Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) – A case report and review of literature

Abstract

CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome) is a rare neurological syndrome of unknown etiology. The main clinical features include bilateral vestibulopathy, cerebellar ataxia and sensory neuropathy. An abnormal visually enhanced vestibulo-ocular reflex is the hallmark of the disease. We present a case of 58-year-old male patient who has demonstrated gait disturbance, imbalance and paresthesia of feet for 2 years. On examination ataxia of gait, diminished knee and ankle reflexes, absence of plantar reflexes, fasciculations of thigh muscles, gaze-evoked downbeat nystagmus and abnormal visually enhanced vestibulo-ocular reflex were found. Brain magnetic resonance imaging revealed cerebellar atrophy. Vestibular function testing showed severely reduced horizontal nystagmus in response to bithermal caloric stimulation. Nerve conduction study revealed loss of upper and lower limb sensory nerve action potentials. The course of illness was progressive with ataxic gait and unsteadiness as the most disabling symptoms. We report 4-year follow-up of the patient since the beginning of the disease.

Introduction

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive, neurodegenerative disorder. Its characteristic symptoms were first described in a group of patients with vestibulopathy by Bronstein et al. [1]. Initially, the syndrome was known under the name of cerebellar ataxia with bilateral vestibulopathy, although sensory neuropathy was already then observed in the majority of patients. It was not until 2011 when Szmulewicz et al. introduced new name for this condition – cerebellar ataxia, neuropathy and vestibular areflexia syndrome, CANVAS, including neuropathy as the core feature [2].

The age of onset is between 50 and 60 years. Although the syndrome has been considered as sporadic, an idea of late-onset autosomal recessive pattern of inheritance arose after it was described in two pairs of siblings [2], [3]. The disease seems to affect male and female with similar frequency [3]. The data on epidemiology of CANVAS are lacking because the disorder is rare. In addition, it is likely to be underdiagnosed due to the fact that (1) usually not all the symptoms are observed simultaneously, especially neuropathy may develop on later stages of the disease [2], [3], (2) nerve conduction studies are not routinely performed among patients with cerebellar ataxia if clinical symptoms of neuropathy are not present on examination and (3) visually enhanced vestibulo-ocular reflex (VVOR) examination that may indicate combined cerebellar and vestibular dysfunction is not the part of routine neurological examination.

Imbalance is the most noticeable feature of CANVAS, present in all cases, in majority being a presenting sign of the syndrome. The cerebellar symptoms of CANVAS include saccadic smooth pursuit, gaze-evoked nystagmus, gait and appendicular ataxia and dysarthria. Symptoms of sensory neuropathy may not be present on clinical examination and in some cases hyperreflexia in lower limbs may be observed [3]. A sign characteristic for CANVAS and easy to check is impaired VVOR [4]. During locomotion VVOR is responsible for stabilization of gaze [5]. Examination of this reflex is possible through slow horizontal turning of patient's head from side to side while his eyes are fixed on a target. The normal eye movements should be smooth and fluent during rotations. In CANVAS patients this maneuver reveals saccadic eye movements. This is possible only if all three components of VVOR, vestibulo-ocular reflex, smooth pursuit, and optokinetic reflex are impaired. Vestibulo-ocular reflex is responsible for compensatory eye movements when a patient is turning his head left and right. Smooth pursuit is responsible for smooth compensatory eye movements during watching small objects moving from side to side. Optokinetic reflex has the same role while watching whole moving scenes, e.g. while sitting in a train and looking through a window. Optokinetic reflex has also been known as “railway nystagmus”. Impairment of the VVOR during turning of the head slower than 1 Hz indicates double pathology, involving both vestibular and cerebellar pathways [4].

The etiology of CANVAS is not known. The only available post-mortem study of a patient with CANVAS revealed severe atrophy of both vestibular nerves, as well as a loss of neurons in facial, trigeminal, and vestibular ganglia, sparing the cochlear ganglion [6]. Loss of Purkinje cells in cerebellum and severe axonal loss on biopsy of sural nerve were also found [3].

Cerebellar atrophy on brain magnetic resonance image (MRI) is evident in most patients with CANVAS. While the severity varies, a consistent pattern of anterior and dorsal vermis atrophy and laterally hemispheric atrophy predominantly affecting crus 1 was observed [7]. Although the diagnosis of CANVAS is made mainly based on clinical features, MRI findings, vestibular loss in caloric stimulation test, and absence of sensory nerve action potentials (SNAPs) on sensory nerve conduction studies are helpful in diagnosis.

The major differential diagnoses include spinocerebellar ataxia type 3 (SCA3), Friedreich's ataxia, multiple system atrophy of cerebellar type (MSA-C), and Wernicke's encephalopathy [2], [3], [8]. SCA3 has an autosomal-dominant pattern of inheritance and symptoms can often be observed among members of the family; however, sporadic forms are also common. Neuropathy typically affects both sensory and motor fibers. The pattern of brain atrophy in MRI is different in SCA3 compared to CANVAS, with cerebellar hemispheres intact. Up to date SCA3 has not been described in Polish population [9]. Friedreich's ataxia is the most common autosomal recessive ataxia. The main symptoms include ataxia of gait and limbs, lack of tendon reflexes and positive Babinski sign. It develops typically since adolescence till 25th year of life; however, cases of late-onset Friedreich's ataxia were also described. Genetic tests are available to confirm the diagnosis of SCA3 and Friedreich's ataxia as well. MSA-C is diagnosed when in addition to cerebellar signs, the patient presents with autonomic dysfunction such as orthostatic hypotension or urinary incontinence. Wernicke's encephalopathy can present subacutely with the classic triad of ocular motor abnormalities (including nystagmus), gait ataxia, and mental state changes, although not all of these symptoms must be present at the same time [10]. Additionally, bilateral vestibulopathy may accompany encephalopathy [11]. Wernicke's encephalopathy should be suspected among alcoholic or malnutritioned patients. Other causes of cerebellar ataxia (e.g. chronic alcohol ingestion), vestibulopathy (e.g. iatrogenic due to aminoglycosides), and sensory neuropathy (e.g. diabetes) should be excluded.

The course of CANVAS is progressive. Disease progression is usually slow but varies greatly between patients. Some of them are only having minor problems with locomotion few years since symptom onset, while others are bed-ridden or use wheelchair [3]. There is no cure for the disease. Physiotherapy and application of walking tools such as cane or crutch may help patient in maintaining physical efficiency and avoid complications from immobilization.