Masao Nagayama

Lipoprotein(a) and ischemic cerebrovascular disease in young adults.

Background and Purpose Serum lipoprotein(a) level is genetically determined and remains almost constant throughout life. Based on this property, we investigated the serum lipoprotein(a) levels of ischemic stroke patients in the chronic stage (mean period after stroke, 27 months) and its relation to the types of ischemic stroke. Methods We measured serum lipoprotein(a) levels in 101 patients with chronic ischemic stroke and 37 normal control subjects, taking the clinical profiles into consideration. Results Lipoprotein(a) levels in patients with atherothrombotic stroke were 28.0±19.6 mg/dL (mean±SD), which were significantly (P < .01) higher than those in patients with lacunar stroke and in normal control subjects (16.4±13.5 and 11.7±10.5 mg/dL, respectively). The lipoprotein(a) levels in patients with atherothrombotic stroke were significantly higher in the subgroup who were a younger age at onset: onset before age 50 years, 35.3±20.5; onset at age 50 to 59, 35.4±21.7; onset at age 60 to 69, 17.0±12.8; and onset at age 70 or older, 16.3±6.8 mg/dL (P < .01 for onset before age 50 versus 60 to 69 years or 70 years or older; P < .01 for onset at 50 to 59 years versus 60 to 69 years or 70 years or older). Serum lipoprotein(a) was significantly increased (40.2 ±20.1 mg/dL) in young adults with atherothrombotic stroke (onset at younger than age 45 years) compared with that in patients older than 45 years (P < .01). Conclusions We conclude that lipoprotein(a) is a genetic, independent, and critical risk factor for ischemic stroke, especially in young adults.

Comparison of the European and Japanese guidelines for the management of ischemic stroke.

Background: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding stroke, GLs have been published by national and international organizations in different languages, most frequently in English. Cerebrovascular Diseases published the European GLs for the management of ischemic stroke and transient ischemic attacks in 2003, with an update in 2008. At about the same time (in 2004), the first Japanese GLs for the management of stroke appeared in Japanese. The first English version of the updated Japanese GLs was published only in 2011 and included differently approved drugs and drug dosages as compared with other American or European countries. Methods: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs. Results: Aspects of major importance were surprisingly similar and hence did not need extensive interpretation. Other aspects of ischemic stroke management differed significantly, e.g. the dosage of recombinant tissue plasminogen activator approved in Japan is lower (0.6 mg/kg) than in Europe (0.9 mg/kg), which derived from different practices in cardiovascular treatment prior to the design of acute ischemic stroke RCTs. Furthermore, comedication with neuroprotective agents (edaravone), intravenous anticoagulants (argatroban) or antiplatelet agents within 1-2 days after stroke onset is recommended in Japan but not in Europe. For cardioembolic stroke prevention, a major difference consists in a higher international normalized ratio target (2.0-3.0) in younger subjects versus in those >70 years (1.6-2.6), without age restrictions in Europe. Conclusion: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe.

Fatal familial insomnia with a mutation at codon 178 of the prion protein gene First report from Japan

Fatal familial insomnia (FFI), or familial selective thalamic degeneration with a mutation at codon 178 of the prion protein (PrP) gene, is a rapidly progressive autosomal dominant disease characterized by progressive insomnia, dysautonomia, and myoclonus.We report here the clinical and postmortem findings as well as genomic analysis in a first non-Western case with FFI. This patient also clinically had cognitive impairments such as memory disturbance, delirium, and hallucinations, along with insomnia, dysautonomia, and myoclonus. This case implies a worldwide distribution of FFI and also highlights the need for more aggressive clinical application of genomic analysis of the PrP gene and polysomnographic study in patients with insomnia and cognitive impairments. NEUROLOGY 1996;47: 1313-1316

Post-ischemic delayed expression of hepatocyte growth factor and c-Met in mouse brain following focal cerebral ischemia.

We investigated long-term changes in the expression of protein and mRNA of hepatocyte growth factor (HGF) and its receptor c-Met in mouse brain after permanent occlusion of the middle cerebral artery, by using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. HGF-immunopositive cells were observed in the periinfarct region from 4 days after occlusion, peaking at 14-28 days. The area containing HGF-immunopositive cells continued to expand until 28 days after occlusion. c-Met-immunopositive cells were observed exclusively at the periinfarct region at 7 and 14 days after occlusion. At 28 days after occlusion, there were many c-Met-immunopositive cells in the widespread periinfarct region. Triple immunohistochemical staining by using confocal laser scanning microscopy (CLSM) demonstrated that most of the HGF-immunopositive cells were localized to reactive astrocytes. The c-Met-immunopositive cells were also localized to reactive astrocytes. HGF mRNA was upregulated exclusively in the periinfarct region at 14 days. c-Met mRNA was upregulated in the periinfarct region from as late as 28 days after occlusion. Thus, HGF and c-Met show delayed expression in the periinfarct region at both protein and mRNA levels after induction of ischemia. Because HGF was recently shown to play critical roles in angiogenesis and neurotrophic activities, the temporal profiles of their expression may imply the involvement of HGF in the process of post-ischemic brain tissue repair.

