Ataxia in Pediatric Age: Clinical Case Discussion & Key Points
Model Case Presentation
Patient Demographics
Name: Master Arjun, Age: 4 years, Gender: Male, Informant: Mother (Reliable)
Chief Complaints
- Sudden onset of unsteady gait — 3 days
- Difficulty in standing and walking — 3 days
- Slurred speech — 2 days
History Summary
Previously healthy child who developed a sudden inability to walk without support 3 days ago. Mother noticed the child swaying to both sides while walking and falling frequently. There is associated slurring of speech. The child had a fever with rash (chickenpox) approximately 10 days prior to the onset of these symptoms, which resolved uneventfully.
No history of headache, vomiting, altered sensorium, seizures, visual disturbances, or limb weakness. No history of trauma, drug ingestion, or toxic exposure. No similar episodes in the past. No family history of neurological illness. Born at term, developmental milestones were normal prior to this illness. Immunization history: not vaccinated against varicella.
Examination Summary
| Parameter | Finding | Significance |
|---|---|---|
| Consciousness | Alert, oriented | Encephalitis unlikely |
| Vitals | Stable, afebrile | Acute phase over |
| Gait | Wide-based, ataxic | Cerebellar dysfunction |
| Romberg's test | Negative | Cerebellar (not sensory) ataxia |
| Finger-nose test | Dysmetria (past-pointing) | Cerebellar dysfunction |
| Heel-knee-shin test | Incoordinate | Cerebellar dysfunction |
| Nystagmus | Horizontal nystagmus present | Cerebellar/vestibular involvement |
| Speech | Dysarthric (scanning speech) | Cerebellar involvement |
| Power/Tone/Reflexes | Normal | No pyramidal or LMN lesion |
| Sensory | Normal — all modalities | Rules out sensory ataxia |
| Skin | Healing varicella lesions | Post-varicella etiology |
Higher Mental Functions: Normal. Cranial Nerves: Normal except nystagmus. No papilledema. No signs of meningeal irritation.
✅ Complete Diagnosis
Acute Post-Infectious (Post-Varicella) Cerebellar Ataxia — an immune-mediated, self-limiting cerebellar syndrome following varicella infection, presenting with acute onset cerebellar signs without encephalopathy.
📝 History — Exam Q&A
Ataxia is a failure of muscular coordination resulting in impaired balance, unsteady gait, and inaccurate limb movements. It is not due to weakness or involuntary movements.
Anatomical basis of cerebellar ataxia: The cerebellum coordinates voluntary muscle activity, maintains posture, and controls balance via its connections with the brainstem, spinal cord, and cerebral cortex. Dysfunction causes ipsilateral limb incoordination (lateral hemisphere lesion), truncal ataxia and wide-based gait (vermis lesion), and abnormal eye movements (flocculonodular lobe lesion).
💡 Mnemonic
DANISH — Dysdiadochokinesia, Ataxia/Asynergia, Nystagmus, Intention tremor, Scanning speech, Hypotonia — features of cerebellar dysfunction.
| Type | Onset/Duration | Key Causes |
|---|---|---|
| Acute (<72 hrs) | Sudden onset, days | Post-infectious, drug/toxin, vascular, trauma |
| Episodic/Intermittent | Recurrent attacks, normal between | Episodic ataxia (EA1, EA2), metabolic disorders (MSUD, urea cycle defects) |
| Chronic Progressive | Weeks–months, worsening | Friedreich ataxia, brain tumors, ADEM, ataxia-telangiectasia |
| Chronic Non-Progressive | Stable long-term | Cerebellar malformations (Dandy-Walker, Joubert syndrome), ataxic cerebral palsy |
Acute Post-Infectious Cerebellar Ataxia (APICA) is the most common cause of acute ataxia in children, accounting for approximately 30–60% of cases. It is most common in children aged 2–7 years.
Pathogenesis: Autoimmune/post-infectious mechanism. Viral infection (most commonly varicella, also EBV, mycoplasma, enterovirus) triggers an immune response producing antibodies or T cells that cross-react with cerebellar antigens (molecular mimicry). This results in cerebellar inflammation without direct viral invasion. Varicella is the single most common preceding infection.
