deficiency (PDH)

• General considerations:
  • Mutation of the gene for the E1 α-subunit of the enzyme
  • X-chromosome; high frequency of manifesting heterozygotes
    • Females have a variable deficit of the enzyme due to inactivation of the X-chromosome (Lyon hypothesis)
  • Infantile form:
    • Lactic acidosis and death
    • Less severe form that may reach adulthood which is more common in females
• Clinical features:
  • Episodic ataxia concomitant with increased lactic acid
  • Seizures mental retardation
  • Spasticity

Multiple Biotin-Dependent Carboxylase Deficiencies

• General considerations:
  • Autosomal recessive
  • Defects of humoral and cell mediated immunity
• Clinical features:
  • Generalized seizures
  • Myoclonus
  • Hypotonia
  • Nystagmus

Progressive Metabolic Ataxias

• General considerations:
  • Ataxia a major feature of storage diseases
  • Enzyme deficiencies with ataxia:
    • Develop in infancy or childhood
    • May develop in adulthood
  • Include:
    • Metachromatic leukodystrophy
    • Adrenomyeloneuropathy
    • Sphingomyelin lipidosis
    • Krabbe's disease (galactosylceramide)
    • Hexosaminidase deficiency

Hexosaminidase Deficiency

• General considerations (see lysosomal storage disease):
• Clinical features:
  • Age of onset is less than 15 years of age
  • Intention tremor and dysarthria are presenting features
  • Limb and gait ataxia
  • Associated in some patients:
    • Failure of upgaze
    • Proximal neurogenic weakness and atrophy
• Pathology:
  • Distension of neurons with lamellar bodies
• MRI evaluation:
  • Cerebellar and brainstem atrophy

Niemann Pick Disease Type C

• General considerations (see lysosomal storage disease):
• Clinical features:
  • Failure of upgaze
  • Ataxia
• Pathology:
  • Normal sphingomyelinase activity
  • Foamy bone marrow cells

Cholestanolsis

• Deficiency of mitochondrial sterol 27 hydroxylase

Ramsay Hunt

• Similar clinically to
  • Neuronal ceroid lipofuscinosis
  • Sialidosis

Differential Diagnosis of Cerebellar Diseases

Acquired Cerebellar Deficits

• Anoxia
• Heat
• Uncontrolled seizures
• Mercury
• Lithium
• Dilantin
• Thallium
• N-ethyl-toluene
• Post dialysis ataxia
• 5-flurouracil
• Hypothyroidism
• Hypnotic sedatives
• Seasonal ataxia (Nigeria; thiamine deficiency)
• Gamma-amino decarboxylase antibodies
• Vitamin E deficiency
• Adult opsoclonus myoclonus syndrome (paraneoplastic)
• Anti-malarial compounds
• CSF leak causing caudal cerebellar tonsillar herniation
• Deterioration of Chiari malformations
• B12 deficiency
• Acquired primary and secondary tremors
• Vascular disease
• Trauma
• Hepatic encephalopathy
• Pontine and extrapontine myelinolysis
• Alcohol
• Cyclosporin
• Lithium
• Tacrolimus

Differential diagnosis of the major acquired cerebellar syndromes

• Major acquired cerebellar syndromes categories:
  • Drug effects
  • Toxins
  • Vascular disease
  • Endocrine disorders
  • Tumors
  • Paraneoplastic disease
  • Metabolic deficiencies
  • Congenital defects that deteriorate in middle age