Brain Perfusion Single-Photon Emission Computed Tomography Using an Easy Z-Score Imaging System Predicts Progression to Neurodegenerative Dementia in Rapid Eye Movement Sleep Behavior Disorder.

INTRODUCTION: Longitudinal studies have reported that patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) have an increased risk of developing synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies (DLB). Clinical trials of disease-modifying therapies for IRBD patients require suitable biomarkers that can predict the short-term onset of neurodegenerative dementia. METHODS: We retrospectively examined if easy Z-score imaging system-specific volume-of-interest analysis (SVA) using brain perfusion single-photon emission computed tomography (SPECT) imaging or the cingulate island sign score can predict the short-term development of neurodegenerative dementia in 30 patients with IRBD. RESULTS: Ten patients (33.3%) who exceeded the thresholds for three indicators (severity, extent, and ratio) were included in an SVA-positive group, while 20 (66.7%) were included in an SVA-negative group. Nine (30.0%) IRBD patients had phenoconversion, of which eight had DLB and one had Parkinson's disease with dementia. In Kaplan-Meier analysis, patients in the SVA-positive group converted to neurodegenerative dementia in a significantly shorter period of time compared to patients in the SVA-negative group. CONCLUSIONS: These data suggest that SVA-positive IRBD patients have an increased short-term risk of developing neurodegenerative dementia.

Analysis of Factors Associated with Progression and Long-Term Outcomes of Penetrating Artery Territory Infarction: A Retrospective Study.

BACKGROUND: Patients with penetrating artery territory infarction occasionally show progressive motor deficits during the acute stage with poor prognosis. Predictive indices or medical therapies for suppressing the symptomatic progression (SP) of penetrating artery infarction have not been established. In this study, we investigated SP-related clinical factors and functional outcomes, specifically improvement 3 months post ictus in patients with penetrating artery infarction. METHODS: We retrospectively examined acute stroke patients with penetrating artery infarction admitted at 7 collaborative hospitals. SP was defined as an increase by 1 point or higher in the National Institutes of Health Stroke Scale score. Functional improvement was assessed based on the modified Rankin Scale at 3 months. The influence of factors, such as patient characteristics, clinical data, medical treatment during the acute stage and on SP, and functional improvement was statistically analyzed. RESULTS: Four hundred eighty-eight patients (310 men; mean age, 70 years) were examined. Sixty-eight patients (14%) exhibited SP. Multivariate logistic regression analysis revealed that higher hemoglobin A1c (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.10-1.55), body mass index (BMI; OR, .85; 95% CI, .77-.94), and systolic blood pressure on admission (OR, 1.63; 95% CI, 1.19-2.25) were independent predictors of SP in penetrating artery infarction. Dual antiplatelet therapy (DAPT; OR, 3.48; 95% CI, 1.52-8.38) independently influenced functional improvement. CONCLUSIONS: Initial high blood pressure, diabetes, and low BMI on admission were associated with early progression of penetrating artery infarction. DAPT during the acute stage may contribute to functional improvement.

[Absence of cortical lesions after the first seizure in a patient with anti-myelin oligodendrocyte glycoprotein-associated cortical encephalitis].

A 31-year-old man developed headache and generalized convulsions. At the time of the first seizure, there was no distinct MRI abnormality. He was admitted to the hospital with repeated seizures, left-sided hemiparesis, and left-sided neglect. He had a slight fever, elevated cerebrospinal fluid (CSF) pressure, and increased CSF cell count with predominance of mononuclear cells. A repeat MRI scan on day 8 after the recurrent seizure showed cortical edema in the right cerebral hemisphere on fluid-attenuated inversion recovery (FLAIR), abnormal high signal on DWI, and decreased apparent diffusion coefficient. The patient was diagnosed with aseptic meningoencephalitis and treated with antiviral drugs and methylprednisolone pulse therapy. Serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody was subsequently detected, and prednisolone was added to treat the FLAIR-hyperintense lesions in anti-MOG antibody associated encephalitis with seizures (FLAMES). It is important to identify the clinical picture and typical images of FLAMES to allow early treatment.

[A case of primary progressive multiple sclerosis with improvement in cognitive impairment by anti-CD20 monoclonal antibody therapy].

The patient was a 44-year-old man who developed cognitive impairment beginning at the age of 35 years that gradually worsened. The cognitive impairment led to a difficult social life, and he retired from his company. After hospitalization and workup, he was diagnosed with primary progressive multiple sclerosis (PPMS) that presented only with cognitive impairment for 10 years. Since he had multiple predictive factors for poor prognosis, anti-CD20 monoclonal antibody therapy was implemented. Cognitive impairment and cerebral blood flow SPECT findings improved, and he returned to a social life 3 months later. Anti-CD20 monoclonal antibody therapy was effective in improving cognitive impairment in a case of an advanced stage of PPMS.

First Report of Klebsiella subsp. Ozaenae Meningitis in Japan.