Onset: Ataxia appears 1–3 weeks after the prodromal illness (rarely during or before rash).
| Type | Site of Lesion | Romberg's Test | Key Feature |
|---|---|---|---|
| Cerebellar ataxia | Cerebellum | Negative (sways with eyes open AND closed equally) | Dysmetria, dysdiadochokinesia, nystagmus, past-pointing |
| Sensory (spinal) ataxia | Posterior columns / peripheral nerve | Positive (worsens on closing eyes) | Loss of proprioception, vibration; normal coordination when visual feedback used |
| Vestibular ataxia | Inner ear / vestibular nerve | Positive (falls to one side) | Vertigo, vomiting, unidirectional nystagmus |
| Frontal/Cortical ataxia | Frontal lobe | Negative | Magnetic gait, gait apraxia, cognitive deficits |
1. Onset and time course: Sudden (vascular, post-infectious, toxic) vs. gradual (hereditary, tumor)
2. Prodromal illness: Fever, rash, viral infection in preceding 1–3 weeks → post-infectious
3. Drug/toxin exposure: Anticonvulsants (phenytoin, carbamazepine), alcohol, benzodiazepines — most common drug cause
4. Trauma: Head injury → posterior fossa hematoma
5. Associated features: Headache + vomiting + ataxia = posterior fossa tumor/raised ICP (red flag); fever + neck stiffness = meningitis; altered consciousness = encephalitis/ADEM
6. Recurrent episodes: Metabolic disorders, episodic ataxia
7. Family history: Consanguinity, siblings affected → hereditary ataxia
8. Developmental history: Regression of milestones → neurodegenerative disease
🚨 Red Flags — Do NOT Miss
- Headache, vomiting + ataxia — Posterior fossa tumor / raised ICP → Urgent MRI
- Altered sensorium / encephalopathy — Encephalitis, ADEM
- Rapid progression over hours — Toxic ingestion, vascular
- Focal neurological signs — Stroke, tumor, demyelination
- Neck stiffness + fever — Meningitis/cerebellitis
- Opsoclonus-myoclonus + ataxia — Paraneoplastic (opsoclonus-myoclonus-ataxia syndrome) → rule out neuroblastoma
- Regression of milestones — Neurodegenerative disorder
- Papilledema — Raised ICP
| Category | Examples |
|---|---|
| Post-infectious (most common) | Post-varicella, post-EBV, post-mycoplasma, post-enterovirus |
| Drug/Toxic | Phenytoin, carbamazepine, benzodiazepines, alcohol, lead |
| Structural | Posterior fossa tumors (medulloblastoma, astrocytoma), hemorrhage |
| Infectious | Acute cerebellitis, meningitis, encephalitis |
| Demyelinating | ADEM, multiple sclerosis |
| Paraneoplastic | Opsoclonus-myoclonus-ataxia (neuroblastoma) |
| Vascular | Cerebellar stroke (rare in children) |
| Metabolic | Hypoglycemia, hyperammonemia, maple syrup urine disease (MSUD) |
| Trauma | Posterior fossa hematoma |
| Psychogenic | Conversion disorder |
| Disease | Inheritance | Gene/Chromosome | Key Feature |
|---|---|---|---|
| Friedreich Ataxia | Autosomal Recessive | FXN / Chr 9 (GAA repeat expansion) | Absent reflexes, positive Romberg, pes cavus, cardiomyopathy |
| Ataxia-Telangiectasia (A-T) | Autosomal Recessive | ATM / Chr 11q22-23 | Oculocutaneous telangiectasia, immunodeficiency, malignancy risk |
| Spinocerebellar Ataxias (SCA) | Autosomal Dominant | Various (CAG repeats, SCAs 1-3, 6, 7) | Adult onset, family history |
| Joubert Syndrome | Autosomal Recessive | Multiple genes (JBTS) | "Molar tooth sign" on MRI, hyperpnea, oculomotor apraxia |
| Abetalipoproteinemia | Autosomal Recessive | MTTP gene | Fat malabsorption, acanthocytosis, low cholesterol, responds to Vit E |
| Refsum Disease | Autosomal Recessive | PHYH gene | Elevated phytanic acid, retinitis pigmentosa, ichthyosis |
OMA syndrome (also called "Dancing Eyes Syndrome") is a rare but critical cause of ataxia characterized by:
- Opsoclonus — chaotic, multidirectional, conjugate eye movements
- Myoclonus — rapid, irregular muscle jerks
- Ataxia — truncal and gait ataxia
It is a paraneoplastic syndrome. In children, it is most commonly associated with occult neuroblastoma (50% of cases). It can also occur post-infectious (viral).
