---

Ataxia Disorders — Classification, Treatable Causes & Clinical Approach

---

1. Classification of Ataxia Disorders

---

A. By Anatomical Type

---

B. By Onset Pattern (Symmetric Ataxia)

---

C. By Aetiology

I. Acquired (Non-genetic) Ataxias

• Alcohol (acute and chronic cerebellar degeneration)
• Drugs: phenytoin, lithium, barbiturates, carbamazepine, fluorouracil, paclitaxel
• Heavy metals: methyl mercury, bismuth
• Solvents: toluene (glue sniffing, spray painting)
• Hypothyroidism
• Vitamin deficiencies: B₁ (thiamine — Wernicke encephalopathy), B₁₂, vitamin E

• Cerebellar infarction or haemorrhage
• Lateral medullary syndrome (Wallenberg)

• Primary cerebellar tumours (medulloblastoma, haemangioblastoma)
• Metastatic disease
• Paraneoplastic cerebellar degeneration — anti-Yo (breast/ovarian), anti-Tr (Hodgkin's), anti-VGCC (SCLC)

• Multiple sclerosis
• Anti-GAD65 antibody-associated cerebellar ataxia
• Gluten ataxia (anti-gliadin, anti-tissue transglutaminase antibodies)
• Steroid-responsive encephalopathy with anti-TPO antibodies (Hashimoto encephalopathy)
• Miller Fisher syndrome (GQ1b antibodies — ataxia, ophthalmoplegia, areflexia)

• Post-varicella cerebellitis (common, reversible)
• Prion disease (Creutzfeldt-Jakob disease) — ataxia + dementia
• HIV, HTLV-1, Lyme disease, Legionella, toxoplasmosis

• Arnold-Chiari malformation
• Hydrocephalus
• Posterior fossa tumours

---

II. Hereditary Ataxias

Autosomal Dominant — Spinocerebellar Ataxias (SCAs)

• ADCA I — cerebellar ataxia + variable extracerebellar (pyramidal, peripheral, slow saccades, dystonia)
• ADCA II — cerebellar ataxia + retinal degeneration (SCA7)
• ADCA III — relatively pure cerebellar ataxia (SCA6)

---

Autosomal Recessive Ataxias

---

X-Linked and Mitochondrial

• Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): FMR1 premutation (55–200 CGG repeats); elderly males; T2 hyperintensity in bilateral middle cerebellar peduncles
• MELAS, MERRF — mitochondrial ataxias

---

2. Treatable Ataxias

"The most important goal in management of patients with ataxia is to identify treatable disease entities." — Harrison's Principles of Internal Medicine, 22nd ed.

---

3. Approach to a Patient with Ataxia

Step 1 — History

• Onset and tempo: Acute (hours/days → vascular, toxic, infectious), Subacute (weeks → paraneoplastic, Wernicke), Chronic/progressive (months-years → hereditary, metabolic)
• Pattern: Symmetric bilateral vs. focal/unilateral (unilateral → mass, stroke)
• Associated symptoms: Vertigo (vestibular), sensory loss/positive Romberg (sensory), corticospinal signs (spastic ataxia), retinopathy (SCA7), dementia (prion, SCA17)
• Family history: Autosomal dominant (SCAs) or recessive (Friedreich, AT)
• Drug and alcohol history
• Systemic symptoms: Weight loss, malignancy (paraneoplastic), thyroid disease

---

Step 2 — Examination

---

Step 3 — Investigations

• MRI brain — essential for all patients
  • Cerebellar cortical atrophy → chronic/hereditary ataxia
  • T2 hyperintensity in middle cerebellar peduncles → FXTAS
  • T2 hyperintensity mamillary bodies/periaqueductal grey → Wernicke
  • "Hot-cross-bun sign" in pons → MSA-C
  • T2 inferior olivary hyperintensity → POLG, Alexander disease, gluten ataxia
  • Mass, haemorrhage, infarction → surgical emergency

• Protein 14-3-3 → CJD
• Low CSF glucose → GLUT-1 deficiency ataxia
• Pleocytosis → infectious/inflammatory
• Autoantibodies (when serum negative)

• Based on clinical phenotype and inheritance pattern
• CAG repeat expansion panels for SCA 1, 2, 3, 6, 7, 17
• GAA repeat for Friedreich ataxia (FXN gene)
• POLG sequencing for mitochondrial ataxia

