Inherited CARD9 Deficiency Due to a Founder Effect in East Asia.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy.

Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.

[A case of myopathy, myocarditis, and encephalitis with nonconvulsive status epileptics after immune checkpoint inhibitor therapy for ureter cancer].

A 72-year-old man, who had received pembrolizumab of immune checkpoint inhibitor (ICI) over 6 months for ureter cancer, developed progressive skeletal muscle weakness, dysarthria, dyspnea, and consciousness disturbance over the past two weeks. The systemic work-up tests documented an encephalitis, myopathy, and myocarditis. Multiple autoimmune antibodies of anti-Tr, anti-titin, anti-kv1.4, anti-GM1 and anti-GD1a were positive in the serum. Although myopathy and myocarditis responded to high-dose steroid pulse therapy, encephalopathy deteriorated. Electroencephalogram showed a fluctuated pattern of rhythmic delta activity with fast waves, and a rapid response to intravenous diazepam revealed a condition of nonconvulsive status epileptics (NCSE). The patient had an uneventful course after anti-epileptic medication. The ICIs therapy may trigger a broader activation of multiple autoimmune mechanisms. When an encephalitis by immune-related adverse events does not respond to standard immunotherapy, NCSE may be a main pathophysiological mechanism, thereby anti-epileptics being an alternative treatment option.

Clinical and pathological characteristics of later onset multiple system atrophy.

BACKGROUND: In the current consensus criteria, onset after age 75 is considered as non-supporting for diagnosis of multiples system atrophy (MSA); however, some MSA patients present after age 75. Clinical and pathological characteristics of such later onset MSA (LO-MSA) compared to usual onset MSA (UO-MSA) remain poorly understood. METHODS: The clinical cohort included patients from Kobe University Hospital and Amagasaki General Medical Center Hospital, while the autopsy cohort was from the brain bank at Mayo Clinic Florida. We identified 83 patients in the clinical cohort and 193 patients in the autopsy cohort. We divided MSA into two groups according to age at onset: UO-MSA (≤ 75) and LO-MSA (> 75). We compared clinical features and outcomes between the two groups in the clinical cohort and compared the findings to the autopsy cohort. RESULTS: LO-MSA accounted for 8% in the clinical cohort and 5% in the autopsy cohort. The median time from onset to death or to life-saving tracheostomy was significantly shorter in LO-MSA than in UO-MSA in both cohorts (4.8 vs 7.9 years in the clinical cohort and 3.9 vs 7.5 years in the autopsy cohort; P = 0.043 and P < 0.0001, respectively). The median time from diagnosis to death was less than 3 years in LO-MSA in the clinical cohort. CONCLUSIONS: Some MSA patients have late age of onset and short survival, limiting time for clinical decision making. MSA should be considered in the differential diagnosis of elderly patients with autonomic symptoms and extrapyramidal and/or cerebellar syndromes.

Anti-Ma2-Associated Limbic Encephalitis after Termination of Immune Checkpoint Inhibitor Therapy for Malignant Pleural Mesothelioma.

Neurological adverse events of immune checkpoint inhibitor (ICI) therapy mostly develop within 3 months after initiation of ICI treatment. An 82-year-old male with malignant pleural mesothelioma developed anti-Ma2-associated limbic encephalitis at a delay of 18 months after the start of nivolumab therapy (3 months after termination of a 15-month course of ICI treatment). Immunotherapy with steroids and immunoglobulins resulted in moderate neurological improvement. Over the next year, malignant pleural mesothelioma gradually worsened, while the anti-Ma2 antibody test remained positive. Anti-Ma2 paraneoplastic encephalitis may occur after a delay following the discontinuation of ICI therapy.

[A case of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy].

A 46-year-old man developed acute meningo-encephalitis with confusion, headache, fever, intractable hiccups, dysuria, myoclonus/tremor, and ataxia. Analysis of cerebrospinal fluid (CSF) showed elevated levels of cell counts and protein. Brain MRI demonstrated multiple linear increased FLAIR signals in bilateral basal ganglia and corona radiata. Repeated MRI showed T2 hyperintensity areas in the lower brainstem, sparing the area postrema. Immunotherapy with intravenous high-dose steroid and subsequent oral steroid was successful, and the symptoms improved completely. Later MRI study showed a striking resolution. Glial fibrillary acidic protein (GFAP) α antibody was positive in the CSF, while anti-aquaporin-4 antibody, anti-myelin oligodendrocyte glycoprotein antibody, and N-methyl-D-aspartate receptor antibody were all negative. There were no relapses at final follow-up of 6 months after onset. Autoimmune GFAP astrocytopathy is not an uncommon immune-mediated inflammatory disorder in the central nervous system.

[A case of adult-onset type II citrullinemia triggered by entering a nursing home with a good response to medium-chain triglyceride oil therapy].