Congenitally abnormal plasminogen in juvenile ischemic cerebrovascular disease.

Background and Purpose Congenitally abnormal plasminogen is characterized by markedly decreased fibrinolytic activity and has been reported mainly in association with venous occlusive disease. Case Description We found three young adult patients (34, 45, and 27 years old at onset) with ischemic cerebrovascular disease, all of whom had congenital plasminogen abnormalities but no other known risk factors. Hemostatic tests of all three patients revealed plasma plasminogen activities at almost one half of the normal level despite normal plasma plasminogen antigen levels. They were found to be heterozygotes with abnormal plasminogen (normal Ala-601[GCT] to abnormal Thr-601[ACT]) by DNA sequence analysis after polymerase chain reaction. Conclusions Congenital plasminogen abnormalities could be one of the risk factors of juvenile ischemic cerebrovascular disease of the arterial as well as venous type.

Postpublication External Review of the Japanese Guidelines for the Management of Stroke 2004

Background and Purpose— Many guidelines for management of stroke have been published throughout the world, but no postpublication external review of any set of stroke guidelines by users, using standard checklists, has been reported. The purpose of this article is to present the results of an external review of the Japanese Guidelines for the Management of Stroke 2004, conducted several months postpublication. Methods— Forty-one evaluators, who had not been involved in developing the guidelines, were selected from representative stroke centers and institutions in Japan. They consisted of 30 physicians including 22 stroke specialists, and 11 nurse practitioners. Three standard checklists, ie, Appraisal of Guidelines for Research and Evaluation (AGREE) instrument, checklist by Shaneyfelt et al, and the Conference on Guideline Standardization (COGS) checklist, were used. Results— Confidence ratios according to the AGREE checklist were 75%, 77%, and 86% for stroke specialists, physicians other than stroke specialists, and nurse practitioners, respectively. The average scores were 2.98, 3.13, and 3.29, respectively. The confidence ratios according to the checklist by Shaneyfelt et al were 72%, 73% and 86% respectively, and those for the COGS checklist were 66%, 74%, and 91%, respectively. Conclusions— Although it is impossible to compare our results with those for other stroke guidelines, because none of them has been externally reviewed by users postpublication, our results seem better than those for published guidelines for treatment of other diseases in Japan. These results should be helpful in the process of updating stroke guidelines in Japan and elsewhere.

Intravascular malignant lymphomatosis manifesting clinically as bilateral sudden hearing loss and cytomegalovirus encephalitis

A 49-year-old man developed bilateral sudden hearing loss followed by cerebral infarction and cytomegalovirus (CMV) encephalitis. Autopsy confirmed intravascular malignant lymphomatosis (IML). A literature review indicates that hearing loss can be the initial manifestation of IML and also that CMV infection is more than an opportunistic infection and may participate in the cognitive manifestations in IML.

Comparison of the European and Japanese guidelines for the acute management of intracerebral hemorrhage.

Background: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding intracerebral hemorrhage (ICH), Cerebrovascular Diseases published the 2006 European stroke initiative recommendations for the management of ICH. In 2009, the revised Japanese GLs for the management of stroke, including that of ICH, appeared in Japanese. Whereas GLs for the prevention and treatment of ischemic stroke were presented in detail, recommendations with regard to ICH are relatively rare both in Japan and Europe. Methods: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs. Results: Aspects of major importance were similar and hence did not need extensive interpretation, mostly due to a lack of evidence from appropriate RCTs worldwide. The target level to which systolic blood pressure should be lowered is quite high; <170 mm Hg for patients with known hypertension in Europe and <180 mm Hg in Japan. The results of ongoing clinical trials are awaited for the optimal target level and optimal medications. Concerning ICH associated with oral anticoagulant therapy, both guidelines give similar recommendations, namely that anticoagulation should be discontinued and the international normalized ratio of prothrombin time should be normalized with prothrombin complex concentrate or fresh-frozen plasma and additional vitamin K. Patients with ICH were treated surgically, often based on individual decisions - more frequently in Japan, depending on the association with hypertension. Patients with large or intraventricular bleedings were only treated if a life-saving performance was considered, irrespective of the neurological outcome. Infra- and supratentorial differences were similarly addressed in both GLs. Conclusion: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe.

Deep Venous Thrombosis after Intracerebral Hemorrhage, Gender and Ethnicity: A Challenge for Therapeutic Approaches

