[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 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.

Brain imaging modality before systemic thrombolysis for ischemic stroke within three hours.

OBJECTIVE: In Japan, MRI-based thrombolysis after CT screening is the most common imaging strategy prior to intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA) within 3 h after ischemic stroke. A choice of MRI with MR angiography (MRA) provides a higher diagnostic accuracy, but may delay an initiation of thrombolysis. METHODS: In our neuro-unit, brain CT is the first screening image for suspected stroke. We retrospectively examined a delay to thrombolysis, imaging modality, diagnostic accuracy, and clinical outcomes at 3 months by the modified Rankin Scale in patients receiving IVT within 3 h. RESULTS: Among 67 patients receiving IVT with tPA, brain imaging prior to IVT was solely CT in 10 (15%) patients and CT + MRI/MRA in 57 (85%) patients. Final diagnosis of brain ischemia was 100%. Patients receiving CT + MRI had significantly shorter pre-hospital delay (mean 54 vs. 83 min; p = 0.012), but longer door-to-needle time (mean 90 vs. 57 min; p = 0.019) than those receiving CT only. Finally, time from onset to thrombolysis was not different between the two groups and clinical outcomes were also comparable. The earlier patients arrived, the longer door-to-needle times were (p < 0.001). CONCLUSIONS: The imaging strategy of initial CT screening with optional MRI/MRA scans prior to IVT was feasible. However, it resulted in an additional 30 min in-hospital delay of tPA administration, which may affect clinical outcomes.

Unruptured Cerebral Aneurysm Detected after Intravenous Tissue Plasminogen Activator for Stroke.

Therapeutic guidelines of intravenous thrombolysis with tissue plasminogen activator (tPA) for hyperacute ischemic stroke are very strict. Because of potential higher risk of bleeding complications, the presence of unruptured cerebral aneurysm is a contraindication for systemic thrombolysis with tPA. According to the standard CT criteria, a 66-year-old woman who suddenly developed aphasia and hemiparesis received intravenous tPA within 3 h after ischemic stroke. Magnetic resonance angiography during tPA infusion was performed and the presence of a small unruptured cerebral aneurysm was suspected at the anterior communicating artery. Delayed cerebral angiography confirmed an aneurysm with a size of 7 mm. The patient did not experience any adverse complications associated with the aneurysm. Clinical experiences of this kind of accidental off-label thrombolysis may contribute to modify the current rigid tPA guidelines for stroke.

Post-licensed 1-year experience of systemic thrombolysis with tissue plasminogen activator for ischemic stroke in a Japanese neuro-unit.

OBJECTIVE: In Japan, intravenous thrombolysis with tissue plasminogen activator (tPA) for ischemic stroke within 3h of onset was officially approved in October 2005. METHODS: We report initial 1-year clinical experience of intravenous alteplase at 0.6mg/kg in a Japanese neuro-unit. RESULTS: Twenty patients received intravenous tPA, corresponding to 12% of all ischemic strokes (n=166) and 38% of ischemic strokes within 3h of onset (n=52). The mean age was 68 years old and 15% had pre-morbid dependency with modified Rankin Scale (mRS) of 3 or 4. The median baseline National Institute of Health Stroke Scale score was 19 points (range; 5-37). Average time from stroke onset to tPA delivery was 136 min (range; 87-180). Of 18 (90%) patients receiving pretreatment vascular imaging, 16 (80%) patients had a large arterial occlusion. At 3 months, excellent outcome with mRS of 0 or 1 was 25%, and good outcome with mRS of 0-2 was 35%. One patient (5%) developed symptomatic intracranial hemorrhage within 36 h. Mortality rate was 15%. CONCLUSIONS: Intravenous tPA within 3h was safe and feasible, and possibly effective in clinical practice. The higher stroke severity in our cohort precluded to compare the sufficient effectiveness with clinical trials. In Japan, a post-licensed national surveillance is currently under way.

The effect of weekends and holidays on stroke outcome in acute stroke units.

BACKGROUND AND PURPOSE: In almost all acute stroke units in Japan, staffing level is lower on weekends and holidays and rehabilitative services are provided only on weekdays. We sought to investigate the effects of low-volume care early after stroke resulting from weekends and holidays on the outcome of stroke. METHODS: Patients with completed stroke within 72 h of onset were prospectively registered by 10 acute stroke units in Japan. Main outcome measures were favorable outcomes as indicated by a score of 0-1 on the modified Rankin scale (mRS01) on their 21st hospital day and at discharge and case fatality during the hospital stay. Cox proportional hazardsmodels were used to identify the effects of weekday admission and a weekday ratio (a number of weekdays / total length of hospital stay, or 21 days if hospitalization was longer than 21 days) on the main outcome measures. RESULTS: In a total of 1,134 patients, Cox proportional hazards regression analyses demonstrated that the weekday admission was significantly associated with mRS01 at discharge (hazard ratio, HR: 1.385, 95% CI: 1.087-1.764) and case fatality (HR: 0.477, 95% CI: 0.285-0.798). In 858 patients with rehabilitative therapy, the weekday ratio was significantly associated with mRS01 at discharge (p = 0.014). Compared with the lowest tertile of weekday ratio (<66.6%), the highest tertile (>71.4%) was significantly positively associated with mRS01 at discharge (HR: 1.524, 95% CI: 1.053-2.206; p < 0.026). CONCLUSIONS: Weekday admission was an independent negative predictor of case fatality and a positive predictor of favorable outcome (mRS01) at discharge from acute stroke units. In patients with rehabilitative therapy, a reduction in the weekday ratio was also associated with unfavorable outcome, probably due to a reduction in multidisciplinary care.

