Brain-specific glycosylation of protein tyrosine phosphatase receptor type Z (PTPRZ) marks a demyelination-associated astrocyte subtype.

Astrocytes are the most abundant glial cell type in the brain, where they participate in various homeostatic functions. Transcriptomically, diverse astrocyte subpopulations play distinct roles during development and disease progression. However, the biochemical identification of astrocyte subtypes, especially by membrane surface protein glycosylation, remains poorly investigated. Protein tyrosine phosphatase receptor type zeta (PTPRZ) is a highly expressed membrane protein in CNS glia cells that can be modified with diverse glycosylation, including the unique HNK-1 capped O-mannosyl (O-Man) core M2 glycan mediated by brain-specific branching enzyme GnT-IX. Although PTPRZ modified with HNK-1 capped O-Man glycans (HNK-1-O-Man+ PTPRZ) is increased in reactive astrocytes of demyelination model mice, whether such astrocytes emerge in a broad range of disease-associated conditions or are limited to conditions associated with demyelination remains unclear. Here, we show that HNK-1-O-Man+ PTPRZ localizes in hypertrophic astrocytes of damaged brain areas in patients with multiple sclerosis. Furthermore, we show that astrocytes expressing HNK-1-O-Man+ PTPRZ are present in two demyelination mouse models (cuprizone-fed mice and a vanishing white matter disease model), while traumatic brain injury does not induce glycosylation. Administration of cuprizone to Aldh1l1-eGFP and Olig2KICreER/+ ;Rosa26eGFP mice revealed that cells expressing HNK-1-O-Man+ PTPRZ are derived from cells in the astrocyte lineage. Notably, GnT-IX but not PTPRZ mRNA was up-regulated in astrocytes isolated from the corpus callosum of cuprizone model mice. These results suggest that the unique PTPRZ glycosylation plays a key role in the patterning of demyelination-associated astrocytes.

Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy.

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

Mollaret Meningitis Caused by Varicella-Zoster Virus: A Case Report.

Mollaret meningitis is a recurrent aseptic meningitis mostly caused by herpes simplex virus type 2. Other causes of the disease rarely exist, and its pathology is not well understood. Herein, we present a 57-year-old man who had been admitted to our hospital eight times with recurrent aseptic meningitis. Although the deoxyribonucleic acid (DNA) of varicella-zoster virus (VZV) was not detected in the cerebrospinal fluid (CSF), his genetic analysis, measurement of anti-VZV immunoglobulin-G (IgG) in the CSF, the VZV IgG index, IgG in the serum, and interleukin-1 beta in the CSF revealed that the Mollaret meningitis had been caused by the VZV. This case demonstrates that Mollaret meningitis can be caused by the VZV when specific factors are associated with decreased immune response. This case is valuable in elucidating the pathophysiology of Mollaret meningitis.

[A case of recurrent cerebral infarction in an adult patient with false Taussig-Bing anomaly].

The case was a 53-year-old woman. At birth, she was diagnosed with a false Taussig-Bing anomaly with pulmonary artery stenosis and a single ventricle. However, no cardiac surgery was performed, and conservative treatment was continued by a cardiovascular surgeon even after adulthood. Because of secondary polycythemia and a history of multiple cerebral infarctions, she took anti-platelet drugs and anti-coagulants. However, she was admitted with the diagnosis of cerebral infarction for the fourth time. It was considered that the patient was at high risk of paradoxical cerebral embolism due to cardiac malformation with cyanotic congenital heart disease accompanied by coagulation abnormalities. Considering the pathophysiology, we decided to use aspirin in combination with warfarin.

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with small cell lung cancer and cytotoxic T-cell-mediated pathology: Case report.

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is caused by a reversible inhibition of ion channel actions by autoantibodies and is associated with a relatively good prognosis. Pathological findings of NMDAR encephalitis usually do not show neurophagorous nodules, but rare or mild inflammatory infiltration. We report a patient of small cell lung cancer (SCLC)-related paraneoplastic encephalitis with NMDAR antibodies, a cytotoxic T-cell-mediated pathology of the brain, and a rapid clinical course. This case highlights that the neuropathological diversity of NMDAR encephalitis may be even broader than previously thought and that NMDAR antibodies may also be found in various pathological conditions with a vigorous immune response.

[Oculomotor nerve palsy with preserved pupillary reaction in two cases of neurolymphomatosis].