It is a medical emergency — must rule out neuroblastoma urgently (abdominal ultrasound, urine catecholamines: VMA/HVA, MIBG scan).
🩺 Examination — Exam Q&A
Gait assessment (most important): Observe walking — wide-based, staggering, and lurching gait suggests cerebellar ataxia. Observe tandem gait (heel-to-toe walking) — exacerbates cerebellar ataxia.
Stance tests: Romberg's test — patient stands with feet together, eyes open then closed. Falls with eyes closed only = sensory ataxia (positive Romberg). Falls with both eyes open AND closed = cerebellar ataxia (Romberg negative).
Upper limb coordination:
- Finger-nose test (dysmetria / past-pointing / intention tremor)
- Dysdiadochokinesia (rapid alternating movements — pronation/supination)
- Rebound phenomenon (Holmes' rebound)
Lower limb coordination: Heel-knee-shin test (incoordinate in cerebellar ataxia)
Eye movements: Nystagmus (horizontal = cerebellar/vestibular; vertical = brainstem)
Speech: Dysarthria — scanning (explosive), slurred, or staccato speech
Muscle tone: Hypotonia in cerebellar ataxia
| Feature | Cerebellar Ataxia | Sensory Ataxia | Vestibular Ataxia |
|---|---|---|---|
| Gait | Wide-based, lurching, staggering to both sides ("drunken sailor") | Wide-based, high-stepping ("stamping"), patient looks at feet | Falls toward affected ear, veers to one side |
| Romberg | Negative (sways eyes open & closed) | Positive (worsens eyes closed) | Positive (falls to one side) |
| Effect of vision | No improvement | Markedly improves | Mild improvement |
| Nystagmus | Horizontal, direction-changing, bidirectional | Absent | Horizontal, unidirectional, fixed direction |
| Deep reflexes | Normal or pendular | Reduced/absent (if dorsal column) | Normal |
| Proprioception/Vibration | Normal | Impaired | Normal |
Dysdiadochokinesia is the inability to perform rapid alternating movements — a cardinal sign of cerebellar dysfunction.
Testing: Ask the patient to alternately pronate and supinate one hand rapidly on the dorsum of the other hand. A cerebellar lesion causes slow, irregular, clumsy movements. Also tested by rapid finger tapping.
Mechanism: The cerebellum is required to time and sequence rapid reciprocal movements. Loss of this timing results in decomposition of movement.
Friedreich Ataxia is unique because it combines cerebellar AND sensory ataxia (mixed).
Neurological:
- Progressive limb and gait ataxia (onset 8–15 years)
- Absent deep tendon reflexes in lower limbs (earliest sign)
- Positive Romberg's sign (sensory component)
- Loss of vibration sense and proprioception (posterior column involvement)
- Dysarthria (scanning speech)
- Extensor plantar responses (upgoing Babinski) — despite absent DTRs (paradox)
- Distal muscle wasting (later)
- Nystagmus (in some)
Systemic features:
- Pes cavus (high-arched feet) — characteristic
- Kyphoscoliosis
- Hypertrophic cardiomyopathy — most common cause of death
- Diabetes mellitus (10–20%)
- Optic atrophy, hearing loss (less common)
💡 Key Paradox in Friedreich Ataxia
Absent reflexes + Upgoing Plantars — seemingly contradictory but explained by simultaneous involvement of both peripheral sensory neurons (causing areflexia) and corticospinal tracts (causing extensor plantar).