Hospital cost of ischemic stroke and intracerebral hemorrhage in Japanese stroke centers.

BACKGROUND: In Japan, the healthcare expenditure has increased to 8.0% of the gross domestic products in 2001. Stroke care is costly. OBJECTIVE: To examine hospital costs and clinical outcomes of ischemic stroke (IS) and intracerebral hemorrhage (ICH) in Japanese stroke centers. DESIGN: A prospective non-interventional multi-center study. SETTING: Ten Japanese stroke centers. STUDY PERIOD: Fourteen months between October 2000 and December 2001. PATIENTS: Patients were those who were consecutively hospitalized with acute IS or ICH within 72 h of onset, excluding subarachnoid hemorrhage. Stroke was defined as focal neurological deficits lasting more than 24 h and the relevant lesions were to be confirmed by brain CT and/or MRI. METHODS: We examined demography, in-hospital cares, length of hospital stay, clinical outcomes at discharge, and direct hospital medical costs including physician's fees. The hospital medical cost data were collected from official hospital medical cost charts for reimbursement to the healthcare insurance systems. RESULTS: There were a total of 1113 patients with a mean age of 70 years, of whom 913 (82%) patients had an IS and 200 (18%) patients had an ICH. The 317 patients (28%) experienced a recurrent stroke. Patients with ICH had the higher baseline stroke severity, resulting in longer hospitalization (39 days for IS and 46 days for ICH; P<0.001), lower independence rate at discharge (55 and 40%; P<0.001), higher mortality rate (5 and 10%; P=0.03), and higher medical costs (US dollar 8662 and US dollar 10,260; P<0.001) than those with IS. Patients with recurrent stroke had significantly older age, higher stroke severity, and lower independence rate at discharge than those with first-ever stroke. The length of stay, in-hospital mortality, and hospital medical costs were similar among first-ever and recurrent strokes. In subtype of IS, patients with cardioembolic stroke had the worst neurological deficits, poorest outcomes, and highest medical costs. The hospital costs had a greatest association with length of stay. CONCLUSIONS: Stroke care is costly in Japan. ICH is more likely to impose substantial physical and economic burden than IS. Because the cares of both first-ever and recurrent stroke were costly, primary and secondary prevention of stroke is important on the healthcare aspects.

Hospital-based study of the care and cost of acute ischemic stroke in Japan.

BACKGROUND AND PURPOSE: To evaluate the current status of care and cost of acute ischemic stroke in Japan, we performed a hospital-based analysis at a tertiary emergency hospital with a 24-hour neurology-neurosurgery team and care unit. METHODS: During the 12-month period of October 2000 to September 2001, we collected data on 179 patients consecutively hospitalized with acute ischemic stroke within 7 days of onset. We examined demographic data, in-hospital care, length of hospital stay, outcome at discharge, and hospital costs. The medical cost data were collected from official hospital medical cost charts, which calculated direct medical costs for beds, staff, examinations, medications, and rehabilitation. RESULTS: The mean age was 70 years, and 69% were male. Hospital arrival was within 3 hours of onset in 30% of the patients. A history of stroke was present in 37%. The mean initial National Institutes of Health Stroke Scale score was 8.3 points (median, 6 points). Using the Trial of Org 10172 in Acute Stroke Treatment classification, 25% were lacunar, 27% were atherothrombotic, 33% were cardioembolic, and 15% were of unknown origin. All patients underwent neuroimaging studies during hospitalization; 96% and 92% underwent CT and MRI with MR angiography, respectively. Antithrombotic medications were given in 94%, none of whom received thrombolysis. A newly licensed neuroprotective agent, edaravone, was given in 16%. More than half of the patients (55%) were initially admitted to the neurological intensive care unit. Overall, 64% received in-hospital rehabilitation. Mean length of stay was 33 days. In-hospital mortality rate was 3%. On the modified Rankin Scale (mRS), 63% were independent (mRS, 0 to 2) and 34% were dependent (mRS, 3 to 5) at discharge. Two thirds of the patients (65%) went directly back home. The mean hospital cost per patient was $6887 ($209/d), of which 69% was attributable to the costs for beds and staff, 12% for medications, 7% for rehabilitation, 6% for imaging studies, 5% for laboratory examinations, and 1% for other costs. CONCLUSIONS: Despite the single hospital-based analysis, this study provided current, precise data on short-term inpatient care and costs of acute ischemic stroke in Japan. Because stroke often carries a permanent dependence, long-term cost-effective stroke care should be established.

[Dropped head plus syndrome; a case report].

We reported a patient with so-called "dropped head plus syndrome", a non-progressive myopathy characterized by striking neck extensor weakness followed by progressive limb weakness which is well controlled by azathioprine. This 74-year-old man complained of neck and shoulder fatigue followed by progressive neck extensor weakness over 7 months. On physical examination, neck extensor strength was 4/5 on the MMT scale, but the remainder of the neurological examination and blood tests were normal. Needle EMG showed myopathic changes in the right trapezius and biceps brachialis muscles. Without any treatment, he developed weakness of upper and lower limb muscles about 8 months later, and Gowers' sign was positive. Blood test and needle EMG was unchanged. Muscle biopsy of the left trapezius, deltoid and supraspinatus muscles disclosed nonspecific myopathic changes consisting of variation in fiber size with disorganized intermyofibrillar networks in all the fibers, and there were rimmed vacuoles in some fibers of the deltoid muscle. There was no change on corticosteroids, but there was a dramatic improvement with azathioprine and his muscle symptoms disappeared. We, therefore, made the diagnosis of "dropped head plus syndrome". This appears to be the first such case in Japan.