Case 1: A 64-year-old woman with acute ptosis and diplopia was admitted to our hospital. She had right oculomotor nerve palsy with preserved pupillary reaction without any other neurological deficits. MRI showed abnormal enhancement in the right oculomotor nerve. An ovarian tumor was detected on CT examination, and was pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL). Cerebrospinal fluid cytology disclosed malignant lymphoma cells. Based on the above findings, we concluded that she had neurolymphomatosis (NL) of the right oculomotor nerve. Case 2: A 63-year-old woman was admitted to our hospital due to weakness of the bilateral lower extremities and gait disturbance. Lumbar MRI showed enhanced lesions in the cauda equina, and we diagnosed her as having DLBCL based on bone marrow aspiration study. She later developed right oculomotor nerve palsy with preserved pupillary reaction together with the right abducens and hypoglossal nerve palsies, which were caused by NL. Our cases suggest that oculomotor nerve palsy with preserved pupillary reaction can be a clinical feature of NL. Although NL mainly affects the subperinerium, as parasympathetic fibers are located in the periphery of the oculomotor nerve and supplied by pia matar blood vessels, patients with NL may shows this clinical feature.

Subclinical involvement of the trunk muscles in idiopathic inflammatory myopathies.

BACKGROUND: Whole-body magnetic resonance imaging (WB-MRI) is a useful tool for revealing the disease-specific distribution of affected muscles and clinically asymptomatic muscle involvements in idiopathic inflammatory myopathies (IIMs). PURPOSE: To examine inflammatory changes in the systemic skeletal muscles, including the thoracoabdominal trunk, in IIMs using WB-MRI. MATERIAL AND METHODS: We prospectively obtained WB-MRI axial images from 10 patients with IIMs, including antisynthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM), sporadic inclusion body myositis, and myopathy associated with antimitochondrial antibody. We evaluated 108 systemic skeletal muscles in short-tau inversion recovery (STIR) images and rated changes in signal intensity using a semiquantitative scale. Correlations between STIR sum score, peak creatine kinase (CK) and muscle strength were examined. We also investigated the correlation between STIR sum score within the thoracoabdominal trunk and forced vital capacity. RESULTS: High STIR signal changes were frequently identified in asymptomatic and routinely unexamined muscles. Thoracoabdominal trunk muscles were frequently involved in ASS and IMNM. Peak CK was positively correlated with the STIR sum score (R 2 = 0.62, p < .01). There was no significant correlation between the STIR sum score within the thoracoabdominal trunk and forced vital capacity. CONCLUSION: WB-MRI can detect subclinical muscle inflammation in the systemic muscles including the trunk muscles. STIR sum score is positively correlated with serum peak CK level; therefore, it could be a biomarker of overall muscle inflammation.

Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments.

BACKGROUND AND AIMS: Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments. METHODS: We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). RESULTS: The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. INTERPRETATION: For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

Candida brain abscesses in a patient with anorexia nervosa receiving total parenteral nutrition.

A 28-year-old woman with anorexia nervosa (AN) and Candida brain abscesses was transferred to our hospital for intensive treatment. On admission, she had a low-grade fever but no clinical neurological abnormalities were observed, even though she had a high-grade fever in the previous hospital. These clinical findings did not suggest a serious disorder in the brain. However, magnetic resonance imaging showed mass lesions in bilateral lentiform nuclei in addition to several abscesses in the whole body. The fungal cultures of specimens from abscesses on the anterior chest wall and iliopsoas muscle detected Candida albicans. She was treated with antifungal therapy (fosfluconazole, fluconazole, liposomal amphotericin B, and flucytosine) and two emergent craniotomies for drainage of the intracranial fluid. Thereafter, antifungal medications (voriconazole and flucytosine) were administered for six months as a longterm treatment, which abolished most abscesses. However, severe frontal lobe dysfunction persisted as a residual symptom. This case suggests that AN can mask clinical manifestations of infection. We should always consider the possibility of infectious complications in these patients.

Meningoencephalitis in relapsing polychondritis: A case report.