Neurological:
- Progressive truncal ataxia — appears when child begins walking (~12–18 months)
- Oculomotor apraxia — difficulty initiating voluntary saccadic eye movements (pathognomonic)
- Horizontal nystagmus
- Dysarthria, hypotonia
- Romberg negative (cerebellar, NOT sensory ataxia — distinguishes from Friedreich's)
- Areflexia develops after age 7–8 years
- Choreoathetosis (extrapyramidal feature, especially older children)
Cutaneous (Neurocutaneous markers):
- Telangiectasias — appear at age 2–6 years; most prominent on bulbar conjunctiva, also ears, neck, antecubital fossa, popliteal fossa
Immunological:
- Recurrent sinopulmonary infections (IgA and IgE deficiency, T-cell dysfunction)
- Thymic hypoplasia
Malignancy risk: 100× increased risk — especially lymphoma and leukemia
💡 Key Differentiating Point: A-T vs Friedreich
| Ataxia-Telangiectasia | Friedreich Ataxia | |
|---|---|---|
| Onset | ~12–18 months (toddler) | 8–15 years (school age) |
| Romberg | Negative | Positive |
| DTRs | Normal early, lost late | Absent early |
| Plantars | Flexor | Extensor (Babinski) |
| Telangiectasia | Present (2–6 yrs) | Absent |
| Cardiomyopathy | Absent | Present (65%) |
| AFP | Elevated | Normal |
| Malignancy | High risk | Not increased |
A pendular knee jerk is a deep tendon reflex where, after tapping the patellar tendon, the leg continues to swing back and forth several times like a pendulum (normally it stops after 1–2 swings). This occurs due to hypotonia (lack of normal dampening by muscle tone) and is a sign of cerebellar disease. Normally, cerebellar output modulates the reflexes. In cerebellar dysfunction, loss of this modulation results in the pendular swing.
| Finding | Diagnosis |
|---|---|
| Telangiectasias on conjunctiva, ears, popliteal fossa | Ataxia-Telangiectasia |
| Café-au-lait spots, axillary freckling, neurofibromas | Neurofibromatosis type 1 (NF1) |
| Adenoma sebaceum, ash-leaf macules, shagreen patch | Tuberous sclerosis |
| Port-wine stain (over face/trigeminal area) | Sturge-Weber syndrome |
| Ichthyosis | Refsum disease |
| Xanthomas | Cerebrotendinous xanthomatosis |
🔬 Investigations — Exam Q&A
Step 1 — Rule out emergencies FIRST:
- Blood glucose — hypoglycemia
- MRI brain (preferred) or CT (if unavailable/urgent) — posterior fossa tumor, hemorrhage, stroke, ADEM
Step 2 — Targeted investigations based on clinical suspicion:
- Toxicology screen (blood + urine) — drug/toxin ingestion
- Serum electrolytes, LFT, ammonia — metabolic causes
- CSF analysis — if meningitis/encephalitis/ADEM suspected (only after ruling out raised ICP)
- Varicella IgM, viral serology — post-infectious
💡 Note
In typical post-infectious cerebellar ataxia (acute onset, preceding viral illness, no headache/vomiting/fever, normal consciousness, no focal signs), MRI brain may be normal and is not always mandatory. However, any red flags mandate urgent imaging.
| Diagnosis | MRI Finding |
|---|---|
| Post-infectious cerebellar ataxia | Often normal (diagnosis of exclusion) |
| Acute cerebellitis | Diffuse cerebellar swelling, T2/FLAIR hyperintensity, meningeal enhancement; can cause obstructive hydrocephalus |
| ADEM | Multiple white matter lesions (bilateral, asymmetric), cortical and brainstem involvement |
| Medulloblastoma | Midline vermian mass, obstructive hydrocephalus, enhancing lesion |
| Cerebellar astrocytoma | Cystic mass ± mural nodule in cerebellar hemisphere |
| Friedreich Ataxia | Cerebellar atrophy (spinal cord atrophy predominates), thinning of cervical cord |
| Joubert Syndrome | "Molar tooth sign" on axial MRI — characteristic |
| Dandy-Walker malformation | Cystic enlargement of 4th ventricle, cerebellar vermis hypoplasia, large posterior fossa |
Indications: Fever + ataxia (meningitis/cerebellitis), suspected encephalitis (altered consciousness), ADEM, GBS (ascending involvement).
