Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS)
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a rare neurodegenerative balance disorder characterized by cerebellar ataxia, sensory neuronopathy (ganglionopathy), and bilateral vestibular hypofunction.
The epidemiology is yet to be defined, but CANVAS is thought to be rare. It often first manifests in middle-aged adults 1.
The diagnosis of CANVAS is challenging because patients will typically have a nonspecific presentation, most commonly with gait imbalance and falls, often worse in the dark 1-3. Less commonly, they may present with dysesthesias or oscillopsia 1-3.
On physical examination, each of the three hallmark features of CANVAS can be demonstrated 1-4:
- cerebellar ataxia: saccadic smooth pursuit, nystagmus, limb ataxia, cerebellar dysarthria
- non-length-dependent sensory neuronopathy (ganglionopathy): deficits of pin-prick sensation (most common) or other sensory modalities, absent ankle jerk reflexes, abnormal corneal reflex, abnormal jaw jerk reflex
- nerve conduction studies are more sensitive to subtle abnormalities
- bilateral vestibulopathy: bilateral abnormal tests of the vestibulo-ocular reflex (e.g. bidirectionally abnormal head impulse test, abnormal dynamic visual acuity)
- the video head impulse test is more sensitive to subtle abnormalities
A particularly useful physical sign in CANVAS is that of an abnormal visually enhanced vestibulo-ocular reflex (also known as the doll’s eye reflex or oculo-cephalic reflex), which can only occur if both cerebellar ataxia and bilateral vestibulopathy are present 1-4, two of the hallmark features of CANVAS. The abnormality can be diagnosed clinically at the bedside or using objective measures such as video-oculography 1-4.
In addition to the classic triad, other commonly associated signs and symptoms include:
- postural hypotension 2,5
- dysphagia 2
- chronic cough 2
The pathophysiology of CANVAS is yet to be fully elucidated. However, there is histopathological and electrophysiological evidence that CANVAS is characterized by a ganglionopathy resulting in bilateral vestibulopathy (i.e. Scarpa’s ganglion involvement) and sensory neuronopathy (i.e. dorsal root ganglion involvement), as well as subclinical involvement of other ganglia such as the geniculate and trigeminal ganglia 2,3,5. In the cerebellum, there is pathological evidence of vermian atrophy, with notable loss of vermian Purkinje cells 2,3,5.
Familial and sporadic cases are caused by biallelic intronic AAGGG repeat expansions in the gene RFC1 (replication factor complex subunit 1) 8,9.
MRI is the imaging modality of choice 6. Evidence of MRI changes in CANVAS can be nonspecific but are usually present 1-3,6. Typically, there will be focal cerebellar atrophy, with particular involvement of the vermian lobules VI, VIIA, and VIIB, as well as hemispheric cerebellar atrophy of crus I 1-4,6. Additionally, but less commonly, spinal cord atrophy may also be present 4.
I-123 metaiodobenzylguanidine scintigraphy shows decreased cardiac uptake of radiotracer, reflecting the involvement of cardiac sympathetic nerves 10.
Treatment and prognosis
There is currently (as of July 2019) no disease-modifying therapy available for CANVAS. Management focuses on symptom-specific management such as vestibular rehabilitation, speech pathology monitoring and management of dysphagia, and neuropathic pain management (e.g. pregabalin) 3. The prognosis varies, but CANVAS is generally considered to be a slowly progressive condition over decades 3.
History and etymology
The hallmark features of CANVAS were first described together by British neurologists T Rinne, Adolfo M Bronstein and colleagues in 1995 7. However, an in-depth clinical and pathological description, and subsequent coining of the term CANVAS, was made by Australian neurologists David Szmulewicz, Elsdon Storey, and colleagues in their 2011 seminal paper 1.
Clinical differential diagnoses include various causes of adult-onset ataxia 1,3:
- 1. Szmulewicz DJ, Waterston JA, Halmagyi GM, Mossman S, Chancellor AM, McLean CA, Storey E. Sensory neuropathy as part of the cerebellar ataxia neuropathy vestibular areflexia syndrome. (2011) Neurology. 76 (22): 1903-10. doi:10.1212/WNL.0b013e31821d746e - Pubmed
- 2. Szmulewicz DJ, McLean CA, MacDougall HG, Roberts L, Storey E, Halmagyi GM. CANVAS an update: clinical presentation, investigation and management. (2014) Journal of vestibular research : equilibrium & orientation. 24 (5-6): 465-74. doi:10.3233/VES-140536 - Pubmed
- 3. Szmulewicz DJ, Waterston JA, MacDougall HG, Mossman S, Chancellor AM, McLean CA, Merchant S, Patrikios P, Halmagyi GM, Storey E. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis. (2011) Annals of the New York Academy of Sciences. 1233: 139-47. doi:10.1111/j.1749-6632.2011.06158.x - Pubmed
- 4. Petersen JA, Wichmann WW, Weber KP. The pivotal sign of CANVAS. (2013) Neurology. 81 (18): 1642-3. doi:10.1212/WNL.0b013e3182a9f435 - Pubmed
- 5. Wu TY, Taylor JM, Kilfoyle DH, Smith AD, McGuinness BJ, Simpson MP, Walker EB, Bergin PS, Cleland JC, Hutchinson DO, Anderson NE, Snow BJ, Anderson TJ, Paermentier LA, Cutfield NJ, Chancellor AM, Mossman SS, Roxburgh RH. Autonomic dysfunction is a major feature of cerebellar ataxia, neuropathy, vestibular areflexia 'CANVAS' syndrome. (2014) Brain : a journal of neurology. 137 (Pt 10): 2649-56. doi:10.1093/brain/awu196 - Pubmed
- 6. Szmulewicz DJ, Roberts L, McLean CA, MacDougall HG, Halmagyi GM, Storey E. Proposed diagnostic criteria for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). (2016) Neurology. Clinical practice. 6 (1): 61-68. doi:10.1212/CPJ.0000000000000215 - Pubmed
- 7. Rinne T, Bronstein AM, Rudge P, Gresty MA, Luxon LM. Bilateral loss of vestibular function. (1995) Acta oto-laryngologica. Supplementum. 520 Pt 2: 247-50. Pubmed
- 8. Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. (2019) Nature genetics. 51 (4): 649-658. doi:10.1038/s41588-019-0372-4 - Pubmed
- 9. Cortese A, Tozza S, Yau WY, Rossi S, Beecroft SJ, Jaunmuktane Z, Dyer Z, Ravenscroft G, Lamont PJ, Mossman S, Chancellor A, Maisonobe T, Pereon Y, Cauquil C, Colnaghi S, Mallucci G, Curro R, Tomaselli PJ, Thomas-Black G, Sullivan R, Efthymiou S, Rossor AM, Laurá M, Pipis M, Horga A, Polke J, Kaski D, Horvath R, Chinnery PF, Marques W, Tassorelli C, Devigili G, Leonardis L, Wood NW, Bronstein A, Giunti P, Züchner S, Stojkovic T, Laing N, Roxburgh RH, Houlden H, Reilly MM. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. (2020) Brain : a journal of neurology. 143 (2): 480-490. doi:10.1093/brain/awz418 - Pubmed
- 10. Nakamura H, Doi H, Mitsuhashi S, Miyatake S, Katoh K, Frith MC, Asano T, Kudo Y, Ikeda T, Kubota S, Kunii M, Kitazawa Y, Tada M, Okamoto M, Joki H, Takeuchi H, Matsumoto N, Tanaka F. Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS. (2020) Journal of human genetics. doi:10.1038/s10038-020-0733-y - Pubmed