RATIONALE: Aseptic meningoencephalitis is a rare central nervous system complication of relapsing polychondritis (RP). PATIENT: We report a 61-year-old Japanese male patient with spiking fever and impaired consciousness. Neurological examination revealed meningealirritation, and cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis with elevated protein (199 mg/dL) and interleukin-6 (3810 pg/mL). Serological analysis showed high levels of anti-type II collagen antibodies, and the result of auricular biopsy was consistent with the diagnosis of RP showing cartilage degeneration surrounded by inflammatory cell infiltrations. DIAGNOSIS: A clinical diagnosis of RP was made according to the diagnostic criteria established by MacAdams et al. INTERVENTION: Steroid pulse therapy (methylprednisolone 1000 mg, consecutive 3 days) followed by oral prednisolone (60 mg/day) resolved the patient's high fever and disturbance of consciousness. OUTCOMES: The patient rapidly improved after steroid treatments and has a normal quality of life under the maintenance dose of steroid plus methotrexate (4 mg/week). LESSONS: RP-associated meningoencephalitis is a rare complication with significant morbidity and mortality. It should be considered and differentiated in patients with RP with unexplained spiking fever and impaired consciousness. In addition, the assessment of cerebrospinal fluid interleukin-6 levels may be useful to investigate the disease activity of RP-related meningoencephalitis. Further prospective studies are required to confirm this result.

A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy.

BACKGROUND: Hereditary motor and sensory neuropathy, also referred to as Charcot-Marie-Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of "double trouble" overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2. CASE PRESENTATION: The 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2. CONCLUSIONS: We described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

Abnormal evoked potentials in autoimmune glial fibrillary acidic protein astrocytopathy.

Autoimmune GFAP astrocytopathy is a new clinical entity and only a limited number of cases have been reported. Here we report the results of multimodal central conduction studies performed in a case of this disorder. A 72-year-old woman developed gradual cognitive decline and gait disturbance. A neurological examination revealed moderate amnesia, papilloedema, and pyramidal tract impairment of the bilateral lower limbs. The diagnosis of autoimmune GFAP astrocytopathy was made based on the typical MRI findings of periventricular radial linear gadolinium enhancement in the brain and longitudinally extensive lesions in the spinal cord, and anti-GFAP antibody detected in the cerebrospinal fluid. Somatosensory evoked potentials and transcranial magnetic stimulation studies revealed prolongation of conduction times. Visual evoked potentials showed an unusual W-shaped pattern. To our knowledge, this is the first neurophysiological demonstration of prolonged central conduction times in the autoimmune GFAP astrocytopathy. Further investigations are needed to establish the clinical value the neurophysiological examinations in this disorder.

Dopaminergic influences on risk preferences of Parkinson's disease patients.

Clinicians are increasingly recognizing impulse control disorders (ICDs) as a complication of dopaminergic treatment in Parkinson's disease (PD). Considering the pivotal role of dopamine in reward information processing, ICDs may originate from dysregulation of reward-oriented behavior, and the behavioral changes may be reflected in shifts of psychological risk preference during decision-making. We used a behavioral economics paradigm to evaluate quantitatively the risk preferences of PD patients in levodopa on and off states. We also examined age-matched healthy controls. We found that levodopa increased the subjective value and prolonged the decision time in PD patients. These effects are apparently not explained by kinematic improvements but are attributed to psychological shifts of risk preferences and increased attention during risky decision-making. The risk preferences of healthy controls were similar to those of PD on levodopa treatment. The risk preferences of PD patients were not correlated with the scores of routine cognitive batteries, suggesting that dopamine-sensitive risk preferences are independent of cognitive capacities as measured by conventional batteries, including general intelligence, memory, and frontal functioning. By contrast, apathy and ICD partially predicted the risk attitude in PD patients, suggesting a common background of limbic origin behind these properties. The present results demonstrated that dopamine deficiency in off-state PD leads to risk-avoiding behavior and levodopa treatment increases the risk preferences. Behavioral economics framework is useful to evaluate short-term psychological changes in response to levodopa in PD patients.

[Devotion to painting in a Parkinson's disease patient].

We report a 77-year-old man who suffered from Parkinson's disease for 12 years. Four years after the disease onset, he started to show excessive hobbyism of painting. His painting skills improved along with escalating enthusiasm. He even held a personal exhibition of his paintings. Dopaminergic treatment was increased as he developed wearing-off phenomenon. Six years after the disease onset, he developed dopamine dysregulation syndrome (DDS). In the same year, he underwent surgery for subthalamic deep brain stimulation. DDS did not improve and he did not lose enthusiasm for painting after surgery. Switching from ropinirole to rotigotine improved the DDS, but did not affect the excessive enthusiasm. At the age of 76, he started to have difficulty in completing the paintings. He had an uncontrollable urge to overlay paint strokes until the colors blurred and the paper was torn. In neuropsychological examinations, Mini-Mental State Examination score was above the cutoff, but Frontal Assessment Battery suggested motor perseveration and disinhibition. In summary, the patient's excessive enthusiasm for painting emerged in association with impulse control disorder (ICD) by dopamine agonist therapy, and subsequent change in his painting style appeared to be related with motor perseveration and/or further escalation of ICD.