• EMG/NCS: peripheral neuropathy (sensory ataxia, Friedreich)
• Echocardiogram: hypertrophic cardiomyopathy (Friedreich ataxia)
• Ophthalmology: retinopathy (SCA7), cataracts (CTX)
• Audiometry: deafness (SCA7, MELAS)

---

Step 4 — Management Principles

• Treat reversible/treatable causes first (nutritional, toxic, immune, structural)
• Symptomatic treatment:
  • Weighted cuffs on ataxic limb to reduce kinetic tremor
  • Mobility aids (cane, walker) for gait ataxia
  • Displacing centre of gravity forward (heel raise, lower walker) improves posture
  • Acetazolamide for episodic ataxias (EA1, EA2)
  • Physiotherapy, occupational therapy, speech therapy
• Genetic counselling for hereditary ataxias
• Monitor complications: cardiomyopathy (Friedreich), scoliosis, respiratory failure, diabetes

---

Summary Algorithm

Ataxia
│
├── Acute onset → Toxic/Drug, Vascular (stroke/bleed), Infection, Trauma
│
├── Subacute onset → Paraneoplastic, Wernicke, Autoimmune, Infection
│
└── Chronic/Progressive
        ├── Symmetric bilateral → Hereditary (SCA, Friedreich), 
        │                         Metabolic (hypothyroid, Vit E), 
        │                         Chronic alcohol, Immune
        └── Asymmetric/Focal → Mass lesion, MS plaque, Vascular

---

• Bradley and Daroff's Neurology in Clinical Practice, 8th ed. — Chapter 23 (Cerebellar Ataxia), Chapter 25 (Gait Disorders)
• Harrison's Principles of Internal Medicine, 22nd ed. — Chapter 450 (Ataxic Disorders)

---

Friedreich Ataxia

Genetics & Pathogenesis

• Inheritance: Autosomal recessive — most common progressive inherited ataxia; accounts for ~50% of all hereditary ataxias
• Mutation: Expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene (chromosome 9q13-q21) on both alleles
  • Normal: 10–21 repeats; Disease: 200–900 repeats
  • Longer repeat length → more severe disease, earlier onset
• Effect: Gene silencing → reduced expression and levels of frataxin (a mitochondrial protein critical for iron export and mitochondrial function)
• Frataxin deficiency → mitochondrial iron accumulation → oxidative damage to neurons, heart, and other tissues

---

Pathology

• Spinocerebellar tracts
• Posterior columns (dorsal columns)
• Corticospinal (pyramidal) tracts
• Dorsal root ganglia and Clarke's columns
• Peripheral nerves
• Heart: ventricular hypertrophy + chronic interstitial myocardial fibrosis (hypertrophic cardiomyopathy)

---

Clinical Features

---

Diagnosis

• Genetic testing for GAA repeat expansion (FXN gene) — confirmatory
• MRI: spinal cord atrophy
• ECG/Echo: hypertrophic cardiomyopathy
• Exclude treatable mimics: vitamin B₁₂ deficiency, abetalipoproteinaemia, AVED (vitamin E deficiency)

---

Treatment

• No disease-modifying therapy currently established
• Supportive: physiotherapy, orthotics, wheelchair
• Cardiac management of hypertrophic cardiomyopathy
• Surgical correction of scoliosis
• Omaveloxolone (Nrf2 activator) — recently FDA-approved; may slow progression
• Investigational: histone deacetylase inhibitors (to increase frataxin expression), gene therapy

---

Neuromyelitis Optica Spectrum Disorder (NMOSD)

---

What is NMOSD?

• Lesions are necrotising (cavitation, necrosis) rather than purely demyelinating
• Gliosis (characteristic of MS) is minimal or absent
• Arcuate fibres (subcortical) are relatively spared (severely damaged in MS)
• Eosinophil and granulocyte infiltrates + IgG/IgM deposition + perivascular complement activation

---

Pathogenesis

• Anti-AQP4-IgG (aquaporin-4 antibodies): Found in ~75% of cases. AQP4 is a water channel protein expressed on astrocyte foot processes at the blood-brain barrier. Anti-AQP4 IgG targeting astrocytic processes around nodes of Ranvier initiates demyelination.
• Anti-MOG antibodies: Found in a smaller proportion (~25%), particularly in children. Considered a separate entity (MOGAD) by most investigators; cord MRI shows predominantly grey matter damage.
• Nearly half of NMOSD cases have other co-existing autoantibodies
• ~1/3 have a co-existing systemic autoimmune disorder: SLE, Sjögren syndrome, thyroiditis
• ~5% are paraneoplastic

