[Transverse myelitis and cauda equina syndrome followed by varicella in a patient with varicella-zoster virus infection].

A 74-year-old man was admitted to our hospital with complaints of weakness in the lower extremities, urinary retention for 10 days, and generalized vesicular rash for 7 days. Spinal magnetic resonance imaging showed contrast enhancement at the Th12-L1 level of the spinal cord and cauda equina. Serum and cerebrospinal fluid varicella-zoster virus (VZV)-immunoglobulin (Ig) G antibody titers were markedly elevated, and VZV-IgM was detected in cerebrospinal fluid. The patient was diagnosed with VZV transverse myelitis and cauda equina syndrome with subsequent varicella and was treated with acyclovir and prednisolone. Two months later, muscle weakness, and dysuria had almost completely resolved. We hypothesize that latent VZV in the ganglia reactivated and caused transverse myelitis, which subsequently spread to the body via the bloodstream, resulting in the development of varicella.

[Diffuse infiltrating primary cerebellar glioma involving the brainstem: a case report].

An 85-year-old woman was admitted to our hospital with unsteady gait, dizziness, nausea, and vomiting. MRI revealed characteristic abnormal signals in the bilateral cerebellar hemispheres. A brain biopsy was performed which confirmed a definitive histological diagnosis of diffuse glioma. Follow-up MRI showed diffuse abnormal signals that extended from the cerebellum to the brainstem through the cerebellar peduncle without mass formation. Her general condition gradually deteriorated even with the best supportive care, and she died 195 days after admission. Gliomatosis cerebri is characterized by a diffuse infiltrating growth pattern without mass formation in the brain. This case showed a similar proliferation mode from the cerebellum to the brain stem without mass formation. This case was diagnosed based on MRI and pathological findings. Only five similar cases have been previously reported, and compared to these reports, the patient in the present case was the oldest with the poorest prognosis. The histopathological features may influence the appropriate treatment and the prognosis. This disorder is a very rare condition; thus, when we encountered this patient showing cerebellar ataxia with diffuse abnormal MRI signals without mass formation in the cerebellum and brainstem, a brain biopsy was necessary to establish the definitive diagnosis.

Frontal cortical dysfunction in Parkinson's disease (PD): Comparison of memory-based smooth-pursuit and anti-saccade tasks, and neuropsychological and motor symptom evaluations.

We reported recently that during a memory-based smooth-pursuit task, most Parkinson's disease (PD) patients exhibited normal cue-information memory but impaired smooth-pursuit preparation and execution. A minority of PD patients had abnormal cue-information memory or difficulty in understanding the task. To further examine differences between these two groups, we assigned an anti-saccade task and compared correct rates with various neuropsychological and motor symptom evaluations. The anti-saccade task requires voluntary saccades in the opposite direction to a visual stimulus, and patients with frontal cortical impairments are known to exhibit reflexive saccades (errors). We classified PD patients into 2 groups: one with normal cue-information memory during memory-based smooth-pursuit (n = 14), and the other with abnormal cue-information memory or with difficulty in understanding the memory task (n = 6). The two groups had significantly different anti-saccade correct rates and frontal assessment battery (FAB) scores (P < 0.01). Anti-saccade correct rates of individual patients (n = 20) correlated significantly with FAB scores (P < 0.01) but not with age, Hoehn-Yahr stage, unified PD rating scale (UPDRS) part III or mini-mental state examination (MMSE) scores. Among FAB subtests, significant correlation was obtained only with motor programming scores. These results suggest that performance of memory-based smooth-pursuit and/or anti-saccades depend on frontal cortical function or dysfunction.

A novel nuclear DnaJ protein, DNAJC8, can suppress the formation of spinocerebellar ataxia 3 polyglutamine aggregation in a J-domain independent manner.

Polyglutamine (polyQ) diseases comprise neurodegenerative disorders caused by expression of expanded polyQ-containing proteins. The cytotoxicity of the expanded polyQ-containing proteins is closely associated with aggregate formation. In this study, we report that a novel J-protein, DNAJ (HSP40) Homolog, Subfamily C, Member 8 (DNAJC8), suppresses the aggregation of polyQ-containing protein in a cellular model of spinocerebellar ataxia type 3 (SCA3), which is also known as Machado-Joseph disease. Overexpression of DNAJC8 in SH-SY5Y neuroblastoma cells significantly reduced the polyQ aggregation and apoptosis, and DNAJC8 was co-localized with the polyQ aggregation in the cell nucleus. Deletion mutants of DNAJC8 revealed that the C-terminal domain of DNAJC8 was essential for the suppression of polyQ aggregation, whereas the J-domain was dispensable. Furthermore, 22-mer oligopeptide derived from C-termilal domain could suppress the polyQ aggregation. These results indicate that DNAJC8 can suppress the polyQ aggregation via a distinct mechanism independent of HSP70-based chaperone machinery and have a unique protective role against the aggregation of expanded polyQ-containing proteins such as pathogenic ataxin-3 proteins.