Findings:
| Condition | Cells | Protein | Glucose |
|---|---|---|---|
| Post-infectious ataxia | Normal or mild lymphocytosis | Normal or mildly elevated | Normal |
| Bacterial meningitis | Neutrophilic pleocytosis | Markedly elevated | Low |
| Viral meningitis/cerebellitis | Lymphocytic pleocytosis | Mildly elevated | Normal |
| ADEM | Lymphocytosis or normal | Elevated | Normal |
| GBS | Normal | Elevated (albumino-cytological dissociation) | Normal |
- Gold standard: Genetic testing — FXN gene (GAA trinucleotide repeat expansion) on chromosome 9q13. Normal: 5–33 repeats. Pathological: ≥66 repeats (usually 600–1200). 96% are homozygous for this expansion.
- Frataxin protein assay (immunoassay) — reduced frataxin levels; useful to detect the 4% who have point mutations not detected by repeat analysis
- ECG: T-wave inversions, ST changes, ventricular hypertrophy (cardiomyopathy)
- Echocardiography: Hypertrophic cardiomyopathy (symmetric or asymmetric hypertrophy)
- NCS/EMG: Absent sensory nerve action potentials (SAPs), normal motor conduction (axonal sensory neuropathy)
- MRI spine: Thinning of cervical spinal cord
- Fasting glucose / HbA1c: Screen for diabetes mellitus
- Serum Alpha-Fetoprotein (AFP) — markedly elevated in >95% of A-T patients; most useful and readily available screening test
- Immunoglobulins: Decreased IgA and IgE (characteristic); reduced IgG subtypes; IgM may be normal or elevated
- Lymphocyte subset analysis: Reduced CD4+ T cells, impaired T-cell function
- ATM gene mutation analysis (chromosome 11q22-23) — definitive diagnosis
- ATM protein level/kinase activity (from lymphocytes or fibroblasts)
- MRI brain: Cerebellar atrophy (progressive), T2 signal changes
- Radiation sensitivity: A-T cells are hypersensitive to X-rays (avoid unnecessary radiation)
- Chest X-ray: Recurrent pneumonias, bronchiectasis, thymic hypoplasia/absence
⚠️ Important
Avoid unnecessary radiation exposure in A-T patients — their cells have defective DNA repair (ATM kinase) and are exquisitely radiation-sensitive, increasing cancer risk.
MRI brain with gadolinium contrast is the investigation of choice for posterior fossa tumors.
- Medulloblastoma: Midline (vermian) mass, hyperdense on CT, restricted diffusion on MRI, homogeneous enhancement, often with hydrocephalus. Most common pediatric posterior fossa malignant tumor.
- Cerebellar astrocytoma (Pilocytic): Most common pediatric cerebellar tumor overall. Cystic mass with enhancing mural nodule in cerebellar hemisphere. Excellent prognosis after surgery.
- Ependymoma: Arises from 4th ventricle floor, "plastic" growth pattern, calcium deposits.
- Brainstem glioma: Diffuse intrinsic pontine glioma (DIPG) — MRI shows T2-hyperintense pontine enlargement.
Additional: Fundoscopy (papilledema), neurological examination (cranial nerve palsies), spine MRI (for metastases in medulloblastoma).
Episodic ataxia warrants metabolic workup:
- Serum ammonia — urea cycle defects, organic acidemias
- Serum lactate + pyruvate — mitochondrial disease
- Urine organic acids — MSUD (maple syrup urine disease: elevated branched chain amino acids), propionic/methylmalonic acidemia
- Urine amino acids, plasma amino acids — Hartnup disease (neutral aminoaciduria), MSUD
- Blood glucose (during attack) — hypoglycemia
- Genetic testing: CACNA1A (Episodic Ataxia type 2, EA2), KCNA1 (EA1)
- EEG: To rule out seizure-related ataxia or ictal ataxia
- Thyroid function tests — hypothyroidism can cause ataxia
💡 MSUD Pearl
Maple Syrup Urine Disease (MSUD) — autosomal recessive BCKAD enzyme deficiency — presents with episodic ataxia, encephalopathy, and sweet/maple-syrup odor of urine. Elevated leucine, isoleucine, and valine on newborn screening or amino acid profile.
