Age- and sex-related oculomotor manifestation of dopamine deficiency in Segawa disease.

OBJECTIVE: To investigate the oculomotor manifestations of Segawa disease (SD), considered to represent mild dopamine deficiency and discuss their pathophysiological basis. METHODS: We recorded visually- (VGS) and memory-guided saccade (MGS) tasks in 31 SD patients and 153 age-matched control subjects to study how basal ganglia (BG) dysfunction in SD evolves with age for male and female subjects. RESULTS: SD patients were impaired in initiating MGS, showing longer latencies with occasional failure. Patients showed impaired ability to suppress reflexive saccades; saccades to cues presented in MGS were more frequent and showed a shorter latency than in control subjects. These findings were more prominent in male patients, particularly between 13 and 25 years. Additionally, male patients showed larger delay in MGS latency in trials preceded by saccades to cue than those unpreceded. CONCLUSIONS: The findings can be explained by a dysfunction of the BG-direct pathway impinging on superior colliculus (SC) due to dopamine deficiency. The disturbed inhibitory control of saccades may be explained by increased SC responsivity to visual stimuli. SIGNIFICANCE: Oculomotor abnormalities in SD can be explained by dysfunction of the BG inhibitory pathways reaching SC, with a delayed maturation in male SD patients, consistent with previous pathological/physiological studies.

A Rare Case of Meningitis Caused by Streptococcus gallolyticus subsp. pasteurianus in an Immunocompetent Young Adult.

Bacterial meningitis is a life-threatening condition that is mainly caused by Streptococcus pneumoniae and Neisseria meningitis. Although Streptococcus gallolyticus subsp. pasteurianus (Sgp) is also known to cause meningitis, its frequency is quite low, especially in adults. We herein report the first immunocompetent Japanese adult patient (20-year-old woman) with bacterial meningitis caused by Sgp. The patient showed dramatic improvement after antibiotic treatment. Although previous reports have described an association between Sgp infection and an immunosuppressive status, bowel and hepatobiliary diseases, or strongyloidiasis, our case did not demonstrate any of these conditions, suggesting that Sgp can cause meningitis even in young immunocompetent adults.

Roles of the cerebellum and basal ganglia in temporal integration: Insights from a synchronized tapping task.

OBJECTIVE: The aim of this study was to clarify the roles of the cerebellum and basal ganglia for temporal integration. METHODS: We studied 39 patients with spinocerebellar degeneration (SCD), comprising spinocerebellar atrophy 6 (SCA6), SCA31, Machado-Joseph disease (MJD, also called SCA3), and multiple system atrophy (MSA). Thirteen normal subjects participated as controls. Participants were instructed to tap on a button in synchrony with isochronous tones. We analyzed the inter-tap interval (ITI), synchronizing tapping error (STE), negative asynchrony, and proportion of delayed tapping as indicators of tapping performance. RESULTS: The ITI coefficient of variation was increased only in MSA patients. The standard variation of STE was larger in SCD patients than in normal subjects, especially for MSA. Negative asynchrony, which is a tendency to tap the button before the tones, was prominent in SCA6 and MSA patients, with possible basal ganglia involvement. SCA31 patients exhibited normal to supranormal performance in terms of the variability of STE, which was surprising. CONCLUSIONS: Cerebellar patients generally showed greater STE variability, except for SCA31. The pace of tapping was affected in patients with possible basal ganglia pathology. SIGNIFICANCE: Our results suggest that interaction between the cerebellum and the basal ganglia is essential for temporal processing. The cerebellum and basal ganglia and their interaction regulate synchronized tapping, resulting in distinct tapping pattern abnormalities among different SCD subtypes.

The Pathophysiology of Gilles de la Tourette Syndrome: Changes in Saccade Performance by Low-Dose L-Dopa and Dopamine Receptor Blockers.

AIM: To elucidate the pathophysiology of Gilles de la Tourette syndrome (GTS), which is associated with prior use of dopamine receptor antagonists (blockers) and treatment by L-Dopa, through saccade performance. METHOD: In 226 male GTS patients (5-14 years), we followed vocal and motor tics and obsessive-compulsive disorder (OCD) after discontinuing blockers at the first visit starting with low-dose L-Dopa. We recorded visual- (VGS) and memory-guided saccades (MGS) in 110 patients and 26 normal participants. RESULTS: At the first visit, prior blocker users exhibited more severe vocal tics and OCD, but not motor tics, which persisted during follow-up. Patients treated with L-Dopa showed greater improvement of motor tics, but not vocal tics and OCD. Patients with and without blocker use showed similarly impaired MGS performance, while patients with blocker use showed more prominently impaired inhibitory control of saccades, associated with vocal tics and OCD. DISCUSSION: Impaired MGS performance suggested a mild hypodopaminergic state causing reduced direct pathway activity in the (oculo-)motor loops of the basal ganglia-thalamocortical circuit. Blocker use may aggravate vocal tics and OCD due to disinhibition within the associative and limbic loops. The findings provide a rationale for discouraging blocker use and using low-dose L-Dopa in GTS.

