Wilson disease (novel ATP7B variants) with concomitant FLNC-related cardiomyopathy.

We report a case of Wilson disease (WD) with dilated cardiomyopathy in which whole-genome sequencing (WGS) revealed the rare co-occurrence of two novel compound heterozygous ATP7B pathogenic variants (NM_001005918.3:c.2250del/p.N751Tfs*9 and c.3496C>T/p.L1166F) and a known FLNC pathogenic variant. Our results highlight the usefulness of WGS, even in the diagnosis of well-characterized genetic diseases such as WD.

Nelarabine-induced myelopathy in patients undergoing allogeneic hematopoietic cell transplantation: a report of three cases.

Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.

The Utility of Automated ASPECTS in Acute Ischemic Stroke for Intravenous Recombinant Tissue Plasminogen Activator (IV-rtPA) Therapy.

PURPOSE: This study aimed to investigate the accuracy and clinical significance of an artificial intelligence (AI)-based automated Alberta Stroke Program Early Computed Tomography (ASPECT) scoring software of head CT for the indication of intravenous recombinant tissue plasminogen activator (rt-PA) therapy. METHODS: This study included two populations of acute ischemic stroke: one comprised patients who had undergone head CT within 48 h of presentation (Population #1, n = 448), while the other included patients within 4.5 h from onset (Population #2, n = 132). The primary endpoint was the concordance rate of ASPECTS of the neurologists and AI software against the benchmark score. The secondary endpoints were to validate the accuracy of the neurologist and AI software in assessing the ability to rule out extensive infarction (ASPECTS of 0-5) in population #2. RESULTS: The reading accuracy of AI software was comparable to that of the board-certified vascular neurologists. The detection rate of cardiogenic cerebral embolism was better than that of atherothrombotic cerebral infarction. By excluding extensive infarction, AI-software showed a higher specificity and equivalent sensitivity compared to those of experts. CONCLUSIONS: The AI software for ASPECTS showed convincing agreement with expert evaluation and would be supportive in determining the indications of intravenous rt-PA therapy.

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

The ASCOD Phenotyping of Embolic Strokes of Undetermined Source.

BACKGROUND AND PURPOSE: Various pathogenesis are presumed to be involved in the etiology of embolic stroke of undetermined source (ESUS), which has a high recurrence rate, and much remains unknown about the clinical subtype of recurrent stroke. The purpose of this study was to clarify the pathogenesis of ESUS using the ASCOD classification for ESUS patients and to examine the factors involved in the recurrence of ischemic stroke. METHODS: The subjects of this study were 236 of these patients who fulfilled the criteria for ESUS. The rate of stroke recurrent, subtype of recurrent ischemic stroke, and new-onset atrial fibrillation (AF) in these patients were surveyed retrospectively, and each patient was graded for the A, S, and C categories of the ASCOD classification. RESULTS: Ischemic stroke recurred in 32 patients during the follow-up period (7 days to 12.9 years [median 54.3 months]), and new-onset AF was seen in 44 (18.6%) patients. The most subtype of recurrent ischemic stroke was ESUS again (19 patients). Multivariate analysis with a Cox proportional hazards model, the S score (hazard ratio 5.21; 95% confidence interval (CI) 2.38-11.42; P < .001) and the number of A, S, C categories (hazard ratio 1.90; 95% CI 1.14-3.10; P = .013) were factors significantly related to recurrent ischemic stroke. CONCLUSIONS: Assessment of comorbid conditions in ESUS patients based on the ASCOD classification may be useful in predicting the likelihood of recurrence of ischemic stroke.

A case of cerebral infarction during a hemodialysis procedure successfully treated with recombinant tissue plasminogen activator.

Thrombolytic therapy is an effective treatment for acute ischemic stroke and provides benefits and improvements that lead to better neurological outcomes. However, thrombolytic therapy with recombinant tissue plasminogen activator (r-tPA) in hemodialysis (HD) patients is limited because HD patients have a higher risk of bleeding. We report a case of a 75-year-old HD patient who presented with sudden aphasia during HD treatment. She was brought to the hospital for treatment for infarction. Following thrombolytic therapy, we achieved re-opening without complications. To our knowledge, no report has been published describing the patients who had a stroke during a maintenance HD session and were treated with r-tPA successfully. Although the number of HD patients treated with r-tPA is small and requires further investigation, thrombolytic therapy can be an alternative option. After weighing the risks and benefits and assessing each patient carefully, the use of r-tPA should be considered, even in HD patients.

Nonbacterial Thrombotic Endocarditis Complicated by Cerebral Infarction in a Patient with Adenomyosis with High Serum CA125 Level; A Case Report.