The authors speculate that the excess of DVT in women may be caused by the use of oral contraceptives or hormone replacement therapy, decreased muscle pumping, variations in hormone concentration, obesity and genetic features. The incidence of DVT in this study was much higher than the 3% of DVT in the placebo group of the Factor Seven for Acute Hemorrhagic Stroke trial [10] , but in line with another recent Japanese study, in which DVT was detected in 40.4% of patients with ICH after 2 weeks [11] . Differences in the ratio of complications between randomized clinical trials and the real world scenario could explain this discrepancy; however, in one report from a tertiary care center in the USA, the incidence of DVT was only 1.1% [12] . Although an alternative explanation for this excessive frequency of DVT may be less intense prophylactic measures in Asian patients, a recent study showed that Asians had a strong trend toward a higher risk of DVT (odds ratio = 3.22, p = 0.09) than Caucasians [13] . Analysis of the Antithrombotic Trialists’ Collaboration database disclosed that mechanical compression methods reduced the risk of DVT by about two thirds when used as monotherapy and by about half when added to a pharmacological method [14] . These benefits were similar irrespective of the particular method used (graduated compression stockings, intermittent pneumatic compression or foot pumps). Despite the existence of several clinical trials of DVT prevention in ischemic stroke, only two trials addressed the prophylaxis of DVT after ICH [15, 16] . A doubleblind randomized phase IV trial has started, assessing the safety and efficacy of enoxaparin (starting 24–48 h after the onset of ICH) in the prevention of venous thromboembolism [17] . Unfortunately, none of the trials above involved Asians. Based on the few randomized clinical trials mentioned above, international guidelines suggest that patients with acute primary ICH and hemiparesis/hemiplegia should have intermittent pneumatic compression for the prevention of DVT (class I or grade 1B recommendation) [18–20] . Optionally, after documentation of cessation of bleeding, low-dose subcutaneous low-molecular-weight heparin or unfractionated heparin may be considered in patients with hemiplegia after 2–4 days from onset (class IIb, grade 2C recommendation). Whether the safety of heparin in the acute phase of ICH can be extrapolated to Asians is unknown. Finally, the study of Kawase et al. [9] teaches us three important lessons: (1) DVT is common after ICH, and some patient characteristics (e.g. female sex, Asians) may put them in a higher risk category; (2) randomized clinical trials are needed and must include Asians, and (3) in the meanwhile, all ICH patients with hemiparesis/hemiplegia should receive intermittent pneumatic compression from the first day of admission, until the highestlevel evidence for standardization of the prophylaxis and acute management of DVT is obtained. Primary intracerebral haemorrhage (ICH) is estimated to affect over 1 million people worldwide each year [1] and is associated with the highest mortality rate, with a 1-month case fatality of 42% [2] . The incidence of ICH is higher in certain populations, including blacks/African Americans and Asians. Up to 40% of strokes in China are hemorrhagic [3] , and ICH represented 30% of strokes in one Japanese study [4] . Although the higher prevalence in blacks is attributed to hypertension, the reason for the excess of ICH in Asians is disputable (e.g. hypertension, low serum cholesterol, higher prevalence of alcohol use). Venous thromboembolism is an important cause of morbidity and mortality for patients in critically ill conditions. Without venous thromboembolism prophylaxis, up to 75% of patients with hemiplegia after stroke develop deep-vein thrombosis (DVT). Pulmonary embolism diagnosed at autopsy is present in a substantial proportion of patients with fatal stroke and accounts for about 10% of deaths after stroke, but is clinically evident in less than 2% of patients [5] . Patients with ICH may in fact be at higher risk for DVT than ischemic stroke patients [6] . A retrospective cohort study revealed a relative risk for clinical DVT after ICH of 4.0 (1.8 vs. 0.4%) [7] . The relative risk for pulmonary embolism was 3.5 (0.4 vs. 0.1%). Data comparing patients with ICH included in the International Stroke Trial with ischemic stroke patients also suggest an increased risk of clinical pulmonary embolism – 1.3 versus 0.7% (p = 0.06) – even after controlling for severity of the disease [8] . In this issue of the journal, Kawase et al. [9] report on the prevalence and variables associated with DVT in 81 Japanese patients with acute ICH. Using duplex ultrasonography, they found that, at 2 weeks, 21% of patients had DVT and that female sex was the only independent predictor for DVT, contrary to the findings from western countries. It is worth mentioning that neither intermittent pneumatic compression nor heparin were used. Patients with paralysis involving the legs were required to wear belowknee elastic stockings. Published online: February 14, 2009

Persistent but reversible coma in encephalitis.

AbstractIntroduction: Nontraumatic coma in adults has a poor prognosis, and late recovery of consciousness is unlikely. Functional recovery is usually extremely poor. However, a few nontraumatic comatose patients have shown late recovery of both awareness and function. Methods: A retrospective survey was conducted by reviewing the medical records of all inpatients to our department during the 1990s. Patients with persistent but reversible nontraumatic coma were identified according to the following criteria: (a) deep coma with a Glasgow Coma Scale (GCS) score of 7 or less on admission; (b) nontraumatic cause; (c) persistence of unconsciousness for longer than 1 month; and (d) subsequent recovery of GCS (total) to normal. The clinical spectrum of patients meeting these criteria was evaluated. Results: Six patients (ages 16–75 years) met the criteria. Viral encephalitis was diagnosed in five (two with herpes simplex virus, two with cytomegalovirus, and one with Epstein-Barr virus or cytomegalovirus). Two young female patients with encephalitis manifested extremely protracted coma persisting for 3 and 18 months, respectively. Complications included nonconvulsive status epilepticus in two patients and relative overdose of clonazepam in one patient. Conclusion: Recognition of the clinical spectrum of persistent but reversible nontraumatic coma is important.