Quick foot placement adjustments during gait are less accurate in individuals with focal cerebellar lesions

Online gait corrections are frequently used to restore gait stability and prevent falling. They require shorter response times than voluntary movements which suggests that subcortical pathways contribute to the execution of online gait corrections. To evaluate the potential role of the cerebellum in these pathways we tested the hypotheses that online gait corrections would be less accurate in individuals with focal cerebellar damage than in neurologically intact controls and that this difference would be more pronounced for shorter available response times and for short step gait corrections. We projected virtual stepping stones on an instrumented treadmill while some of the approaching stepping stones were shifted forward or backward, requiring participants to adjust their foot placement. Varying the timing of those shifts allowed us to address the effect of available response time on foot placement error. In agreement with our hypothesis, individuals with focal cerebellar lesions were less accurate in adjusting their foot placement in reaction to suddenly shifted stepping stones than neurologically intact controls. However, the cerebellar lesion group’s foot placement error did not increase more with decreasing available response distance or for short step versus long step adjustments compared to the control group. Furthermore, foot placement error for the non-shifting stepping stones was also larger in the cerebellar lesion group as compared to the control group. Consequently, the reduced ability to accurately adjust foot placement during walking in individuals with focal cerebellar lesions appears to be a general movement control deficit, which could contribute to increased fall risk.     

A novel variant of dehydrodolichol diphosphate synthase (DHDDS) mutation with adult-onset progressive myoclonus ataxia

We report a novel variant of DHDDS mutation in a patient with progressive adult-onset myoclonus ataxia. The mutation in our patient was different from previous reports of denovo mutations in DHDDS in 6 patients who showed tremor-like myoclonus and generalized epilepsy.     

Heterotopic Purkinje cells in ataxia‐telangiectasia

Ataxia‐telangiectasia (A‐T) is a heritable disorder of cerebellar ataxia and oculocutaneous telangiectasias caused by mutation of the ATM gene. The most prominent and consistent neuropathologic finding in the disorder is cerebellar cortical degeneration involving significant loss of granule and Purkinje cells. Several past autopsy studies of A‐T patients have also noted large‐bodied cells located within the molecular layer of the cerebellar cortex and, noting similarities in morphology between these cells and Purkinje cells, hypothesized that the cells were heterotopic Purkinje cells. This study aimed to test this hypothesis using an antibody that labels Purkinje cells, and also to investigate other cell types in the degenerating cerebellar cortex in A‐T. Using the anti‐calbindin D‐28K antibody to label Purkinje cells in cerebellar tissue from five A‐T patients and five age‐ and sex‐matched controls, the study found calbindin‐positive heterotopic Purkinje cells in the molecular layer occurring at a significantly higher rate in A‐T patients than in controls (P = 0.012). Further immunohistochemistry with the anti‐Iba‐1 and anti‐parvalbumin antibodies showed, respectively, an increase in microglial activity (P = 0.14) and stellate‐cell density (P = 0.0048) in the cerebellar cortex of A‐T patients versus controls. These data add to the as yet unresolved debate over the origin and significance of heterotopic Purkinje cells in A‐T.     

Medical treatment of vestibular disorders

Background: The lifelong prevalence of rotatory vertigo is 30%. Despite this high figure, patients with vertigo generally receive either inappropriate or inadequate treatment. However, the majority of vestibular disorders have a benign cause, take a favorable natural course, and respond positively to therapy. Objective: This review puts special emphasis on the medical rather than the physical, operative, or psychotherapeutic treatments available. Methods: A selected review of recent reports and studies on the medical treatment of peripheral and central vestibular disorders. Results/conclusions: In vestibular neuritis, recovery of the peripheral vestibular function can be improved by oral corticosteroids; in Menière's disease, there is first evidence that high-dose, long-term administration of betahistine reduces attack frequency; carbamazepine or oxcarbamazepine is the treatment of first choice in vestibular paroxysmia, a disorder mainly caused by neurovascular cross-compression; the potassium channel blocker aminopyridine provides a new therapeutic principle for treatment of downbeat nystagmus, upbeat nystagmus, and episodic ataxia type 2.     

Balint syndrome

We report a patient who presented with complaints of blindness following stroke and was subsequently diagnosed to have Balint syndrome     

Mice with a conditional deletion of Talpid3 (KIAA0586) – a model for Joubert syndrome

Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11–12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre-derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Automatic classification of gait in children with early-onset ataxia or developmental coordination disorder and controls using inertial sensors

Early-Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) are two conditions that affect coordination in children. Phenotypic identification of impaired coordination plays an important role in their diagnosis. Gait is one of the tests included in rating scales that can be used to assess motor coordination.A practical problem is that the resemblance between EOA and DCD symptoms can hamper their diagnosis. In this study we employed inertial sensors and a supervised classifier to obtain an automatic classification of the condition of participants. Data from shank and waist mounted inertial measurement units were used to extract features during gait in children diagnosed with EOA or DCD and age-matched controls. We defined a set of features from the recorded signals and we obtained the optimal features for classification using a backward sequential approach. We correctly classified 80.0%, 85.7%, and 70.0% of the control, DCD and EOA children, respectively. Overall, the automatic classifier correctly classified 78.4% of the participants, which is slightly better than the phenotypic assessment of gait by two pediatric neurologists (73.0%). These results demonstrate that automatic classification employing signals from inertial sensors obtained during gait maybe used as a support tool in the differential diagnosis of EOA and DCD. Furthermore, future extension of the classifier’s test domains may help to further improve the diagnostic accuracy of pediatric coordination impairment. In this sense, this study may provide a first step towards incorporating a clinically objective and viable biomarker for identification of EOA and DCD.     

Ataxia in childhood: a pragmatic approach

Ataxia is a term used to describe a clinical presentation of incoordinated or inaccurate movements which occur without an alteration of tone or weakness. It is not a diagnosis, but its presentation has a wide differential diagnosis depending upon its onset. These can be a challenging group due to its varied aetiology. Broadly causes can be divided into genetic and acquired. Investigations are invasive and expensive. It is extremely important to liaise with a paediatric neurologist early following presentation as some of the ataxia are treatable. A methodological approach with history taking, detailed clinical evaluation and appropriate investigations are essential in establishing a diagnosis although it is still not uncommon to not to find a diagnosis in some of these children. Next generation exome sequencing is likely to improve the diagnostic yield in this group.