Clinical Analysis: Probable Diagnosis

What the Clinical Signs Tell You

Most Probable Diagnosis: CANVAS Syndrome

(Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome)

• She has a neurologist-confirmed sensory ataxia — the hallmark of CANVAS is sensory neuropathy/neuronopathy causing large-fiber proprioceptive loss
• The vestibular screening is "not significant" — in bilateral vestibular areflexia (the "areflexia" in CANVAS), there is no asymmetric nystagmus to find. Standard VNG/caloric tests will often show bilaterally reduced or absent responses rather than a unilateral finding. This is frequently missed on routine screening because the clinician expects a lateralizing sign
• Positive sharpened Romberg + Fukuda with normal positional tests is the classic dissociation in CANVAS
• Onset typically in middle adult life, progressive over 10–15 years

"CANVAS appears to be the most common cause of autosomal recessive ataxia. It usually manifests in middle adult life with a sensory neuropathy/neuronopathy... Examination reveals loss of large-fiber sensory modalities with a sensory ataxia as well as cerebellar ataxia." — Harrison's Principles of Internal Medicine 22E, p. 553

"Vestibular areflexia may be detected as diminished vestibulo-ocular reflex gain on the head impulse test, abnormal dynamic visual acuity, and abnormal occlusive fundoscopy (Zee test)." — Bradley & Daroff's Neurology in Clinical Practice

Why She Avoids Turning Left for a Year

1. Develop en bloc turning (turning the whole body rather than the head)
2. Avoid rapid head movements in certain planes — if the loss is asymmetric, the more-affected side causes more oscillopsia and she avoids it
3. The head shivering/nodding toward the left may represent a cerebellar titubation or a compensatory postural head tilt toward the side of lesser vestibular input

What You Should Do Next as the Audio-Vestibular Specialist

1. Video Head Impulse Test (vHIT) — Specifically look for bilaterally reduced VOR gain with catch-up saccades. Standard caloric testing may underestimate bilateral loss. This is the critical investigation you may have missed.
2. Rotational chair testing — More sensitive for bilateral vestibular hypofunction; reduced gain at all frequencies is the hallmark.
3. Caloric irrigation with quantitative recording — Bilateral Canal Paresis? If both ears show < 50% of normal, this confirms bilateral vestibular hypofunction consistent with CANVAS.
4. Dynamic Visual Acuity test — A bedside surrogate for VOR failure during head movement.
5. Refer back to neurology for:
   • NCS/EMG — Non-length-dependent sensory neuropathy (low/absent SNAPs) is expected in CANVAS
   • RFC1 gene repeat expansion testing — now commercially available
   • MRI brain — may show cerebellar atrophy (posterior lobe dominant)
6. Ask about chronic dry cough — seen in 25–35% of CANVAS cases, highly specific when present

Differential Diagnosis to Keep Open

Summary

Complete Follow-Up Plan

As the Audio-Vestibular Specialist

TIER 1 — Immediate Vestibular Investigations (Your Domain)

1. Video Head Impulse Test (vHIT) — Most Critical

• Expected finding: Bilateral horizontal canal gain < 0.6 (normal ≥ 0.8), with bilateral corrective saccades
• Her avoidance of leftward turns likely reflects asymmetric bilateral loss — the left side having greater VOR deficit, causing worse oscillopsia on left head rotation

2. Bithermal Caloric Testing (VNG/ENG)

• Look for bilateral canal paresis (not a unilateral weakness)
• In bilateral vestibular hypofunction: total response (sum of all four irrigations) markedly reduced, no asymmetry
• If both ears show < 6°/sec peak slow-phase velocity, this confirms bilateral hypofunction
• Do NOT rely on just a unilateral canal paresis percentage (Jongkees formula) — it will mislead you if both sides are equally hypo-responsive

3. Rotational Chair (Sinusoidal Harmonic Acceleration)

• More sensitive than calorics for detecting bilateral loss
• Expected finding: Reduced VOR gain at low frequencies (0.01–0.04 Hz), marked phase lead, reduced time constant (Tc)
• Absence of directional preponderance at asymmetric frequencies helps confirm bilateral symmetrical hypofunction vs. unilateral compensated

4. Cervical VEMP (cVEMP) and Ocular VEMP (oVEMP)

• cVEMP assesses saccular function (inferior vestibular nerve)
• oVEMP assesses utricular function (superior vestibular nerve)
• In CANVAS: both are typically absent or severely attenuated bilaterally
• This is an often-missed test that will confirm bilateral end-organ vestibular failure at the otolith level
• "Vestibular diagnostic testing has extended the region of identifiable pathology to include the otolith organs. Cervical and ocular VEMP potentials are clinical tests of saccular and utricular function respectively." — Cummings Otolaryngology

