Michael Halmagyi

Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia

Friedreich ataxia (FRDA), the commonest of the inherited ataxias, is a multisystem neurodegenerative condition that affects ocular motor function. We assessed eye movement abnormalities in 20 individuals with genetically confirmed FRDA and compared these results to clinical measures. All subjects were assessed with infrared oculography. Fifteen individuals underwent a full protocol of eye movement recordings. Ten subjects were analysed using two-dimensional scleral coil equipment and five using three-dimensional scleral coil recording equipment. We also recorded visual quality of life, Sloan low contrast letter acuity and Friedreich Ataxia Rating Scale scores to compare to the visual measures. Whilst saccadic velocity was essentially normal, saccadic latency was prolonged. The latency correlated with clinical measures of disease severity, including the scores for the Friedreich Ataxia Rating Scale and the Sloan low contrast letter acuity tests. Fixation abnormalities consisting of square wave jerks and ocular flutter were common, and included rare examples of vertical square wave jerks. Vestibular abnormalities were also evident in the group, with markedly reduced vestibulo-ocular reflex gain and prolonged latency. The range of eye movement abnormalities suggest that neurological dysfunction in FRDA includes brainstem, cortical and vestibular pathways. Severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FRDA and differentiate it from a number of the dominant spinocerebellar ataxias. The correlation of saccadic latency with FARS score raises the possibility of its use as a biomarker for FRDA clinical trials.

High acceleration impulsive rotations reveal severe long-term deficits of the horizontal vestibulo-ocular reflex in the guinea pig

Abstract While there is agreement that unilateral vestibular deafferentation (UVD) invariably produces an immediate severe horizontal vestibulo-ocular reflex (HVOR) deficit, there is disagreement about whether or not this deficit recovers and, if so, whether it recovers fully or only partly. We suspected that this disagreement might mainly be due to experimental factors, such as the species studied, the means chosen to carry out the UVD, or the nature of the test stimulus used. Our aim was to sort out some of these factors. To do this, we studied the HVOR of alert guinea pigs in response to low and high acceleration sinusoidal and high acceleration impulses after UVD by either labyrinthectomy or by vestibular neurectomy. The HVOR in response to high acceleration impulsive yaw rotations was measured before, and at various times after, either unilateral labyrinthectomy or superior vestibular neurectomy. Following UVD, there was a severe impairment of the HVOR for ipsilesional rotations and a slight impairment for contralesional rotations, after either operation. This asymmetrical HVOR deficit in the guinea pig parallels the deficit observed in humans. Between the first measurement, which was made 1 week after UVD, and the last, which was made 3 months after UVD, there was no change in the HVOR. This lack of recovery was the same after labyrinthectomy as after vestibular neurectomy. The HVOR to low and high acceleration sinusoidal yaw rotations were measured after UVD, and the results were compared with those in response to impulsive rotations. For low acceleration sinusoidal rotations (250°/s2), the gain was symmetrical, although reduced bilaterally. As the peak head acceleration increased, the HVOR became increasingly asymmetric. The HVOR asymmetry for sinusoidal rotations was significantly less than for impulsive rotations that had the same high peak head acceleration (2500°/s2). Our results show that the HVOR deficit after UVD is the same in guinea pigs as in humans; that it is the same after vestibular neurectomy as after labyrinthectomy; that it is lasting and severe in response to high acceleration rotations; and, that it is more obvious in response to impulses than to sinusoids.

Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS

Objective: To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit. Method: Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem. Results: Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis. Conclusion: The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia—in other words, it is a “neuronopathy” rather than a “neuropathy.” Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation.

Abnormal configural face perception in a patient with right anterior temporal lobe atrophy

Face perception is a vital aspect of human social functioning and involves specialized cognitive and neural mechanisms. For example, configural face processing involves determining the relationship between the parts of the face, and this process enables us to differentiate between different faces. Here, we report an unusual case in which right anterior temporal lobe atrophy resulted in a profound deficit in the ability to recognize faces. We demonstrate that this patient is not able to process faces via configural information, raising the possibility that the right anterior temporal lobe has a role in configural face processing.

CANVAS an update: Clinical presentation, investigation and management

BACKGROUND Cerebellar Ataxia with Neuropathy and bilateral Vestibular Areflexia Syndrome (CANVAS) is a multi-system ataxia which results in cerebellar ataxia, a bilateral vestibulopathy and a somatosensory deficit. This sensory deficit has recently been shown to be a neuronopathy, with marked dorsal root ganglia neuronal loss. The characteristic oculomotor clinical sign is an abnormal visually enhanced vestibulo-ocular reflex. OBJECTIVE To outline the expanding understanding of the pathology in this condition, as well as diagnostic and management issues encountered in clinical practice. METHODS Retrospective data on 80 CANVAS patients is reviewed. RESULTS In addition to the triad of cerebellar impairment, bilateral vestibulopathy and a somatosensory deficit, CANVAS patients may also present with orthostatic hypotension, a chronic cough and neuropathic pain. Management of falls risk and dysphagia is a major clinical priority. CONCLUSIONS CANVAS is an increasingly recognised cause of late-onset ataxia and disequilibrium, and is likely to be a recessive disorder.