Although the frequency of community-acquired infections caused by Klebsiella pneumoniae subsp. ozaenae (K. ozaenae) is low, they are often detected in sputum specimens. In addition, lung abscesses, necrotizing pneumonia, and urinary tract infections caused by K. ozaenae have also been reported. We herein report the first detection of K. ozaenae as an etiological agent of bacterial meningitis in Japan. Cases of K. ozaenae meningitis complicated by diabetes mellitus and sinusitis have been reported elsewhere. When Klebsiella pneumoniae is detected in such cases, it is important to use other detection methods in addition to mass spectrometry for correct identification.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

[A case of meningovascular syphilis presenting with bilateral oculomotor nerve palsy, cerebral aneurysm, and cerebral hemorrhage].

The patient was a 32-year-old man with no HIV infection and possible syphilis infection at the age of 22 years. At the age of 29 years, he visited an ophthalmologist for diplopia due to right oculomotor nerve palsy. He underwent diplopia strabismus surgery for unexplained oculomotor nerve palsy. At the age of 31 years, he had a left oculomotor nerve palsy and was referred to our department. He was diagnosed with neurosyphilis based on positive serum and cerebrospinal fluid syphilis antibodies. MRI showed aneurysm, asymptomatic cerebral hemorrhage, and contrast enhancement of the left oculomotor nerve, leading to the diagnosis of meningovascular syphilis. The patient's symptoms improved with penicillin and corticosteroids. The oculomotor nerve palsy may be due to microcirculatory disorder caused by syphilitic cerebral endarteritis.

Striatal dopamine transporter degeneration in right-handed REM sleep behavior disorder patients progresses faster in the left hemisphere.

OBJECTIVE: In right-handed patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) or Parkinson's disease (PD), dopamine transporter (DAT) single-photon emission computed tomography (SPECT) shows a predominant nigrostriatal deficit in the left striatum. To confirm this hypothesis, we longitudinally investigated whether the nigrostriatal function is asymmetric in Japanese patients with IRBD. METHODS: In 91 polysomnography-confirmed IRBD patients, which included 87 right-handed IRBD patients who underwent 33 repeat DAT-SPECT scans, we retrospectively examined the striatal dopaminergic terminals in each hemisphere using DAT-SPECT. We calculated the values of interhemispheric laterality index for the right and left sides. RESULTS: The proportion of IRBD patients with lower SBR in the striatum was different between the left (n = 60, 69.0%) and right (n = 27, 31.0%) hemispheres. In the repeat DAT-SPECT scan (n = 33), the rate of decline in the striatum was greater on the left than on the right side, and the proportion of patients with lower decline rates in the left striatum (n = 25, 73.5%) was greater than the that in the right striatum (n = 3, 8.8%). The proportion of lower SBR side at baseline did not predict the development of PD or DLB. CONCLUSION: Right-handed IRBD patients have asymmetric nigrostriatal dopaminergic function, as evidenced by the faster estimated rate of decline for the left striatum than the right striatum. The left-right hemispheric striatal predominance of the nigrostriatal deficit in the right-handed prodromal PD or DLB patients represents a difference in the early pathological process of the disease.

Reduced dopamine transporter binding predicts early transition to Lewy body disease in Japanese patients with idiopathic rapid eye movement sleep behavior disorder.

PURPOSE: We examined dopamine transporter (DAT) binding in Japanese patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) as a biomarker for the development of Lewy body disease (LBD). METHODS: [123I]FP-CIT SPECT (DAT-SPECT) scans of 74 IRBD patients were compared to those from healthy Japanese subjects, and the predictive value for conversion to LBD during a 5-year follow-up was evaluated. RESULTS: Baseline DAT deficits (Z-score ≤ -2.5) were observed in 25 (33.8%) of the IRBD patients. During follow-up, 25 patients (33.8%) developed LBD [19 Parkinson's disease and 6 dementia with Lewy bodies], with a mean latency of 2.4 ± 1.6 years from imaging. The receiver operating characteristics curve revealed that the Z-score of baseline DAT binding in the striatum of abnormal DAT-SPECT patients who later developed LBD differed from those who remained disease-free. Kaplan-Meier survival analysis showed an increased risk of LBD in patients with a Z-score ≤ -2.5 for DAT binding in the striatum of abnormal DAT-SPECT patients compared to patients with a Z-score > -2.5. CONCLUSIONS: DAT-SPECT identifies IRBD patients at short-term risk for developing LBD. Decreased DAT binding in the striatum (Z-score ≤ -2.5) predicts development of LBD within 5 years, and may be useful in future disease-prevention trials in IRBD patients.

[Cryptococcal meningoencephalitis in an immunocompetent patient caused by late onset exacerbation].