We report a case of a 48-year-old woman with multiple cerebral infarctions caused by nonbacterial thrombotic endocarditis (NBTE) because of adenomyosis with high serum carbohydrate antigen (CA)125 level. Transesophageal echocardiography (TEE) showed a vegetation, 4 mm in diameter, adjacent to the anterior leaflet of the mitral valve on day 2. Soluble CA125 level was elevated to 901 U/mL. Intravenous infusion of unfractionated heparin sodium was started. On day 35, TEE revealed reduction of the vegetation in size, 2 mm in diameter. On day 38, she was transferred to the hospital for further rehabilitation. CA125 is a transmembrane mucin that contributes to the progression of epithelial ovarian cancer. It is important to keep in mind that adenomyosis with abnormally high serum CA125 level may be at high risk of NBTE.

Nerve conduction study of lower extremities in cutaneous arteritis patients with neurological manifestations.

Some patients originally diagnosed with cutaneous arteritis (CA) could develop additional disease manifestations, including peripheral neurological involvement. We evaluated the biological neurological parameters among CA patients who underwent nerve conduction studies for neurological involvement in the lower extremities. We reviewed 164 patients who were originally diagnosed with CA at our dermatology department between 2004 and 2015. Seventeen (10.4%) of the CA patients underwent further nerve conduction studies to determine their peripheral neurological manifestations, primarily in the lower extremities, in our neurology division. The frequency of low compound muscle action potential (CMAP) was significantly higher compared with that of delayed latency in both the peroneal nerve and sural nerve based on nerve conduction studies. The frequency of low CMAP was significantly higher compared with that of prolonged distal latency in both the peroneal and sural nerves. We suggest that impairment of the nerve axon pathways in the peroneal and sural nerves could result in the peripheral neurological manifestations in the lower extremities in CA patients.

Reversible Cerebral Vasoconstriction Syndrome Presenting with Transient Global Amnesia.

A 65-year-old man who had been diagnosed with transient global amnesia (TGA) 15 years previously was admitted to hospital with complaints of amnesia and headache. His symptoms improved on day-2. The initial brain MRI and electroencephalography findings were normal. He was diagnosed with a recurrence of TGA and discharged. However, he returned with right leg weakness and complained of a thunderclap headache. MRI demonstrated subarachnoid hemorrhage and multifocal segmental narrowing of the left posterior cerebral artery (PCA) and large intracranial arteries, and he was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS). He was discharged on day-30 without any neurological deficits. This case suggested that TGA should be interpreted as one of the symptoms of RCVS or a prodromal symptom of RCVS.

Mononeuritis multiplex in a patient with cutaneous arteritis diagnosed by skin biopsy.

A 55-year-old man was admitted with paralysis of the left lower leg. He had purpura in the left lower extremity for three years, left calf pain for two years, and dysesthesia in the left plantar region and first toe for one year. A physical examination revealed livedo reticularis on the left leg and mononeuritis multiplex was diagnosed in the bilateral tibial and left peroneal nerve area. Anti-neutrophil cytoplasmic antibody was negative. A nerve conduction study showed decreased amplitude of compound muscle-action potential in the bilateral tibial and the left peroneal nerve, sensory nerve action potential in the bilateral sural nerve. A skin biopsy revealed inflammatory cells on blood vessel walls and cutaneous arteritis was diagnosed. Cyclophosphamide pulse therapy with steroid and anti-coagulation improved the neurological symptoms. A skin biopsy should be considered when patients present with mononeuritis multiplex in the lower extremities and cutaneous findings such as livedo reticularis in the symptomatic area.

Association between inflammatory biomarkers and progression of intracranial large artery stenosis after ischemic stroke.

BACKGROUND: Proinflammatory state has been implicated as a pathogenetic mechanism in the progression of intracranial large artery atherosclerosis (ILA). High levels of inflammatory biomarkers in healthy populations and in patients with acute stroke or acute coronary syndrome are known to be associated with subsequent stroke events. This study investigated the relationship between circulating biomarkers measured early after stroke onset and future ILA progression. METHODS: In 48 patients with acute ischemic stroke, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), IL-18, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2 and MMP-9 were measured within 48 hours after onset. Baseline severity and ILA progression were assessed by serial magnetic resonance angiography (MRA). The median follow-up period for MRA was 3.1 years. Hazard ratio (HR) was calculated using the Cox proportional hazard model adjusted for traditional risk factors, and accuracy of predicted ILA progression was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: ILA progression was observed in 6 of 48 patients (12.5%). After adjusting for age, sex, and presence of hypertension, baseline ILA severity score (HR 2.814; 95% confidence interval [CI] 1.172-6.754) and IL-6 (HR 1.215; 95% CI 1.002-1.473) were significantly associated with ILA progression. Area under the ROC curve (AUC) for prediction of ILA progression by traditional risks, baseline ILA severity score and IL-6, was 0.647. When IL-6 was removed from this model, AUC remained at 0.631. CONCLUSIONS: In addition to traditional risk factors and baseline radiologic findings, circulating levels of IL-6 measured soon after stroke onset are associated with future ILA progression.