5. Dynamic Visual Acuity (DVA) Test

• Bedside surrogate for VOR failure
• Measure Snellen acuity with head still, then with passive horizontal oscillation at ~2 Hz
• Loss of ≥ 3 lines of acuity = clinically significant VOR failure
• Specifically test with head moving to the left — she will lose more lines on leftward oscillation if left-sided VOR loss is greater

6. Computerised Dynamic Posturography (CDP) / Sensory Organisation Test (SOT)

• Will objectively quantify the sensory weighting problem
• Expected pattern: Normal conditions 1–2, impaired conditions 3 (eyes-closed surface stable), 5–6 (vestibular conditions) — "vestibular pattern" failure
• Confirms she cannot use vestibular inputs to maintain balance when proprioception is also unreliable (dual sensory ataxia)

7. Tandem Romberg / Foam Pad Romberg

• Standard and sharpened Romberg already done — now add:
  • Foam pad Romberg (eliminates proprioceptive input from feet) — she will be highly unstable, confirming she cannot use either proprioception or vestibular fallback
  • Eyes open vs. eyes closed on foam — isolation of pure vestibular contribution

TIER 2 — Neurological Investigations (Refer to Neurology)

8. Nerve Conduction Studies (NCS) + EMG — High Priority

• 100% had moderate-to-severe sensory axonal neuropathy/neuronopathy
• Motor nerve conduction — normal
• H-reflexes — preserved in 85.7%
• Tibial nerve somatosensory evoked potentials (SEPs) — absent or severely attenuated in ALL patients
• The pattern is a non-length-dependent sensory neuronopathy (dorsal root ganglion involvement), unlike typical length-dependent diabetic neuropathy

This is the electrophysiological fingerprint of CANVAS — order it urgently.

9. Somatosensory Evoked Potentials (SEPs)

• Tibial and median nerve SEPs
• Expected: absent/attenuated tibial SEPs bilaterally
• Reflects dorsal column/posterior pathway failure

10. MRI Brain + Spine

• Brain: Look for cerebellar atrophy, predominantly posterior lobe/vermis
• Spine: Look for posterior column signal change (T2 hyperintensity) in cervical/thoracic cord — seen in vitamin B12 deficiency and other posterior column diseases
• Sequences: Include DWI (stroke), FLAIR (demyelination), post-contrast (tumour/paraneoplastic)

11. RFC1 Gene Testing — Diagnostic Confirmation

• Biallelic (AAGGG)n pentanucleotide repeat expansion in intron 2 of RFC1 gene (chromosome 4p14)
• Standard sequencing will MISS this — repeat-primed PCR or long-read sequencing required
• Now commercially available in most neurology genetics centres
• This single test can confirm or exclude CANVAS definitively

TIER 3 — Blood Tests (Rule Out Treatable Causes)

TIER 4 — Specific Tests if Paraneoplastic Suspected

• CT Chest/Abdomen/Pelvis (or PET-CT) — occult malignancy (small cell lung, breast, ovary, thymoma)
• CSF analysis — oligoclonal bands, raised protein, lymphocytes
• Urgent oncology referral

TIER 5 — Management / Rehabilitation Plan (Your Role)

Vestibular Rehabilitation Therapy (VRT)

1. Gaze stabilisation exercises — VOR × 1 and × 2 substitution training (horizontal and vertical)
2. Balance retraining on foam/unstable surfaces — force her to use the vestibular system, not just proprioception or vision
3. Walking in low-light or eyes-closed environments — supervised, progressive challenge
4. Head movement desensitisation — graduated exposure to the leftward turns she is avoiding (bilateral VOR substitution)
5. Canalith repositioning is NOT indicated — positional tests are normal, no BPPV component

Note: VRT in sensory ataxia with bilateral vestibular loss is more challenging than unilateral vestibular lesions — improvement is slower, gains are functional rather than curative. Set realistic expectations.

Fall Prevention Counselling

• High-risk of falls in darkness, on uneven ground, stairs
• Home environment modification: adequate lighting, handrails, remove loose rugs
• Walking aid assessment (stick/frame)
• Advise on driving — oscillopsia from VOR failure may impair safe driving; this must be formally assessed

Avoid Ototoxic Agents

• If CANVAS confirmed, document bilateral vestibular hypofunction and add to medical records
• Any future aminoglycoside use (gentamicin, tobramycin) must be avoided — will cause catastrophic worsening

TIER 6 — Multidisciplinary Referrals

Priority Action Summary

URGENT (this week):
1. vHIT — bilateral gain measurement
2. Caloric bithermal (quantitative)
3. cVEMP + oVEMP (bilateral)
4. Bloods: B12/MMA, Vitamin E, HbA1c, anti-neuronal antibodies, Anti-Ro/SSA

