Yoichi Ohnuki

Phase I Study of Intravenous Low-dose Granulocyte Colony-stimulating Factor in Acute and Subacute Ischemic Stroke

BACKGROUND Granulocyte colony-stimulating factor (G-CSF; filgrastim) may be useful for the treatment of acute ischemic stroke because of its neuroprotective and neurogenesis-promoting properties, but an excessive increase of neutrophils may lead to brain injury. We examined the safety and tolerability of low-dose G-CSF and investigated the effectiveness of G-CSF given intravenously in the acute phase (at 24 hours) or subacute phase (at 7 days) of ischemic stroke. METHODS Three intravenous dose regimens (150, 300, or 450 μg/body/day, divided into 2 doses for 5 days) of G-CSF were examined in 18 patients with magnetic resonance imaging (MRI)-confirmed infarct in the territory of the middle cerebral artery. Nine patients received the first dose at 24 hours poststroke (acute group) and 9 patients received the first dose on day 7 poststroke (subacute group; n = 3 at each dose in each group). A scheduled administration of G-CSF was skipped if the patients leukocyte count exceeded 40,000/μL. Patients received neurologic and MRI examinations. RESULTS We found neither serious adverse event, drug-related platelet reduction nor splenomegaly. Leukocyte levels remained below 40,000/μL at 150 and 300 μg G-CSF/body/day, but rose above 40,000/μL at 450 μg G-CSF/body/day. Neurologic function improvement between baseline and day 90 was more marked after treatment in the acute phase versus the subacute phase (Barthel index 49.4 ± 28.1 v 15.0 ± 22.0; P < .01). CONCLUSIONS Low-dose G-CSF (150 and 300 μg/body/day) was safe and well tolerated in ischemic stroke patients, and leukocyte levels remained below 40,000/μL.

A case of scrub typhus with acalculous cholecystitis, aseptic meningitis and mononeuritis multiplex.

We present an unusual case of a patient with scrub typhus who developed acalculous cholecystitis, aseptic meningitis and mononeuritis multiplex. The patient was successfully treated with oral minocycline. To our knowledge, this is the first report of mononeuritis multiplex caused by scrub typhus.

Cerebral Microbleeds on T2*-Weighted Images and Hemorrhagic Transformation after Antithrombotic Therapies for Ischemic Stroke

To assess the predictive value of cerebral microbleeds (CMBs) on gradient-echo T2*-weighted magnetic resonance imaging for hemorrhagic transformation (HT) after antithrombotic therapy for an acute ischemic stroke, we prospectively examined the relationship between CMBs on T2*-weighted images before the start of therapy and the appearance of HT in a series of patients treated with antithrombotic therapies. The subjects were consecutive acute ischemic stroke patients admitted to Tokai University Hospital (187 subjects, mean age±SD: 74±11 years). The prevalence of CMBs was not significantly different between the subjects with and without HT on computed tomography (CT) (19% versus 36%, P=.081). In both the subgroup of patients treated with anticoagulants and the subgroup treated with antiplatelets, the prevalence of HT was not significantly different between the subjects with and without CMBs (anticoagulants, 9% versus 21%, P=.161; antiplatelets, 0% versus 9%, P=.542). The odds ratios (ORs) of increasing the National Institutes of Health Stroke Scale score (1.14, 95% confidence interval [CI]: 1.04-1.26, P=.005) and decreasing the Alberta Stroke Program Early CT Score on diffusion-weighted images (ASPECTS-DWI) (1.32, 95% CI: 1.10-1.59, P=.003) were significantly increased for the appearance of HT, but the OR of CMBs (.35, 95% CI: .09-1.41, P=.140) was not significantly increased for the appearance of HT. In conclusion, the severity of neurological deficits and the ASPECTS-DWI are closely correlated to the development of HT related to anticoagulants/antiplatelets but not to CMBs on T2*-weighted images.

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome) Complicated by Perforation of the Small Intestine and Cholecystitis

We report a case of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) complicated by perforation of the small intestine and necrotizing cholecystitis. A 69-year-old man with a history of bronchial asthma was admitted with mononeuritis multiplex. The laboratory findings included remarkable eosinophilia. He was treated with corticosteroids and his laboratory indices showed improvement; however, his functional deficits remained. His neuropathy gradually improved after the addition of intravenous immunoglobulin (IVIG). He was subsequently treated with oral prednisolone (40 mg/day) as maintenance therapy. Within a month after finishing IVIG, he developed perforation of the small intestine and necrotizing cholecystitis. Intestinal perforation has often been reported as a gastrointestinal complication of EGPA. In contrast, cholecystitis is a rare complication. We report this case because the manifestation of more than one complication is extremely rare. Gastrointestinal symptoms may be a complication of EGPA itself and/or immunosuppressive treatment.