[Visual tracking with/without passive whole-body rotation in Parkinson's disease (PD): Dissociation of smooth-pursuit and cancellation of vestibulo-ocular reflex (VOR)].

Although impaired smooth-pursuit in Parkinson's disease (PD) is well known, reports are conflicting on the ability to cancel vestibulo-ocular reflex (VOR) when the target moves with head, requiring gaze-pursuit. To compare visual tracking performance with or without passive whole-body rotation, we examined eye movements of 10 PD patients and 6 age-matched controls during sinusoidal horizontal smooth-pursuit and passive whole-body rotation (0.3 Hz, ± 10°). Three tasks were tested: smooth-pursuit, VOR cancellation, and VORx1 while subjects fixated an earth-stationary spot during whole-body rotation. Mean ± SD eye velocity gains (eye velocities/stimulus velocities) of PD patients during the 3 tasks were 0.32 ± 0.24 0.25 ± 0.22, 0.85 ± 0.20, whereas those of controls were 0.91 ± 0.06, 0.14 ± 0.07, 0.94 ± 0.05, respectively. Difference was significant between the two subject groups only during smooth-pursuit. Plotting eye-velocity gains of individual subjects during VOR cancellation against those during smooth-pursuit revealed significant negative linear correlation between the two parameters in the controls, but no correlation was found in PD patients. Based on the regression equation of the controls, we estimated expected eye velocity gains of individual subjects during VOR cancellation from their smooth-pursuit gains. Estimated gains of PD patients during VOR cancellation were significantly different from their actual gains, suggesting that different neural mechanisms operate during VOR cancellation in the controls and PD.

Impaired smooth-pursuit in Parkinson's disease: normal cue-information memory, but dysfunction of extra-retinal mechanisms for pursuit preparation and execution.

While retinal image motion is the primary input for smooth-pursuit, its efficiency depends on cognitive processes including prediction. Reports are conflicting on impaired prediction during pursuit in Parkinson's disease. By separating two major components of prediction (image motion direction memory and movement preparation) using a memory-based pursuit task, and by comparing tracking eye movements with those during a simple ramp-pursuit task that did not require visual memory, we examined smooth-pursuit in 25 patients with Parkinson's disease and compared the results with 14 age-matched controls. In the memory-based pursuit task, cue 1 indicated visual motion direction, whereas cue 2 instructed the subjects to prepare to pursue or not to pursue. Based on the cue-information memory, subjects were asked to pursue the correct spot from two oppositely moving spots or not to pursue. In 24/25 patients, the cue-information memory was normal, but movement preparation and execution were impaired. Specifically, unlike controls, most of the patients (18/24 = 75%) lacked initial pursuit during the memory task and started tracking the correct spot by saccades. Conversely, during simple ramp-pursuit, most patients (83%) exhibited initial pursuit. Popping-out of the correct spot motion during memory-based pursuit was ineffective for enhancing initial pursuit. The results were similar irrespective of levodopa/dopamine agonist medication. Our results indicate that the extra-retinal mechanisms of most patients are dysfunctional in initiating memory-based (not simple ramp) pursuit. A dysfunctional pursuit loop between frontal eye fields (FEF) and basal ganglia may contribute to the impairment of extra-retinal mechanisms, resulting in deficient pursuit commands from the FEF to brainstem.

Normal aging affects movement execution but not visual motion working memory and decision-making delay during cue-dependent memory-based smooth-pursuit.

Aging affects virtually all functions including sensory/motor and cognitive activities. While retinal image motion is the primary input for smooth-pursuit, its efficiency/accuracy depends on cognitive processes. Elderly subjects exhibit gain decrease during initial and steady-state pursuit, but reports on latencies are conflicting. Using a cue-dependent memory-based smooth-pursuit task, we identified important extra-retinal mechanisms for initial pursuit in young adults including cue information priming and extra-retinal drive components (Ito et al. in Exp Brain Res 229:23-35, 2013). We examined aging effects on parameters for smooth-pursuit using the same tasks. Elderly subjects were tested during three task conditions as previously described: memory-based pursuit, simple ramp-pursuit just to follow motion of a single spot, and popping-out of the correct spot during memory-based pursuit to enhance retinal image motion. Simple ramp-pursuit was used as a task that did not require visual motion working memory. To clarify aging effects, we then compared the results with the previous young subject data. During memory-based pursuit, elderly subjects exhibited normal working memory of cue information. Most movement-parameters including pursuit latencies differed significantly between memory-based pursuit and simple ramp-pursuit and also between young and elderly subjects. Popping-out of the correct spot motion was ineffective for enhancing initial pursuit in elderly subjects. However, the latency difference between memory-based pursuit and simple ramp-pursuit in individual subjects, which includes decision-making delay in the memory task, was similar between the two groups. Our results suggest that smooth-pursuit latencies depend on task conditions and that, although the extra-retinal mechanisms were functional for initial pursuit in elderly subjects, they were less effective.