---

Clinical Features

1. Optic Neuritis

• Usually bilateral (hours to days between eyes) — unlike MS which is typically unilateral
• Rapid and severe; complete blindness not uncommon
• Central scotoma most common visual field defect
• Disc swelling (papillitis) in majority
• OCT shows thinner retinal nerve fibre layer compared to MS
• Visual recovery possible but often incomplete; severe permanent visual loss can occur
• Can present as recurrent optic neuritis without myelitis (anti-AQP4 positive)

2. Transverse Myelitis (Acute Myelopathy)

• Usually sudden and severe — paraplegia or quadriplegia depending on level
• Flaccidity, areflexia, bladder atonicity (reflects necrotising grey + white matter damage)
• Longitudinally Extensive Transverse Myelitis (LETM): MRI lesion ≥3 contiguous vertebral segments — hallmark finding
• Sensory level; sphincter paralysis
• Lhermitte symptom, paroxysmal tonic spasms, radicular pain
• May leave permanent complete paralysis; recovery is often incomplete

3. Area Postrema Syndrome (Brainstem — Dorsal Medulla)

• Intractable hiccups, nausea and vomiting — highly distinctive, not explained by GI causes
• May precede or accompany optic neuritis or myelopathy attacks
• Dorsal medullary lesion on MRI is highly confirmatory of NMOSD

4. Diencephalic Syndrome

• Hypothalamic involvement → symptomatic narcolepsy, involuntary weight loss, behavioural change, endocrinopathy

5. Brainstem/Cerebral Involvement

• Parinaud syndrome, one-and-a-half syndrome
• Posterior reversible encephalopathy syndrome (PRES)
• In children: hemiparesis, focal cerebral signs, seizures may predominate

Key Features Distinguishing from MS

---

Diagnostic Criteria (2015 IPND Criteria for NMOSD)

NMOSD with Anti-AQP4-IgG

1. Optic neuritis
2. Acute myelitis
3. Area postrema syndrome (intractable hiccups/nausea/vomiting)
4. Acute brainstem syndrome
5. Symptomatic narcolepsy or acute diencephalic syndrome with NMOSD-typical MRI lesions
6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions

NMOSD without Anti-AQP4-IgG (Seronegative) or Unknown Status

1. Contiguous spinal cord MRI lesion extending ≥3 vertebral segments (LETM)
2. Brain MRI not meeting diagnostic criteria for MS
3. (If anti-AQP4 negative: MOG-IgG testing performed)

Supporting Criteria (Older Wingerchuk 2006 Criteria — still quoted):

• Optic neuritis
• Acute myelitis
• At least 2 of 3:
  1. LETM on MRI (≥3 segments)
  2. Brain MRI not diagnostic of MS
  3. Positive NMOSD-IgG (anti-AQP4)

Laboratory Diagnosis

• Anti-AQP4-IgG (NMO-IgG): Sensitivity 60–91%, Specificity >99% by indirect immunofluorescence
• May be detectable in CSF when serum is negative → LP warranted when clinical suspicion high
• CSF: pleocytosis (inflammatory), elevated protein; oligoclonal bands typically absent (unlike MS)
• Anti-MOG antibody testing in seronegative cases

MRI Findings

• Spinal cord: LETM (≥3 segments), central cord, T2 hyperintense; gadolinium enhancement acutely; atrophy/cavitation in chronic lesions
• Optic nerve: full-length involvement (vs. spotty in MS)
• Brainstem: dorsal medullary lesion — highly confirmatory
• Brain: periependymal lesions around 3rd/4th ventricle, diencephalon, hypothalamus

---

Treatment

A. Acute Attack Management

---

B. Relapse Prevention (Long-term Immunosuppression)

• Interferon-beta, natalizumab, fingolimod — contraindicated or may exacerbate NMOSD

---

C. Special Situations

• Pregnancy: Relapse rate ↓ in 1st/2nd trimesters, ↑↑ in postpartum period (up to 3–5× annualised rate in 6 months post-partum) — close monitoring essential
• Seronegative NMOSD: Similar immunosuppressive approach; MOG-IgG positive cases may need different management

---

Summary Table