Dual Therapy with Aspirin and Cilostazol May Improve Platelet Aggregation in Noncardioembolic Stroke Patients: A Pilot Study

Objective Some previous studies have found clinical benefit of dual antiplatelet therapy with aspirin and cilostazol for prevention of secondary stroke, but the physiological mechanism involved remains unknown. We aimed to clarify the effects of aspirin/cilostazol therapy on the platelet and endothelial functions of patients with acute noncardioembolic ischemic stroke, in comparison to patients who were treated with aspirin alone. Methods The present randomized prospective pilot study enrolled 24 patients within a week after the onset of noncardioembolic ischemic stroke. The patients were randomly allocated to receive aspirin (100 mg/day) (A group; 11 patients) or cilostazol (200 mg/day) plus aspirin (100 mg/day) (CA group; 13 patients). We measured platelet aggregation, platelet activation, and the thrombomodulin (TM), highly sensitive C-reactive protein (hs-CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand (vWF) antigen levels and vWF activity over a 4-week period after enrollment. Results There was no significant difference in the platelet functions of the A and CA groups. However, the platelet aggregation induced by adenosine diphosphate (ADP) was decreased at 2 and 4 weeks (p<0.05) after treatment in comparison to the pre-treatment values in the CA group, but not in the A group. Platelet activation, and the hs-CRP, TM, ICAM-1, VCAM-1 and vWF values did not significantly decrease after treatment in either group. Conclusion Although there were no significant differences in platelet aggregation, platelet activation or the endothelial biomarker levels of the A and CA groups, dual therapy with aspirin and cilostazol inhibited platelet aggregation in comparison to the pre-treatment values, similarly to patients who received aspirin alone. This may suggest the clinical usefulness of dual therapy with aspirin and cilostazol in the treatment of patients with noncardioembolic ischemic stroke.

Acute Cerebellar Ataxia Induced by Nivolumab

A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment.

Trigeminal Neuropathy Accompanied by a Pontine Lesion on MRI

A 63-year-old man presented with the loss of the sensations of pain and temperature sensation in the right facial region innervated by the trigeminal nerve (V1 to 3). He showed abnormal lesions in the pons and the trigeminal nerve on magnetic resonance imaging (MRI). He had recurrent herpes in the nasal cavity, and a history of left facial palsy. We herein present the unique MRI findings and suggest that herpes simplex infection may cause trigeminal neuropathy. This is the first reported case of dissociated trigeminal neuropathy with herpes simplex infection which was accompanied by a pontine lesion on MRI.

Effect of atorvastatin co‐treatment on inhibition of platelet activation by clopidogrel in patients with ischemic stroke

Clopidogrel is used to achieve sustained platelet inhibition in ischemic stroke patients (1). 3-Hydroxy-3methylglutaryl-CoA reductase inhibitors also reduce the stroke events (2). We hypothesized that an interaction between clopidogrel and 3-Hydroxy-3methylglutaryl-CoA reductase inhibitors would decrease P2Y12 receptor and inhibit platelet activation by acting on lipid rafts (3,4). To test this idea, we evaluated the effect of coadministration of atorvastatin on the inhibition of platelet activation in ischemic stroke patients receiving clopidogrel. Twenty ischemic stroke patients (13 atherothrombotic, 7 lacunar; mean age 68 ± 12, 65% male) receiving clopidogrel with dyslipidemia were recruited. Written informed consent was obtained from all patients, and the study was approved by Tokai University Ethics Committee. Blood samples were taken before, and at twoweeks and two-months after the administration of 10-mg/day atorvastatin. PAC1, CD62P, and WBC-platelet complex were quantified by means of three-color flow cytometry, according to our previous reports (5–8). Coadministration of atorvastatin for two-months significantly reduced LDLcholesterol from 143 ± 26 to 92 ± 20 mg/dl (P < 0·01). No significant difference in PAC-1-positive platelets beyond the cutoff value was observed (Fig. 1a). However, the percentage of CD62Ppositive platelets beyond the cutoff value was significantly reduced by coadministration of atorvastatin for two-months, compared with clopidogrel alone (Fig. 1b, P < 0·05). The percentage of WBCplatelet complex beyond the cutoff value was also significantly reduced by coadministration of atorvastatin for twoweeks and two-months, compared with clopidogrel alone (Fig. 1c, P < 0·05). The suppression of CD62P may suggest that the translocation of P2Y12 receptors away from lipid rafts, due to reduction of lipid rafts by atorvastatin (4), inhibits platelet activation by suppressing adenylate cyclase activation via Gi (9). Further, WBC-platelet complex is associated with expression of P-selectin (CD62P), which mediates adhesion of platelets to leukocytes (10). Our results indicate that coadministration of atorvastatin in ischemic stroke patients receiving clopidogrel further enhances the inhibition of platelet activation.