Effects of edaravone, a free radical scavenger, on serum levels of inflammatory biomarkers in acute brain infarction.

The potent free radical scavenger edavarone is widely used in Japan to treat acute ischemic stroke within 24 hours after onset. Recent experimental studies have shown that edavarone alleviates blood-brain barrier disruption in conjunction with suppression of the inflammatory reaction in acute brain ischemia. We investigated the effects of edaravone on circulating inflammatory biomarkers in patients with ischemic stroke. Patients with acute ischemic stroke admitted 12-36 hours after onset of symptoms were prospectively enrolled. Intravenous edaravone at 60 mg/day for 14 days was administered to patients admitted 12-24 hours after symptom onset (edaravone group; n = 29). Patients admitted 24-36 hours after onset served as controls (control group; n = 34). Venous blood samples were obtained on admission and at 48 hours, 7 days, and 14 days after symptom onset. Serum concentrations of high-sensitivity C-reactive protein, interleukin (IL)-6, IL-10, IL-18, tumor necrosis factor α, matrix metalloproteinase (MMP)-2, and MMP-9 were measured. General linear models were used to compare changes in concentrations of these biomarkers over time between the groups. In the control group, the mean MMP-9 concentration increased gradually from 3.857 ± 1.880 ng/mL to 4.538 ± 1.966 ng/mL over the 14-day period (P = .027, one-way repeated-measures analysis of variance [ANOVA]), but the edavarone group demonstrated no such increase (P = .564). A significant group-time interaction was demonstrated only for MMP-9 (P = .029, two-way repeated-measures ANOVA), and no significant differences in other biomarkers were seen between groups. Our data indicate that edaravone suppresses serum MMP-9 level in patients with acute ischemic stroke. Further studies with a larger sample size are needed to explore the relationship between circulating MMP-9 level and the protective effect of edaravone.

[Effects of early statin treatment on inflammatory biomarkers and clinical deterioration in patients with acute ischemic stroke].

We prospectively studied the effects of early statin treatment on stroke-induced changes in the levels of inflammatory biomarkers. Patients admitted within 48 hours after the onset of ischemic stroke were enrolled. They were divided into 2 groups according to their lipid profiles and history of statin treatment. In patients who had received statin treatment prior to admission and those who had abnormal lipid profiles on admission, daily treatment with 10 mg atorvastatin was initiated within 48 hours after the onset of stroke (Statin group; n = 45). In patients who had normal lipid profiles on admission, statin was not administered for at least 2 weeks after admission (Non-Statin group; n = 101). The serum concentrations of interleukin (IL)-6, IL-10, IL-18, matrix metalloproteinase (MMP)-2, MMP-9, and high sensitive C-reactive protein were measured on days 1, 3, 7, and 14. In percentage changes in serially measured circulating IL-6 levels, a significant interaction between group and repeated measures (group X time factor) was demonstrated (p = 0.047). Frequency of neurological deterioration episodes (NIHSS score > or = 2) during 14 days after admission was lower in the Statin group than in the Non-Statin group, however the difference did not reach statistically significant level (7.9% vs 20.2%, p = 0.118). The initiation of usual dose of atorvastatin early after the onset of ischemic stroke significantly decreased the elevation of IL-6 and may protect against the early neurological deterioration. Circulating levels of IL-6 may be one of the candidates for monitoring the acute effects of statin. Further studies wherein IL-6 levels are monitored in larger samples would be feasible for investigating the effect of early treatment with usual dose of atorvastatin on the functional outcome.

Listeria endocarditis with acute thoracoabdominal aortic dissection.

The patient was 71-year-old male under treatment at a clinic for hypertension, aortic regurgitation, alcoholic hepatitis and dental treatment. He mainly complained fever and anorexia. Since blood culture examination revealed Listeria monocytogenes and echocardiography exhibited vegetation at the mitral leaflet, the patient was diagnosed as infective endocarditis. Fever and inflammatory reaction were improved after penicillin administration; however, he had fever on the 24th hospital day. CT revealed type IIIb acute thoracoabdominal aortic dissection which was not observed on admission. The blood pressure was controlled with antihypertensive agents. He could leave the hospital on the 61st day.