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Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.


Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a rare form of multisystem ataxia defined by a triad of cerebellar impairment, bilateral vestibular hypofunction, and somatosensory deficit. Here we present a patient with CANVAS. A 76-year-old woman whose parents were cousins had noted slowly worsening gait imbalance since age 67. Peripheral sensory impairment was evident since age 73. When examined at 74, she had a frequent cough. The neurologic examinations showed scanning speech, downbeat nystagmus, pursuit eye movements with saccadic features, truncal ataxia, and mild dysmetria of the extremities. The Romberg test was positive. Light touch, pinprick, and vibration sensation were absent in the distal lower limbs, where allodynia could be demonstrated. Ankle jerk reflex was diminished. Muscle strength was normal. Nerve conduction studies disclosed absence of sensory nerve action potentials in all limbs, while motor conduction was normal except for decreased amplitude of left median and bilateral ulnar nerve compound motor action potentials. MRI of the brain demonstrated cerebellar atrophy. The eye tracking test for the smooth pursuit and visually enhanced vestibulo-ocular reflex test demonstrated functional impairments. Both the bithermal caloric test and the video head impulse testing showed sever hypofunction of the bilateral semicircular canal. In sum, somatosensory deficit and otoneurologic examinations indicated bilateral vestibulopathy which, together with the patient's and cerebellar impairment, confirmed the diagnosis of CANVAS.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough.

Detrusor areflexia is observed most commonly in cauda equina lesions where the sacral reflex is disrupted. However, people with cauda equina lesions may also present atypically with autonomic detrusor contraction which causes a continuous increase of intravesical pressure during urination (Shin et al. 2002). Detrusor areflexia can also occur below the S2 spinal cord level and involve the conus medularis or peripheral nerves. Clinically, this means that the bladder cannot empty completely or at all, leading to overdistension and stasis. Additionally, there is frequently incontinence due to lack of external sphincter tone, most often due to increased abdominal pressure on the bladder (i.e. stress incontinence). This can be especially problematic in persons with paraplegia that may require high valsalva forces for activities such as transferring from wheelchairs.

Unfortunately, there is a great paucity of research examining the impact and treatment of detrusor areflexia. Although the goals remain the same as with overactive bladder in SCI, (i.e., avoiding incontinence, stasis, UTI, and upper urinary tract damage), these goals may be achieved differently. In general, the goal is either: 1) stopping leakage and improving storage with medications and intermittent catheterization, or 2) improving emptying, either voluntarily in the incomplete injury, and/or into condom drainage in males with more severe neurogenic bladder impairments. However, further discussion on detrusor areflexia will not occur in this chapter given the extremely sparse evidence base. It should be noted that in two other studies described in the sections pertaining to DESD therapy there were mixed samples with a few subjects with detrusor areflexia. In one instance, subjects with detrusor areflexia comprised all study participants providing level 4 evidence from a single case series (n=10) for the surgical anastomosis of the T11 ventral nerve root to the S2-S3 ventral nerve roots in improving bladder function (e.g., Table 20 for Other Miscellaneous Treatments).

A rare autosomal dominant neurological disorder characterized by early onset cerebellar ataxia, associated with areflexia, progressive optic atrophy, sensorineural deafness, a pes cavus deformity, and abnormal eye movements.

Basic blood tests and cultures showed a mildly raised white cell count and aspartate transaminase (AST) only. An ultrasound scan of the abdomen showed widespread lymphadenopathy in the epigastrium, mesentery, and iliac and para-aortic areas, which was confirmed on CT. Five days after his admission, he developed a complex opthalmoplegia, mild dysphagia, lower limb weakness with areflexia in the upper and lower limbs, and ataxia. There was no sensory involvement, and cognition was normal. Nerve conduction studies showed a motor neuropathy in keeping with the clinical picture of an MFS. Intracranial CT and MRI with contrast were normal, apart from some nonspecific increased signal within the medulla on T2 imaging. Antiganglioside antibodies were negative. A lumbar puncture showed a normal opening pressure and protein, but 35 white cells (90% lymphocytes, 10% polymorphs) and glucose of 2.8 (no matched sample sent) and no organisms on Gram stain. CSF cytology was unremarkable.

Our patient presented with an ataxia, generalised areflexia, and complex opthalmoplegia mimicking a Miller Fisher syndrome. As can be deducted from the above data, absent reflexes and ocular paresis are fairly common in the cases described, so it may be that his clinical presentation can be fully explained by direct meningeal invasion along the neuroaxis. However, the question arises as to whether this presentation of an exact phenotype of what is thought to be an antibody-mediated syndrome (MFS) suggests a paraneoplastic component to MFS.

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.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) presents with progressive ataxia due to cerebellar impairment, sensory ganglionopathy and bilateral vestibulopathy.1 Orthostatic hypotension secondary to dysautonomia is a common associated feature, and chronic cough may precede the symptoms by decades.1,2 The mean age of onset is 60 years.1 CANVAS is a late-onset autosomal recessive disorder resulting from biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1).1,2 Diagnosis is supported by MRI (preferential cerebellar vermis atrophy), neurophysiological studies (sensory neuronopathy) and rapid video-oculography (abnormal visuo-vestibulo-ocular reflex).3 Differentials include Friedreich ataxia, spinocerebellar ataxia types 1 and 3, and olivo-ponto-cerebellar atrophy.1,3 Management is symptomatic with neurologic and vestibular rehabilitation showing significant benefit.

The neuro-ophthalmological presentation of a young female with possible encephalomyelitis was identical to that of the syndrome of ophthalmoplegia, ataxia and areflexia (SOAA). In addition, the patient had bilateral, presumably demyelinative, optic neuropathy, as well as features of transient peripheral neuropathy. Based on this unique patient it is predicted that pontomesencephalic inflammatory lesions result in SOAA.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a slowing progressive ataxic disorder characterized by bilateral vestibulopathy, cerebellar ataxia and somatosensory impairment. Autonomic dysfunction is recently considered as a core feature in CANVAS in addition to these symptoms. In most cases, patients with CANVAS show cerebellar atrophy in brain imaging, but some cases show minimal or no atrophy of cerebellum. Brain (18F)-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) study can be a complimentary tool to diagnosis CANVAS in cases of no structural abnormality such as cerebellar atrophy. Hereby, we present a case of CANVAS with minimal atrophy of cerebellum but showing a prominent hypometabolism in cerebellum, thalamus and posterior cingulate cortex in 18F-FDG PET. 041b061a72


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