💊 Management — Exam Q&A
APICA is self-limiting. Management is supportive:
- Reassurance to parents — majority recover completely within 2–4 weeks
- Bed rest and fall prevention — padded cot rails, supervision
- Physiotherapy — balance and gait training during recovery
- Occupational therapy if needed
Role of steroids: Not routinely recommended for APICA. May be considered in severe or prolonged cases or if acute cerebellitis is suspected (with MRI evidence), but evidence is limited.
Prognosis: Excellent. 90% recover completely within 2–3 months. A small percentage may have persistent mild ataxia or behavioural issues.
- Identify and withdraw/reduce the offending drug
- Common drugs: Phenytoin (most common anticonvulsant cause), carbamazepine, phenobarbitone, benzodiazepines, alcohol
- Check serum drug levels — phenytoin toxicity causes nystagmus → dysarthria → ataxia → altered consciousness (in increasing order of toxicity)
- Supportive care
- Ataxia resolves once drug is eliminated
No curative treatment currently available. Management is multidisciplinary and symptomatic:
Neurological:
- Physiotherapy — maintain mobility and balance as long as possible
- Speech therapy — for dysarthria and dysphagia
- Orthotics — ankle-foot orthoses for foot drop
- Wheelchairs — eventually needed (average within 10–15 years of onset)
Cardiac:
- Regular echocardiography and ECG monitoring
- Beta-blockers or ACE inhibitors for cardiomyopathy (under cardiology guidance)
Musculoskeletal:
- Spinal bracing or surgical correction for scoliosis
- Orthopaedic management for pes cavus
Metabolic:
- Screen and manage diabetes mellitus
Pharmacological (investigational/approved):
- Omaveloxolone (Skyclarys) — NRF2 activator; FDA approved (2023) for Friedreich Ataxia in patients ≥16 years — first approved disease-modifying therapy
- Idebenone (antioxidant) — used for cardiac protection; evidence for neurological benefit limited
- Gene therapy, frataxin replacement — under investigation
No curative treatment. Multidisciplinary management:
Neurological: Physiotherapy, speech therapy, occupational therapy. No drug reverses cerebellar degeneration.
Immunological:
- Prophylactic antibiotics for recurrent infections (cotrimoxazole)
- IVIG (Intravenous Immunoglobulin) — for significant IgG deficiency to prevent infections
- Influenza and pneumococcal vaccines (AVOID live attenuated vaccines due to immunodeficiency)
Cancer surveillance:
- Regular screening — CBC, lymph node examination, abdominal ultrasound
- Avoid unnecessary radiation (X-rays, CT scans) — use MRI instead
- If malignancy develops, reduce radiation doses in chemotherapy protocols
Genetic counseling: Autosomal recessive — 25% recurrence risk. Heterozygous carriers (~1% of population) have increased cancer risk (especially breast cancer in females).
- Urgent workup for neuroblastoma — urine VMA/HVA, abdominal ultrasound, CT chest-abdomen-pelvis, MIBG scan
- Treat underlying neuroblastoma — surgery, chemotherapy, radiation
- Immunotherapy for OMS:
- ACTH (corticotropin) — first-line in many centers
- Corticosteroids (dexamethasone or prednisone)
- IVIG
- Rituximab (anti-CD20) — for refractory cases
- Mycophenolate mofetil — steroid-sparing agent
- Tumour removal alone often does not resolve OMS — combined immunotherapy needed
- Prognosis: Neurodevelopmental sequelae (cognitive, behavioral) common even after treatment
| Post-Infectious Cerebellar Ataxia (APICA) | Acute Cerebellitis | |
|---|---|---|
| MRI | Normal | Cerebellar swelling, T2 hyperintensity, ± enhancement |
| Severity | Mild, good recovery | Can be severe, life-threatening |
| Complication | Rare | Obstructive hydrocephalus, tonsillar herniation |
| Treatment | Supportive | IV corticosteroids (methylprednisolone), IVIG; neurosurgical intervention if hydrocephalus (EVD or decompressive craniectomy) |
Acute cerebellitis requires urgent management and neurosurgical standby.