SOON (within 2–4 weeks):
5. Rotational chair
6. Computerised posturography / SOT
7. NCS + EMG (neurology referral)
8. MRI brain + spine with posterior fossa sequences

DEFINITIVE:
9. RFC1 repeat expansion genetic test
10. SEPs (tibial + median)
11. Start VRT once diagnosis confirmed

SENSORY ATAXIA & CANVAS SYNDROME

A Comprehensive Clinical Reference

PART 1: SENSORY ATAXIA

Definition

• Cerebellar ataxia — due to cerebellar/cerebellar pathway disease
• Vestibular ataxia — due to peripheral or central vestibular dysfunction
• Motor/spastic ataxia — due to upper motor neuron lesions

Neuroanatomical Basis

Peripheral large-fiber nerve (Ia afferents)
        ↓
Dorsal root ganglion (DRG)
        ↓
Posterior columns (dorsal funiculi) of spinal cord
  [Gracile tract — lower limb; Cuneate tract — upper limb]
        ↓
Nucleus gracilis / cuneatus (medulla)
        ↓
Medial lemniscus
        ↓
Thalamus (VPLc nucleus)
        ↓
Somatosensory cortex (parietal lobe)

1. Peripheral large-fiber neuropathy (e.g., diabetes, CANVAS, paraneoplastic)
2. Dorsal root ganglion (DRG) neuronopathy/ganglionopathy (e.g., CANVAS, Sjögren's, paraneoplastic anti-Hu)
3. Posterior column disease (e.g., Vitamin B12 deficiency/subacute combined degeneration, tabes dorsalis, MS)
4. Medial lemniscus lesions (brainstem strokes)

"Dorsal horn and column injury alone may result from tabes dorsalis... Friedreich ataxia represents a genetic etiology, and vitamin B12 deficiency may result in subacute combined degeneration with spastic paretic gait and sensory ataxia." — Bradley & Daroff's Neurology in Clinical Practice

Clinical Features of Sensory Ataxia

Gait

• High-stepping, stamping, or stomping gait — patient lifts feet high and brings them down forcefully to get ground-contact feedback
• Wide-based stance — compensatory base widening for stability
• Worsens dramatically in darkness or with eyes closed — vision is the primary compensatory mechanism
• Patient looks at the ground when walking (visual substitution)
• Tandem walking severely impaired

Romberg Sign (Positive / Sharpened)

• Eyes open: patient stands adequately (visual compensation active)
• Eyes closed: patient sways markedly and may fall
• Positive = sensory ataxia — the test specifically unmasks proprioceptive failure by removing vision
• Cerebellar ataxia produces instability with eyes OPEN as well; sensory ataxia is markedly worse with eyes CLOSED

Fukuda Stepping Test

• 50 marching steps in place, eyes closed, arms forward
• Rotation > 30° or marked drift toward one side = positive
• In sensory ataxia, there is deviation because proprioceptive feedback cannot correct body position during stepping

Limb/Digit Signs

• Loss of joint position sense (JPS) — patient cannot detect finger/toe movement
• Loss of vibration sense — tuning fork (128 Hz) not felt at toes/ankles
• Pseudo-athetosis — involuntary writhing movements of fingers/toes when eyes closed (loss of position sense allows drift)
• Positive Romberg with pseudo-athetosis of hands is highly specific for posterior column / DRG pathology
• Finger-nose test may be normal (proprioception in upper limbs often relatively preserved early)
• Heel-shin test impaired — foot slides off the shin when eyes closed

Other Features

• Deep tendon reflexes often reduced or absent (large Ia afferent fibers carry the reflex arc)
• No weakness (purely sensory syndrome)
• Sensory examination: loss of vibration, JPS, light touch, 2-point discrimination; pain and temperature usually preserved (small-fiber involvement occurs in some subtypes)

Causes of Sensory Ataxia (Classification)

Distinguishing Sensory vs Cerebellar Ataxia (Key Table)

PART 2: CANVAS SYNDROME

Definition and Historical Overview

• First described clinically by Szmulewicz et al. in 2011 as a triad of bilateral vestibular areflexia, cerebellar ataxia, and sensory neuropathy
• Genetic basis identified in 2019 by Cortese et al.: biallelic AAGGG pentanucleotide repeat expansions in intron 2 of the RFC1 gene
• Now recognised as the most common cause of autosomal recessive ataxia in adults
• Mean age at onset: 54 ± 9 years (range: onset always after age 35)

Genetics

Pathology — What Degenerates?