Abnormal saccade profiles in hereditary spinocerebellar degeneration reveal cerebellar contribution to visually guided saccades.

OBJECTIVE: To study how the pathophysiology underlying hereditary spinocerebellar degeneration (spinocerebellar ataxia; SCA) with pure cerebellar manifestation evolves with disease progression using saccade recordings. METHODS: We recorded visually- (VGS) and memory-guided saccade (MGS) task performance in a homogeneous population of 20 genetically proven SCA patients (12 SCA6 and eight SCA31 patients) and 19 normal controls. RESULTS: For VGS but not MGS, saccade latency and amplitude were increased and more variable than those in normal subjects, which correlated with cerebellar symptom severity assessed using the International Cooperative Ataxia Rating Scale (ICARS). Parameters with significant correlations with cerebellar symptoms showed an aggravation after disease stage progression (ICARS > 50). The saccade velocity profile exhibited shortened acceleration and prolonged deceleration, which also correlated with disease progression. The main sequence relationship between saccade amplitude and peak velocity as well as saccade inhibitory control were preserved. CONCLUSIONS: The cerebellum may be involved in initiating VGS, which was aggravated acutely during disease stage progression. Dysfunction associated with disease progression occurs mainly in the cerebellum and brainstem interaction but may also eventually involve cortical saccade processing. SIGNIFICANCE: Saccade recording can reveal cerebellar pathophysiology underlying SCA with disease progression.

Early detection of cognitive decline in Alzheimer's disease using eye tracking.

Background: Patients with Alzheimer's disease (AD) are known to exhibit visuospatial processing impairment, as reflected in eye movements from the early stages of the disease. We investigated whether the pattern of gaze exploration during visual tasks could be useful for detecting cognitive decline at the earliest stage. Methods: Sixteen AD patients (age: 79.1 ± 7.9 years, Mini Mental State Examination [MMSE] score: 17.7 ± 5.3, mean ± standard deviation) and 16 control subjects (age: 79.4 ± 4.6, MMSE score: 26.9 ± 2.4) participated. In the visual memory task, subjects memorized presented line drawings for later recall. In the visual search tasks, they searched for a target Landolt ring of specific orientation (serial search task) or color (pop-out task) embedded among arrays of distractors. Using video-oculography, saccade parameters, patterns of gaze exploration, and pupil size change during task performance were recorded and compared between AD and control subjects. Results: In the visual memory task, the number of informative regions of interest (ROIs) fixated was significantly reduced in AD patients compared to control subjects. In the visual search task, AD patients took a significantly longer time and more saccades to detect the target in the serial but not in pop-out search. In both tasks, there was no significant difference in the saccade frequency and amplitude between groups. On-task pupil modulation during the serial search task was decreased in AD. The number of ROIs fixated in the visual memory task and search time and saccade numbers in the serial search task differentiated both groups of subjects with high sensitivity, whereas saccade parameters of pupil size modulation were effective in confirming normal cognition from cognitive decline with high specificity. Discussion: Reduced fixation on informative ROIs reflected impaired attentional allocation. Increased search time and saccade numbers in the visual search task indicated inefficient visual processing. Decreased on-task pupil size during visual search suggested decreased pupil modulation with cognitive load in AD patients, reflecting impaired function of the locus coeruleus. When patients perform the combination of these tasks to visualize multiple aspects of visuospatial processing, cognitive decline can be detected at an early stage with high sensitivity and specificity and its progression be evaluated.

Rippling Muscle Disease with Irregular Toe Jerks and Anti-acetylcholine Receptor Antibodies: Remission after Extended Thymectomy.

We herein report a 63-year-old rippling muscle disease (RMD) patient who presented with painless stiffness, muscle hypertrophy and muscle contractions elicited by mechanical stimulation. He also showed irregular toe jerks and a slightly elevated level of anti-acetylcholine receptor antibody (AChR-Ab). Since he had a mediastinal mass mimicking thymoma, which was later revealed to be a bronchial cyst, he underwent extended thymectomy. The irregular toe jerks disappeared within a week after the operation. The other muscle symptoms completely remitted 27 months after the onset. This is the first report of a sporadic case of RMD with irregular toe jerks that resolved after extended thymectomy.