Cue-dependent memory-based smooth-pursuit in normal human subjects: importance of extra-retinal mechanisms for initial pursuit.

Using a cue-dependent memory-based smooth-pursuit task previously applied to monkeys, we examined the effects of visual motion-memory on smooth-pursuit eye movements in normal human subjects and compared the results with those of the trained monkeys. These results were also compared with those during simple ramp-pursuit that did not require visual motion-memory. During memory-based pursuit, all subjects exhibited virtually no errors in either pursuit-direction or go/no-go selection. Tracking eye movements of humans and monkeys were similar in the two tasks, but tracking eye movements were different between the two tasks; latencies of the pursuit and corrective saccades were prolonged, initial pursuit eye velocity and acceleration were lower, peak velocities were lower, and time to reach peak velocities lengthened during memory-based pursuit. These characteristics were similar to anticipatory pursuit initiated by extra-retinal components during the initial extinction task of Barnes and Collins (J Neurophysiol 100:1135-1146, 2008b). We suggest that the differences between the two tasks reflect differences between the contribution of extra-retinal and retinal components. This interpretation is supported by two further studies: (1) during popping out of the correct spot to enhance retinal image-motion inputs during memory-based pursuit, pursuit eye velocities approached those during simple ramp-pursuit, and (2) during initial blanking of spot motion during memory-based pursuit, pursuit components appeared in the correct direction. Our results showed the importance of extra-retinal mechanisms for initial pursuit during memory-based pursuit, which include priming effects and extra-retinal drive components. Comparison with monkey studies on neuronal responses and model analysis suggested possible pathways for the extra-retinal mechanisms.

[Cerebellum and eye movement control -- neuronal mechanisms of memory-based smooth-pursuit and their early clinical application].

Recent studies implicate the cerebellum in cognitive functions in addition to its well-established roles in motor control and learning. Using a memory-based smooth-pursuit task that separates visual working memory from motor preparation and execution, monkeys were trained to pursue (i.e., go) or not pursue (i.e., no-go), a cued direction, based on the working memory of visual motion-direction and a go/no-go instruction. Task-related neuronal activity was examined in cerebral and cerebellar major smooth-pursuit pathways. Different cerebral and cerebellar areas carried distinctly different signals during memory-based smooth-pursuit. In the cerebellum, prediction-related signals (visual working memory, pursuit selection and movement preparation) were represented in the vermal lobules VI-VII and caudal fastigial nucleus, whereas the floccular region (flocculus and ventral paraflocculus) contained predominantly execution-related signals. This task was applied to patients with cerebellar degeneration and idiopathic Parkinson's disease (PD). None of the PD patients tested exhibited impaired working memory of motion-direction and/or go/no-go selection, but they did show task-specific difficulty in generating an initial smooth-pursuit component, suggesting difficulty in smooth-pursuit preparation. In contrast, most cerebellar patients exhibited impaired visual working memory in addition to difficulty in preparing for and executing smooth-pursuit. These results suggest different roles for the basal ganglia and cerebellum in smooth-pursuit planning.

Memory-based smooth pursuit: neuronal mechanisms and preliminary results of clinical application.

Using a memory-based smooth-pursuit task, macaque monkeys were trained to pursue (i.e., go) or not pursue (i.e., no-go), a cued direction, based on the memory of visual motion-direction and a go/no-go instruction. Task-related neuronal activity was examined in the supplementary eye fields, caudal frontal eye fields, cerebellar floccular region, dorsal vermis lobules VI-VII, and caudal fastigial nuclei. Different cerebral and cerebellar areas carried distinctly different signals during memory-based smooth pursuit. Chemical inactivation of these areas produced effects consistent with the differences in signals represented in each area. This task was applied to patients with idiopathic Parkinson's disease (PD), because impaired visual working memory has been reported during cognitive tasks in PD. None of the PD patients tested exhibited impaired working memory of motion-direction and/or go/no-go selection, but they had difficulty in preparing for and executing smooth-pursuit eye movements, suggesting a selective motor-related disturbance in Parkinson's disease.