- Vitamin E deficiency ataxia (AVED): Caused by mutation in TTPA gene (alpha-tocopherol transfer protein). Clinically similar to Friedreich ataxia but responds dramatically to high-dose Vitamin E supplementation — important treatable cause.
- Abetalipoproteinemia: Fat-soluble vitamin malabsorption causes Vit E deficiency → ataxia. Treated with Vitamin E + Vitamin A + Vitamin K + Vitamin D supplementation and low-fat diet.
- Refsum disease: Elevated phytanic acid causes ataxia. Treatment: low phytanic acid diet (restrict chlorophyll-containing foods) + plasmapheresis in severe cases.
- Vitamin B12 deficiency: Causes subacute combined degeneration of spinal cord with sensory ataxia, paresthesias. Treated with IM Vitamin B12.
🔭 Recent Advances — Exam Q&A
Omaveloxolone (Skyclarys) is an oral NRF2 activator (nuclear factor erythroid 2-related factor 2). NRF2 is a transcription factor that upregulates antioxidant and anti-inflammatory pathways in the mitochondria.
In Friedreich Ataxia, frataxin deficiency impairs mitochondrial iron-sulfur cluster synthesis, leading to oxidative stress and mitochondrial dysfunction. Omaveloxolone compensates by activating NRF2, reducing oxidative damage.
Significance: First FDA-approved (February 2023) disease-modifying therapy for Friedreich Ataxia — approved for patients ≥16 years. MOXIe phase 3 trial showed significant improvement in neurological function scores (mFARS) compared to placebo.
- Gene therapy: AAV-vector mediated frataxin gene delivery to dorsal root ganglia and heart — phase 1/2 trials ongoing
- Frataxin protein replacement therapy: Recombinant fusion protein delivery under investigation
- Epigenetic therapy: Histone deacetylase (HDAC) inhibitors (nicotinamide, RG2833) — aim to reverse GAA repeat-induced gene silencing and increase frataxin expression
- Deferiprone (iron chelator): Removes excess mitochondrial iron; some studies show stabilization of neurological scores
- Stem cell therapy: Early research phase
Increasing recognition of ataxias caused by autoantibodies targeting cerebellar antigens:
| Antibody | Target | Clinical Association |
|---|---|---|
| Anti-CASPR2 | Contactin-associated protein-2 | Cerebellar ataxia, limbic encephalitis |
| Anti-GAD65 | Glutamic acid decarboxylase | Cerebellar ataxia (stiff-person spectrum) |
| Anti-Yo (PCA-1) | Purkinje cell proteins | Paraneoplastic cerebellar degeneration (ovarian, breast cancer) |
| Anti-GQ1b | Ganglioside | Miller-Fisher syndrome (ataxia + ophthalmoplegia + areflexia) |
| Anti-NMDAR | NMDA receptor | Autoimmune encephalitis, ataxia, choreoathetosis |
Significance: These are treatable causes. CSF and serum autoantibody panels are increasingly available. Treatment with immunotherapy (steroids, IVIG, plasmapheresis, rituximab) can result in significant improvement.
Miller-Fisher Syndrome (MFS) is a variant of Guillain-Barré Syndrome (GBS) presenting with the classic triad:
- Ataxia (sensory/cerebellar)
- Areflexia
- Ophthalmoplegia (external ± internal)
Pathogenesis: Molecular mimicry following a prodromal infection (commonly Campylobacter jejuni) produces anti-GQ1b antibodies which target nodes of Ranvier in cranial and peripheral nerves.
CSF shows albumino-cytological dissociation (elevated protein, normal cells). NCS shows absent or reduced sensory nerve action potentials.
Treatment: IVIG or plasmapheresis. Prognosis is excellent — most recover within 3–6 months.