Multiple Cranial Neuropathies Similar to Orbital Apex Syndrome Associated with Pembrolizumab: A Case Report.

Neurotoxicity is one of the more serious immune-related adverse events (irAEs) linked to immune checkpoint inhibitors and calls for prompt diagnosis and treatment. We describe a case of posttreatment anti-programmed death-1 immune checkpoint inhibitor pembrolizumab-induced oculomotor, optic, and trigeminal neuropathy in an 84-year-old female patient with recurrent pulmonary adenocarcinoma. After she received 13 cycles of pembrolizumab, she experienced hyponatremia, anorexia, and right ptosis. There were signs of the suspected irAEs of pembrolizumab, including trigeminal neuropathy, optic neuropathy, and oculomotor neuropathy. Steroid pulse therapy had good results for her neurological findings. We reported this case despite reports of pembrolizumab-induced mononeuropathy of the oculomotor and optic nerves because multiple cranial neuropathies like orbital apex syndrome are thought to be uncommon.

Aseptic Meningitis-retention Syndrome Associated with Tocilizumab in a Patient with Idiopathic Multicentric Castleman Disease.

This is the first report of tocilizumab-associated meningitis-retention syndrome in a patient with idiopathic multicentric Castleman disease. A 57-year-old man presented with headache, nuchal rigidity, impaired consciousness, pyramidal tract signs and urinary retention. A cerebrospinal fluid examination revealed increased cell counts and protein levels. These symptoms were improved by intravenous methylprednisolone. Tocilizumab-associated meningoencephalitis has been reported in patients with rheumatoid arthritis and juvenile idiopathic arthritis but not with multicentric Castleman disease. This case presents evidence of the increased probability of meningitis as a neurological complication of tocilizumab administration.

Premature saccades: A detailed physiological analysis.

OBJECTIVE: Premature saccades (PSs) are those made with latencies too short for the direction and amplitude to be specifically programmed. We sought to determine the minimum latency needed to establish accurate direction and amplitude, and observed what occurs when saccades are launched before this minimum latency. METHODS: In Experiment 1, 249 normal subjects performed the gap saccade task with horizontal targets. In Experiment 2, 28 normal subjects performed the gap saccade task with the targets placed in eight directions. In Experiment 3, 38 normal subjects, 49 patients with Parkinson's disease (PD), and 10 patients with spinocerebellar degeneration (SCD) performed the gap saccade task with horizontal targets. RESULTS: In Experiment 1, it took 100 ms to accurately establish saccade amplitudes and directions. In Experiment 2, however, the latencies needed for accurate amplitude and direction establishment were both approximately 150 ms. In Experiment 3, the frequencies of PSs in patients with PD and SCD were lower than those of normal subjects. CONCLUSIONS: The saccade amplitudes and directions are determined simultaneously, 100-150 ms after target presentation. PSs may result from prediction of the oncoming target direction or latent saccade activities in the superior colliculus. SIGNIFICANCE: Saccade direction and amplitude are determined simultaneously.

[A case of lymphomatosis cerebri rapidly confirmed by brain biopsy].

Lymphomatosis cerebri (LC) is a variant of primary central nervous system lymphoma, which demonstrates diffuse white matter infiltrates without showing definite enhanced mass lesions on MR scans. We present a case of seventy-one year-old immunocompetent male who manifested with progressive truncal ataxia and drowsiness. The MRI exhibited diffuse white matter lesions from brainstem to cerebral hemispheres with minimum enhanced lesions at the first presentation. Because the diagnosis of LC was suspected, we performed a brain biopsy from the enhanced lesion near the right thalamus, which revealed diffuse large B cell lymphoma. After he underwent methylprednisolone pulse therapy and methotrexate chemotherapy, he obtained remission. Making a diagnosis of LC is often difficult because image findings resemble those of inflammatory or autoimmune diseases. LC is an important differential diagnosis to be considered in patients presenting with diffuse white matter disease. Performing a brain biopsy at the early phase is essential for the correct diagnosis and the favorable prognosis.

[A 64-year-old male with recurrence of herpes simplex encephalitis after suffering from severe pneumonia and sepsis].