1. DORSAL ROOT GANGLIA (DRG) — "Ganglionopathy"
   → Large sensory neurons degenerate
   → Loss of proprioception → sensory ataxia
   → Non-length-dependent pattern (feet AND hands affected early)
   → Sural nerve biopsy: loss of large myelinated axons

2. VESTIBULAR END-ORGAN / NERVE
   → Bilateral degeneration of hair cells and/or vestibular ganglia
   → Absent or severely reduced bilateral VOR
   → No nystagmus (bilateral loss = no asymmetry)
   → Oscillopsia and gait failure in darkness

3. CEREBELLUM — especially posterior lobe/vermis
   → Progressive Purkinje cell degeneration
   → MRI: cerebellar atrophy (posterior lobe, vermis lobules VI–VIIb)
   → Contributes additional kinetic ataxia beyond the sensory component

Clinical Features

The Core Triad

Additional Features (Expanding Spectrum)

"CANVAS can also present with dysautonomia and features of parkinsonism. NCS reveal low-amplitude or absent sensory responses that are in a non-length-dependent pattern." — Harrison's Principles of Internal Medicine 22E (2025)

RFC1 Spectrum Disorder (Not Just Classic CANVAS)

• 63% had full CANVAS triad
• 16% had complex sensory ataxia + cerebellar OR vestibular (incomplete triad)
• 15% had sensory neuropathy only — no clinically detectable cerebellar or vestibular features

Neuroimaging Findings (MRI)

• Cerebellar vermal atrophy — most prevalent (~90%), predominantly posterior vermis
• Cerebellar hemispheric atrophy
• Brainstem atrophy — pontine in more severe cases
• Spinal cord thinning — cervical and thoracic, reflecting posterior column degeneration
• Some cases show bilateral pallidal T2 abnormalities (less common)

Electrophysiology

Vestibular Testing in CANVAS

Diagnostic Criteria / When to Suspect CANVAS

• Onset after age 35
• Any combination of:
  • Complex imbalance/coordination problem of peripheral + vestibular + cerebellar origin
  • Sensory neuropathy or neuronopathy (non-length-dependent)
  • Bilateral vestibular areflexia (or bilateral hyporeflexia)
  • Cerebellar dysfunction (progressive)
  • Chronic dry cough (highly specific — pursue RFC1 testing in any ataxia patient with unexplained chronic cough)
  • Dysautonomia

1. NCS showing absent/low SNAPs, non-length-dependent, normal motor
2. Bilateral vestibular hypofunction on vHIT / caloric / rotational chair
3. MRI brain: cerebellar (posterior lobe/vermis) atrophy
4. Absent tibial SEPs
5. RFC1 biallelic AAGGG repeat expansion confirmed on repeat-primed PCR

Differential Diagnosis

Management

Symptomatic

• Chronic cough: Gabapentin, pregabalin, speech therapy (laryngeal sensory retraining); avoid ACE inhibitors (worsen cough)
• Neuropathic pain (if thermoalgesic fibers involved): Duloxetine, pregabalin, amitriptyline
• Dysautonomia: Fludrocortisone, compression stockings (orthostatic hypotension); bladder anticholinergics if indicated
• Cerebellar tremor/ataxia: No proven pharmacotherapy; riluzole and acetyl-DL-leucine are under investigation

Rehabilitation

• Vestibular rehabilitation — gaze stabilisation exercises, bilateral VOR substitution training
• Balance physiotherapy — ataxia-specific programs (progressive foam/unstable surface training)
• Occupational therapy — fall prevention, home adaptation
• Walking aids — canes, rollators; particularly important in darkness

Safety

• Avoid aminoglycosides absolutely (will catastrophically worsen bilateral vestibular function)
• Driving assessment — oscillopsia from VOR failure may render driving unsafe
• Adequate lighting at home; remove trip hazards

Genetic Counselling

• Autosomal recessive — siblings have 25% risk
• Offspring are obligate carriers (not affected), but partner carrier status matters
• Family cascade testing if symptomatic relatives

Prognosis

• Slowly progressive over 10–15 years
• Most patients eventually require a walking aid
• Cognitive function generally preserved
• Life expectancy not markedly reduced in typical CANVAS
• Severe cases with ALS-like features or marked dysautonomia have worse prognosis

Summary Diagram

RFC1 gene — biallelic (AAGGG)n repeat expansion
                        ↓
         Degeneration of 3 systems:

  DRG Ganglionopathy        Vestibular Areflexia       Cerebellar Atrophy
        ↓                          ↓                          ↓
Sensory neuropathy          Bilateral loss of          Posterior lobe
(non-length-dependent)       VOR/otolith function        vermis atrophy
Loss of proprioception,     No nystagmus; oscillopsia  Limb dysmetria
vibration, JPS              Imbalance in dark           Kinetic tremor
        ↓                          ↓                          ↓
Positive Romberg         vHIT bilat gain ↓↓          MRI cerebellar atrophy
Fukuda deviation         Caloric bilat absent         Gait cerebellar component
Stamping gait            cVEMP/oVEMP absent

                + Chronic cough (64%) + Dysautonomia (32%)