For chronic progressive ataxia of unknown etiology after standard workup, next-generation sequencing (NGS) has revolutionized diagnosis:
- Ataxia gene panels — targeted sequencing of known ataxia genes (FXN, ATM, SETX, POLG, SACS, etc.) — cost-effective first step
- Whole Exome Sequencing (WES) — covers all protein-coding regions; identifies novel mutations; has a diagnostic yield of 30–50% in unsolved hereditary ataxias
- Whole Genome Sequencing (WGS) — identifies intronic, regulatory, and structural variants missed by WES; increasingly accessible
- RNA sequencing — can detect pathogenic splice variants not identified by DNA sequencing
These techniques have led to identification of many new hereditary ataxia genes and reclassification of previously "idiopathic" ataxias.
⚡ Key Points — Quick Revision
One-Liners for Exam
- Most common cause of acute ataxia in children: Acute Post-Infectious Cerebellar Ataxia (post-varicella most common)
- Most common hereditary ataxia: Friedreich Ataxia (~50% of all hereditary ataxias)
- Cerebellar vs Sensory ataxia: Romberg negative (cerebellar) vs Romberg positive (sensory)
- DANISH mnemonic: Dysdiadochokinesia, Ataxia, Nystagmus, Intention tremor, Scanning speech, Hypotonia = cerebellar signs
- Friedreich Ataxia gene: FXN gene, Chr 9q — GAA trinucleotide repeat expansion → frataxin deficiency
- Friedreich Ataxia paradox: Absent DTRs + Upgoing plantar (Babinski) — simultaneous peripheral neuropathy + corticospinal tract involvement
- Friedreich Ataxia systemic: Pes cavus + Kyphoscoliosis + Hypertrophic cardiomyopathy (most common cause of death)
- Ataxia-Telangiectasia gene: ATM gene, Chr 11q22-23
- A-T biomarker: Elevated AFP — most useful screening test
- A-T vs FA: A-T → Romberg negative, conjunctival telangiectasia, elevated AFP, immunodeficiency, malignancy risk; FA → Romberg positive, pes cavus, cardiomyopathy
- OMA Syndrome: Opsoclonus + Myoclonus + Ataxia → rule out neuroblastoma (check urine VMA/HVA)
- Red flag ataxia: Headache + vomiting + ataxia → posterior fossa tumor → urgent MRI
- Drug toxicity ataxia: Phenytoin most common anticonvulsant cause
- Molar tooth sign on MRI: Joubert Syndrome
- Treatable ataxia causes: Drug-induced, metabolic (hypoglycemia, MSUD), Vitamin E deficiency ataxia (AVED), Refsum disease, Miller-Fisher syndrome, autoimmune ataxia, Wernicke's encephalopathy
- First approved drug for Friedreich Ataxia: Omaveloxolone (Skyclarys, 2023) — NRF2 activator
- Avoid in A-T: Unnecessary radiation, live vaccines
- Miller-Fisher Syndrome triad: Ataxia + Areflexia + Ophthalmoplegia (anti-GQ1b antibody)
- Post-infectious ataxia prognosis: 90% complete recovery within 2–3 months, treatment is supportive
⚡ High-Yield Comparison Table
| Feature | Post-Infectious Ataxia | Friedreich Ataxia | Ataxia-Telangiectasia | Posterior Fossa Tumor |
|---|---|---|---|---|
| Onset | Acute (days) | Subacute (years, 8–15) | Infancy (~12–18 months) | Progressive (weeks–months) |
| Course | Self-limiting | Progressive | Progressive | Progressive |
| Headache/vomiting | Absent | Absent | Absent | Present (raised ICP) |
| Reflexes | Normal | Absent (lower limbs) | Normal → lost late | Usually normal |
| Romberg | Negative | Positive | Negative | Variable |
| Systemic | Healing rash | Pes cavus, scoliosis, cardiomyopathy | Telangiectasia, infections | — |
| MRI | Normal | Cerebellar/spinal atrophy | Cerebellar atrophy | Mass lesion, hydrocephalus |
| Key test | Clinical diagnosis | FXN gene / frataxin level | AFP, ATM gene | MRI with contrast |