A 49-year-old woman with intellectual disability and a food preference for fried chicken entered a nursing home. After nursing home diet, she developed episodic attacks of hyperammonemic encephalopathy. Her characteristic food preference and the negative results for brain and liver imaging studies suggested urea cycle disorder. A high plasma citrulline level on amino acid analysis and a genetic test for citrine gene confirmed a citrine deficiency (adult-onset type II citrullinemia). Although a low-carbohydrate diet was insufficient, a combination therapy of a low-carbohydrate diet and a medium-chain triglyceride (MCT) oil was effective. MCT oil may be a promising treatment option.

A Rare Case of Capgras Syndrome in Moyamoya Disease.

Moyamoya disease is a rare cerebrovascular disorder with unknown etiology and psychiatric symptoms occasionally manifest initially. Capgras syndrome is a unique neuropsychiatric symptom that is a delusional misidentification of a familiar person replaced by an identical imposter. We report the case of a 51-year-old woman with frontal lobe ischemic stroke caused by moyamoya disease, presenting with Capgras syndrome. Dysfunction of frontal areas may be attributable to development of Capgras syndrome.

Cerebral Sinovenous Thrombosis and Subdural Hematoma as Treatment-Related Complications in Suprasellar Germ Cell Tumor Associated with Adipsic Diabetes Insipidus.

Cerebral sinovenous thrombosis (CSVT) is a rare but not a negligible complication in pediatric brain tumor. An 11-year-old male with suprasellar germ cell tumor developed treatment-related vascular complications of CSVT and subdural hematoma. The underlying mechanism of CSVT was attributed to multiple risk factors, such as adipsic diabetes insipidus, obesity, central apnea, and chemotherapy-induced endothelial injury. In an attempt to minimize the possible risk of vascular complications, including late effect in pediatric brain tumors, we would like to stress the importance of individualized supportive therapy, i.e., hormone replacement, fluid management, thromboprophylaxis, and bi-level positive airway pressure therapy.

[Cerebral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein (MOG) antibody].

A 27-year-old man developed acute encephalitis with headache, fever, seizures, and aphasia. Analysis of cerebrospinal fluid showed elevated levels of cell counts and protein. A brain MRI demonstrated increased FLAIR signals in the left cerebral cortex with cortical swelling. An MRA also showed mild vasodilatation of the left middle cerebral artery branches. After admission, severe psychomotor excitement developed. Immunotherapy with intravenous high-dose steroid and subsequent oral steroid was successful, and the patient returned to premorbid working position. Repeated MRI study showed complete resolution. Serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody was positive, while anti-aquaporin-4 antibody, anti-N-methyl-D-aspartate (NMDA) receptor antibody, and other autoimmune antibodies were all negative. There were no relapses at final follow-up of 8 months after onset. Cerebral cortical encephalitis with unknown etiology can occur associated with anti-MOG antibody, and anti-MOG antibody may play certain role in the pathogenesis.

Adult-onset Krabbe disease presenting with an isolated form of peripheral neuropathy.

INTRODUCTION: Adult-onset Krabbe disease is clinically rare and usually affects the pyramidal tracts in the central nervous system. Patients develop a spastic gait, and peripheral neuropathy sometimes occurs simultaneously. METHODS: A 55-year-old woman with consanguineous parents developed slowly progressive, asymmetric muscle weakness and atrophy in her forearms, while her ability to walk remained unaffected without pyramidal tract signs after onset at age 51 years. RESULTS: Nerve conduction studies demonstrated an asymmetric demyelinating-type peripheral neuropathy, and sural nerve biopsy documented reduced myelinated nerve fiber density with uniformly thin myelin sheaths, suggesting hypomyelination. Brain MRI demonstrated minor white-matter injury along the optic radiations, which was associated with asymptomatic, mild, prolonged latency on visual evoked potentials. Laboratory analysis documented low enzyme activity of galactocerebrosidase (GALC) and a known mutation of the GALC gene. CONCLUSION: Isolated peripheral neuropathy occurs very rarely in adult-onset Krabbe disease. Muscle Nerve 54: 152-157, 2016.

Intravenous tissue plasminogen activator for an ischemic stroke with occult double primary cancer.

BACKGROUND: In patients with advanced-stage cancer, systemic thrombolysis with tissue plasminogen activator (tPA) for hyperacute ischemic stroke is not strictly off-label, but it is at higher risk of complications (including bleeding). CASE REPORT: A 71-year-old male with unrecognizable malignancy developed a hemispheric ischemic stroke and received intra-venous tPA within 4.5 h of onset, followed by anticoagulation treatment after 24 h of throm-bolysis. Two days later, the patient had tarry stool and progressive anemia, receiving a blood transfusion. The systemic workup documented the presence of double primary cancers with advanced stage gastric and rectal cancers, and the patient subsequently received palliative care. The outcome at 3 months was a modified Rankin Scale of 5, and the patient died 6 months after the stroke. DISCUSSION: Although systemic thrombolysis with tPA for ischemic stroke in patients with advanced-stage cancer may be performed relatively safely, optimal post-thrombolysis management is important to prevent the complications.

[Cervical retro-odontoid pseudo-tumor treated with posterior decompression surgery].