[Thoracoabdominal muscle involvement in anti-PL-7 myopathy revealed by whole-body magnetic resonance imaging].

A 33-year-old woman developed progressive weakness in the proximal limbs with myalgia and morning stiffness. Physical examination revealed low-grade fever, heliotrope eyelids and mechanic's hand. On neurological examination, she showed Medical Research Council grade 4 weakness in the shoulder girdle, proximal limb muscles, and grade 4 weakness in the abdominis muscle according to Daniels's scale. Laboratory tests revealed elevated serum creatine kinase (6,824 IU/l) and positive anti-PL-7 antibody. A needle electromyography study detected short motor unit potentials of myogenic pattern with abundant fibrillations and positive sharp waves. Whole-body MRI detected high intensity signals in the muscles of the shoulder girdle, proximal limbs, and thoracoabdominal trunk on short-tau inversion recovery sequence images. We diagnosed her as anti-PL-7 myopathy. After treatments with steroid, immunosuppressant, and immunoglobulin, her symptoms improved and abnormal MRI signals were normalized. Although MRI is known to be useful for detection of asymptomatic muscular inflammation in myositis, thoracoabdominal muscles are generally not covered in routine evaluation. To our knowledge, ours is the first case to detect acute inflammation of the thoracoabdominal muscles in antisynthetase syndrome. The present study suggests that whole-body MRI is useful for comprehensive evaluation of muscular involvement and longitudinal assessment for treatment outcomes.

The Motor Network Reduces Multisensory Illusory Perception.

Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion.SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception.

[A case of leptomeningeal melanomatosis with acute paraplegia and multiple cranial nerve palsies].

A 62-year-old man with acute paraplegia was transferred to our hospital. He had flaccid paraplegia and multiple cranial nerve palsies, such as mydriasis of the left pupil, abduction palsy of the left eye, hoarseness and dysphagia, but no meningeal irritation signs. MRI of the spinal canal showed swellings of the conus medullaris and the cauda equine, and also contrast enhancement of the spinal meninges. The cerebrospinal fluid (CSF) showed pleocytosis and protein increment. The lymph node was swollen in his right axilla. The biopsy specimen from the right axillary lymph node revealed metastasis of malignant melanoma histologically. Careful check-up of his whole body found a malignant melanoma in the subungual region of the right ring finger. Repeated cytological examination revealed melanoma cells in the CSF, confirming the diagnosis of leptomeningeal melanomatosis. His consciousness was gradually deteriorated. His family members chose supportive care instead of chemotherapy or surgical therapy after full information about his conditions. Finally, he died 60 days after transfer to our hospital. This is a rare case of leptomenigeal melanomatosis presenting with acute paraplegia and multiple cranial nerve palsies. Careful follow-up and repeated studies are vital for the early diagnosis of leptomenigeal melanomatosis in spite of atypical clinical presentation.

A case of paroxysmal kinesigenic dyskinesia which exhibited the phenotype of anxiety disorder.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare heritable neurologic disorder characterized by attacks of involuntary movement induced by sudden voluntary movements. No previous reports have described cases showing comorbidity with psychiatric disease or symptoms. In this case, we showed a patient with PKD who exhibited several manifestations of anxiety disorder. CASE: A 35-year-old Japanese man with PKD had been maintained on carbamazepine since he was 16 years of age without any attacks. However, 10 years before this referral, he became aware of a feeling of breakdown in his overall physical functions. He had then avoided becoming familiar with people out of concern that his physical dysfunctions might be perceived in a negative light. One day he was referred by the neurologic department at our hospital to the Department of Psychiatry because of severe anxiety and hyperventilation triggered by carbamazepine. We treated with escitalopram, aripiprazole, and ethyl loflazepate. Both his subjective physical condition and objective expressions subsequently showed gradual improvement. At last, the feelings of chest compression and anxiety entirely disappeared. Accordingly, increases in plasma monoamine metabolite levels were observed, and the c.649dupC mutation, which has been found in most Japanese PKD families, was detected in his proline-rich transmembrane protein 2 gene. CONCLUSION: This is the first report to describe psychiatric comorbidities or symptoms in a PKD case. The efficacy of psychotropic medication used in this case, the resulting changes in plasma monoamine metabolite levels, and the recent advances in the molecular understanding of PKD suggested slight, but widespread alterations to the neurotransmitter systems in the brain.