Stable neuropsychological deficits in adult polyglucosan body disease

We describe a 61-year-old woman who gradually developed deficits of balance, gait, and the ability to negotiate movement in space, together with an unusual pattern of cognitive deficits. A series of non-invasive investigations over three years including EEG, CT, MRI, PET and serial neuropsychological review had not provided a diagnosis. Significantly, the four neuropsychological assessments had revealed no progressive decline in cognition. Brain biopsy revealed an abundance of corpora amylacea, and a diagnosis of adult polyglucosan body disease (APBD) was made. This case contributes to the body of knowledge about the cognitive manifestations of this rare disease, and the stability of its functional impact over time.

The eyes as a window into disease prevention

The search for neuroprotective therapeutic interventions for Huntington disease (HD) is accelerating. Most of the efforts to date have focused on manifest HD, in which the goal of therapeutic trials is to slow the progression of the underlying disease process, and thus decrease the decline in functional and clinical measures.1 However, the neurodegenerative process begins long before manifest HD can be diagnosed.2 Thus it is important to start treatment in this presymptomatic population to postpone the onset of illness (manifest HD). However, the ability to detect a clinical benefit in presymptomatic individuals is challenging due to long and variable time horizons between the presymptomatic stages and disease onset and the clinical heterogeneity surrounding disease onset. Reports in this issue of Neurology by Blekher et al.3 and Golding et al.4 describe quantitative assessments of eye movements in presymptomatic and symptomatic individuals with HD that may facilitate the development of meaningful preventive trials. Both articles describe the systematic evaluation of quantitative eye movements in individuals carrying the HD mutation who are either presymptomatic or have manifest illness. The methods used are simple and robust, requiring only an eye movement tracker (video, infrared, or EOG), and a computer for presenting the targets …

Fatal reversible cerebral vasoconstriction syndrome

We report four fatal cases of fulminant reversible cerebral vasoconstriction syndrome, all initially diagnosed as primary central nervous system vasculitis and treated with corticosteroids. Although reversible cerebral vasoconstriction syndrome is usually self-limiting without permanent neurologic deficits, rarely it can be fatal and worse outcomes have been associated with corticosteroid treatment.

043 Rheumatoid leptomeningitis: an acute presentation of neuropsychiatric disturbance

Introduction We report a case of an isolated acute neuropsychiatric presentation due to rheumatoid meningitis (RM), successfully treated with steroids and rituximab. Case A 41 year old man with a chronic headache and acute neuropsychiatric disturbance including impulsivity, grandiose delusions and agitation on a background of no known psychiatric history. Incidentally, he reported migratory palindromic, large and small joint polyarthritis over the preceding 18 months accompanied by headache, symptomatically treated with indomethacin. He had no prior diagnosis of rheumatoid arthritis (RA) or other connective tissue disorder. Serum and cerebrospinal fluid (CSF) cyclic citrullinated peptide antibodies were strongly positive, with a normal serum rheumatoid factor. An interferon-gamma release assay was positive, suggestive of prior tuberculosis (TB) exposure. CSF examination was unremarkable with an MRI brain demonstrating asymmetric features of leptomeningeal thickening and enhancement over both cerebral cortices, suggesting an inflammatory or infiltrative leptomeningitis. Lymphoma, IgG4–related disease, granulomatous diseases such as TB, granulomatosis with polyangiitis, neurosarcoidosis, neurosyphilis and meningeal metastasis were considered as differential diagnoses. A leptomeningeal and brain biopsy showed necrotising inflammation with ill-defined granulomas and a dense lymphoplasmacytic infiltrate. No organisms were identified. Mycobacterial polymerase chain reaction and cultures over three months were negative. RM was the favoured histological diagnosis. Empirical treatment for prior TB exposure was commenced in conjunction with steroids. Subsequent addition of iv rituximab resulted in sustained improvement of neuropsychiatric and joint symptoms. Conclusion This report illustrates for the first time isolated acute neuropsychiatric disturbances attributable to RM without a prior history of RA that was responsive to rituximab. Clinicians should consider infiltrative and inflammatory leptomeningeal causes, particularly with asymmetric meningeal thickening and enchantment on MRI and should commit to a tissue biopsy when no other systemic connective tissue, infective or neoplastic causes are identified.