The case is a 64-year-old male who had a past history of herpes simplex virus encephalitis (HSE) two years prior to his admission. He was admitted to our hospital due to severe pneumonia and sepsis. Several days later, he developed HSE again. It has been known that immunosuppressive state called immune paralysis occurs in the patient with sepsis due to the amplification of anti-inflammatory responses after the initial hyper-inflammatory phase, which increases the susceptibility to various latent viruses including herpes simplex virus. In the present case, we consider that the severe infection may trigger the recurrence of HSE through the viral reactivation due to immune paralysis. When we see a patient suffering from severe infection who had a past history of HSE, we should keep in mind that such a patient may have a risk of the recurrence of HSE.

Effect of subthalamic nucleus deep brain stimulation on visual scanning.

OBJECTIVE: Deep brain stimulation (DBS) can provide insights into the workings of the basal ganglia (BG) by interfering with their function. In patients with Parkinson's disease (PD) treated with DBS of the subthalamic nucleus, we studied the effect of DBS on scanning eye movements. METHODS: In the visual memory task, subjects viewed images of various complexities for later recall. In visual search tasks, subjects looked for and fixated one odd target ring, embedded among 48 Landolt rings, which either stood out or not from the distractors. We compared the parameters of scanning saccades when DBS was on and off. RESULTS: In the visual memory task, DBS increased the amplitude of saccades scanning simple but not complex drawings. In the visual search tasks, DBS showed no effect on saccade amplitude or frequency. CONCLUSIONS: Saccades when viewing simple images were affected by DBS since they are internally guided saccades, for which the involvement of BG is large. In contrast, saccades when viewing complex images or during visual search, made with the help of visual cues in the images (externally guided saccades) and less dependent on BG, were resistant to the effect of DBS. SIGNIFICANCE: DBS affects saccades differentially depending on the task.

Does the Clock Tick Slower or Faster in Parkinson's Disease? - Insights Gained From the Synchronized Tapping Task.

The rhythm of the internal clock is considered to be determined by the basal ganglia, with some studies suggesting slower internal clock in Parkinson's disease (PD). However, patients may also show motor hastening when they walk (festination) or are engaged in repetitive tapping, indicating faster ticking of the internal clock. Is the internal clock slower or faster in PD? The purpose of this study was to answer this question, i.e., how fast and slow a rhythm they can synchronize with, especially with reference to the limit of sensorimotor synchronization or temporal integration, representing the threshold of slower pace they can entrain into their motor actions, which is known to lie between 2 and 3 s in normal subjects but not yet studied in PD. We employed a synchronized tapping task that required subjects to tap the key in synchrony with repetitive tones at fixed interstimulus intervals (ISI) between 200 and 4800 ms. Twenty normal subjects and sixteen PD patients were enrolled, who were classified into early and advanced PD groups by UPDRS-III (early: 15 or less, advanced: more than 15). The ISI at which the response changes from synchronizing with the tones to lagging behind them was considered to be the limit of temporal integration. Early PD patients responded ahead of the tones (negative asynchrony), which became more apparent with repeated tapping. This suggested "faster" ticking clock even in the presence of the pacing tones. In normal subjects, the limit of temporal integration was around 2-3 s: below this, subjects could synchronize with the tones, while above it they had difficulty in synchronization. In early PD patients, the limit of temporal integration was significantly longer than in normal subjects, pointing to their enhanced ability to synchronize also with slower paces of tones, but advanced PD patients had significantly shortened limits, suggesting that advanced patients lost this ability. In conclusion, the limit of temporal integration is initially longer but gets shorter as the disease progresses. It can be explained by the hastening of the internal clock at the earlier stages of PD, followed by the loss of temporal integration.

The 3-second rule in hereditary pure cerebellar ataxia: a synchronized tapping study.

The '3-second rule' has been proposed based on miscellaneous observations that a time period of around 3 seconds constitutes the fundamental unit of time related to the neuro-cognitive machinery in normal humans. The aim of paper was to investigate the temporal processing in patients with spinocerebellar ataxia type 6 (SCA6) and SCA31, pure cerebellar types of spinocerebellar degeneration, using a synchronized tapping task. Seventeen SCA patients (11 SCA6, 6 SCA31) and 17 normal age-matched volunteers participated. The task required subjects to tap a keyboard in synchrony with sequences of auditory stimuli presented at fixed interstimulus intervals (ISIs) between 200 and 4800 ms. In this task, the subjects required non-motor components to estimate the time of forthcoming tone in addition to motor components to tap. Normal subjects synchronized their taps to the presented tones at shorter ISIs, whereas as the ISI became longer, the normal subjects displayed greater latency between the tone and the tapping (transition zone). After the transition zone, normal subjects pressed the button delayed relative to the tone. On the other hand, SCA patients could not synchronize their tapping with the tone even at shorter ISIs, although they pressed the button delayed relative to the tone earlier than normal subjects did. The earliest time of delayed tapping appearance after the transition zone was 4800 ms in normal subjects but 1800 ms in SCA patients. The span of temporal integration in SCA patients is shortened compared to that in normal subjects. This could represent non-motor cerebellar dysfunction in SCA patients.