A cervical retro-odontoid pseudo-tumor, which is considered as a reactive fibrocartilaginous mass, is a rare condition in cervical myelopathy. A 63-year-old male, with repeated neck axial movements by a long-term leisure-time cycling, developed subacute myelopathy. Cervical MRI showed a mass lesion at the retro-odontoid region, compressing to the upper spinal cord. After detailed systemic and local examinations that ruled out primary or metastatic malignancy and inflammatory disorders such as rheumatoid arthritis or chronic kidney diseases, a retro-odontoid pseudo-tumor was diagnosed clinically. The patient underwent posterior C1-laminectomy without tumor resection and its pathological confirmation. After the surgery, his neurological signs of cervical myelopathy improved, and a follow-up MRI one year later showed a mild reduction of the tumor size. The neuro-physicians should recognize the relatively benign pseudotumor in cervical myelopathy, because the tumor size usually shows no further enlargement or regression only after decompression surgery without tumor resection.

[Endogenous endophthalmitis and meningo-encephalitis in septic bacteremia of Klebsiella pneumoniae].

Endogenous endophthalmitis may be a rare condition in acute meningo-encephalitis. A 69-year-old compromised adult abruptly developed septic bacteremia and meningo-encephalitis by Klebsiella pneumoniae. After an improvement from initial conscious disturbance and systemic inflammatory unstable vital conditions by treatment of intensive antibiotic medications, severe unilateral endogenous endophthalmitis with impaired visual acuity was diagnosed by detailed ophthalmological assessments and it deteriorated rapidly. After early vitreous surgery with anti-biotic direct injection, the patient successfully regained visual acuity of 20/200. Among the organisms of endogenous bacterial endophthalmitis, Klebsiella pneumoniae is the worst pathogen mostly resulting in vision loss or enucleation despite any aggressive treatments. The neuro-physicians should recognize the presence of refractory endophthalmitis by Klebsiella pneumoniae, even if clinically asymptomatic, because prompt ophthalmologic diagnosis and managements may improve the outcome.

Reversal of large ischemic injury on hyper-acute diffusion MRI.

Reversal of early ischemic injury on diffusion-weighted MRI (DWI) occurs rarely. In a stroke patient who abruptly developed stupor and left hemiparesis, DWI scanned 78 min after onset demonstrated a large ischemic injury in the right hemisphere with a DWI-ASPECTS (Albert Stroke Program Early Computed Tomography Score) of 5 points, although baseline brain CT was perfectly normal. MR angiography (MRA) showed an occlusion of the right middle cerebral artery trunk, and the patient received intravenous thrombolysis 105 min after onset. A second MRA 30 h later showed complete vessel recanalization, and DWI demonstrated a perfect reversal of the initial large ischemic injury, associated with very small thrombus-fragmented cortical surface infarctions. Outcome at 3 months was a modified Rankin Scale score of 0, and the fluid-attenuated inversion recovery image showed only a small final infarction at the cortical surface. Hyper-acute DWI-defined large ischemic injury may very rarely represent a nearly perfect reversible area, and it may be a therapeutic target.

Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

[Three cases of small brain infarction in the lateral wall of the fourth ventricle presenting with paroxysmal positional vertigo and vomiting].

A lesion responsible for central paroxysmal positional vertigo (PPV) is often found in the dorsolateral wall of the fourth ventricle. A relatively large tumor or hemorrhage in the dorsolateral wall of the fourth ventricle usually causes central PPV, but small brain infarction has hardly been reported to cause central PPV. We report three cases of a small brain infarction in the lateral wall of the fourth ventricle presenting with central PPV. All of the cases showed similar clinical features in which a given recumbent position and a sitting position caused a dizziness associated with nausea and vomiting over an acute period. The symptom lasted one to two months after the onset. In two of our cases, no neurological abnormal signs, except nystagmus, were observed, and initial differentiation of central PPV from peripheral PPV was difficult. Interruption of the vestibular nuclei-archicerebellar loop seems to be responsible for the central PPV. Recognition of the clinical features of central PPV and diffusion-weighted MRI images are important for a precise local diagnosis in small brain infarction showing PPV.

[A case of adult-onset Huntington disease presenting with spasticity and cerebellar ataxia, mimicking spinocerebellar degeneration].

We report an adult-onset case of Huntington disease presenting with spasticity and cerebellar ataxia. The patient, a 47-year old woman, was admitted to our clinic because of progressive involuntary movements. Her elder brother suffered from the similar symptoms. Neurologically, she had quick temper, dementia, generalized chorea, spasticity and truncal ataxia. MRI demonstrated atrophy of caudate, midbrain, pons and cerebellum. From these clinical and MRI findings, she was suspected to have a form of spinocerebellar degeneration (SCD), particularly DRPLA. However, DNA analysis showed CAG repeats in huntington gene was expanded (47/20). Accordingly she was diagnosed as having adult-onset Huntington disease, mimicking SCD. This case indicates Huntington disease may present atypical clinical features and it is crucial to determine CAG repeat size in huntington gene for the patient with dementia and/or movement disorders, etiology of which is unknown. The relationships between clinical phenotypic variations and huntington gene expression are not determined.