Visual scanning area is abnormally enlarged in hereditary pure cerebellar ataxia.

The aim of paper was to investigate abnormalities in visual scanning using an eye-tracking device with patients with spinocerebellar ataxia type 6 (SCA6) and SCA31, pure cerebellar types of spinocerebellar degeneration. Nineteen SCA patients (12 patients with SCA6 and 7 patients with SCA31) and 19 normal subjects in total participated in the study. While the subjects viewed images of varying complexity for later recall, we compared the visual scanning parameters between SCA patients and normal subjects. SCA patients had lower image recall scores. The scanned area in SCA patients was consistently larger than that in normal subjects. The amplitude of saccades was slightly larger in SCA patients than that in normal subjects, although it did not statistically differ between the two groups and correlated significantly with the scanned area in most images in SCA patients. The instability ratio of fixation, reflecting gaze-evoked nystagmus and downbeat nystagmus, was higher in SCA patients than that in normal subjects. Since SCA patients showed low scores despite wide visual scanning, the scanned area is considered to be abnormally enlarged. The larger scanned area in SCA patients was supposed mainly to result from the slightly larger saccade amplitude. Additionally, SCA patients showed prominent fixation disturbances probably due to gaze-evoked nystagmus and downbeat nystagmus. Consequently, SCA patients suffer from recognizing various objects in daily life, probably due to the impaired saccade control and impaired fixation.

Top-down but not bottom-up visual scanning is affected in hereditary pure cerebellar ataxia.

The aim of this study was to clarify the nature of visual processing deficits caused by cerebellar disorders. We studied the performance of two types of visual search (top-down visual scanning and bottom-up visual scanning) in 18 patients with pure cerebellar types of spinocerebellar degeneration (SCA6: 11; SCA31: 7). The gaze fixation position was recorded with an eye-tracking device while the subjects performed two visual search tasks in which they looked for a target Landolt figure among distractors. In the serial search task, the target was similar to the distractors and the subject had to search for the target by processing each item with top-down visual scanning. In the pop-out search task, the target and distractor were clearly discernible and the visual salience of the target allowed the subjects to detect it by bottom-up visual scanning. The saliency maps clearly showed that the serial search task required top-down visual attention and the pop-out search task required bottom-up visual attention. In the serial search task, the search time to detect the target was significantly longer in SCA patients than in normal subjects, whereas the search time in the pop-out search task was comparable between the two groups. These findings suggested that SCA patients cannot efficiently scan a target using a top-down attentional process, whereas scanning with a bottom-up attentional process is not affected. In the serial search task, the amplitude of saccades was significantly smaller in SCA patients than in normal subjects. The variability of saccade amplitude (saccadic dysmetria), number of re-fixations, and unstable fixation (nystagmus) were larger in SCA patients than in normal subjects, accounting for a substantial proportion of scattered fixations around the items. Saccadic dysmetria, re-fixation, and nystagmus may play important roles in the impaired top-down visual scanning in SCA, hampering precise visual processing of individual items.

Motor cortical epilepsia partialis continua in a patient with a localized sensory cortical lesion.

We describe a 33-year-old man with cyclosporine encephalopathy who showed continuous jerking in the left upper limb due to epilepsia partialis continua. Jerk-locked back averaging (JLA) of magnetoencephalogram disclosed a spike preceding the jerk localized at the hand motor area, whereas JLA of electroencephalogram revealed no premyoclonus spikes. The paired-pulse motor cortical transcranial magnetic stimulation revealed motor cortical hyperexcitability, while the paired-pulse somatosensory evoked potential showed no sensory cortical hyperexcitability. The brain MRI showed a high intensity lesion localized at the hand sensory area. These results suggest that the jerks were produced by discharges at the motor cortex probably disinhibited by the sensory cortical lesion.

Chemoenzymatic synthesis of amylose-grafted cellulose.

This paper reports the chemoenzymatic synthesis of an amylose-grafted cellulose. A maltoheptaose was chemically introduced to the amine-functionalized cellulose by reductive amination to produce the maltoheptaose-grafted cellulose. Then, the phosphorylase-catalyzed enzymatic polymerization of glucose 1-phosphate from the graft-chain ends on the cellulose derivative was performed, giving the amylose-grafted cellulose. The obtained material is shown to form gels and films. The dry and wet cycles of the materials were repeated.