The case was a 29-year-old male with no previous history of serious disease. He developed headache and fever, which then worsened and he was admitted to our hospital. His temperature was 38.3°C and he had a stiff neck. In cerebrospinal fluid (CSF) tests, the opening pressure was high, the cell count was increased, and the CSF/serum glucose ratio was decreased. In addition, he was positive for cryptococcal antigen. According to these findings, he was diagnosed with cryptococcal meningoencephalitis and antifungal treatment was initiated. His symptoms then improved, but on day 18 after admission, he developed convulsions, and on day 28, right visual field defects appeared. Brain MRI showed disseminated lesions in the bilateral cerebral cortex. Despite a decrease of the cryptococcal antigenic value in the CSF, the IgG index was elevated. IL-6, 8 and 10 in CSF were high levels on Day 1, then gradually reduced as the symptoms improved. But on Day 28, worsening of symptoms, IL-10 was significantly increased dispite IL-6 and 8 reducing. Therefore, the exacerbation of his symptoms and expansion of the lesions were not caused by the Cryptococcus itself, and it was considered that they were due to the late deterioration of cryptococcosis, which responded to steroid treatment.

Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan.

CYP2C9, a drug-metabolizing enzyme, converts the angiotensin II receptor blocker losartan to its active form, which is responsible for its antihypertensive effect. We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients under treatment with losartan. Of two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance toward diclofenac when expressed in a baculovirus-insect cell system, while the Arg335Gln variant had no substantial effect. Several known missense variations were also found, and approximately 7% of the Japanese individuals (53 out of 724) carried one of the deleterious alleles (CYP2C9*3, *13, *14, *30, and Arg132Gln) as heterozygotes. After 3 months of losartan treatment, systolic blood pressure was not lowered in two patients with CYP2C9* 1/*30, suggesting that they exhibited impaired in vivo CYP2C9 activity. CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan.

High Incidence of Deep Vein Thrombosis in the Perioperative Period of Neurosurgical Patients.

INTRODUCTION: A prospective study was designed to elucidate incidence and predictors of deep venous thrombosis (DVT) in patients undergoing craniotomies. MATERIALS AND METHODS: Ninety-two patients who underwent craniotomies received pre- and postoperative venous ultrasonography and/or contrast-enhanced spiral computed tomography for diagnosis of DVT. The primary endpoint was DVT occurrence. Serial levels of serum D-dimer, soluble fibrin, and thrombin-antithrombin complex (TAT) were analyzed. RESULTS: Twenty-four of 92 patients (26.1%) had DVT, of whom 10 (41.7%) were diagnosed preoperatively. In patients with preoperative DVT, age, incidence of decreased performance status and leg paresis, levels of D-dimer, soluble fibrin, and TAT were significantly greater. In patients with postoperative DVT, length of surgery, incidence of decreased postoperative performance status, levels of D-dimer on postoperative days (POD) 3, 7, and 14, and TAT on POD7 were significantly greater. Patients with postoperative DVT had elevated D-dimer levels on POD 7 compared with POD 3. The D-dimer cutoff of 2.65 µg/mL at POD 7 could be used to identify DVT with 85.7% sensitivity and 72.3% specificity. A cutoff of 5.25 µg/mL at POD 7 yielded a specificity of 96.9%. Decreased performance status and elevated D-dimer were independent predictors for preoperative DVT, prolonged operation time, and elevated D-dimer on POD 7 for postoperative DVT. CONCLUSIONS: DVT frequently was observed in patients before and after undergoing craniotomies. Patients with decreased performance status should be preoperatively screened for DVT by checking D-dimer levels. Elevated D-dimer levels on POD 7 compared with POD 3 and D-dimer levels greater than 2.65 µg/mL at POD7 suggest the presence of DVT.

Blood biomarkers associated with neurological deterioration in patients with acute penetrating artery territory infarction: A multicenter prospective observational study.

Background and purpose Neurological deterioration in acute penetrating artery territory infarction is unpredictable and associated with unfavorable clinical outcomes. The aim of this prospective study was to clarify the cause of neurological worsening and predict clinical outcomes using blood biomarkers. Methods Eight Japanese stroke centers participated. Blood samples were obtained within 24 h (the first sampling) and on day 7 in hospital (the second sampling) in patients with penetrating artery territory infarction, arriving within two days of stroke onset. Symptomatic worsening was defined as a minimum increase of one point on the National Institutes of Health Stroke Scale. Poor outcome was defined as a modified Rankin Scale score of ≥3 at 90 days after ictus. Results Of the 89 patients, 25 (28%) had symptomatic worsening, and 25 (28%) had a poor outcome. Although tumor necrosis factor-alpha, high-sensitivity C-reactive protein levels were significantly increased in both groups at the second sampling, soluble lectin-like oxidized low-density lipoprotein receptor-1, CD40 ligand, and pro-adrenomedullin levels were significantly increased and ADAMTS13 activity was decreased in symptomatic worsening patients ( p < 0.05 for all). After multivariate adjustment, a low number of CD34+ cells at the first sampling was an independent predictor of poor outcome (odds ratio, 0.20; 95% confidence interval, 0.04-0.74, p = 0.011, per 1 cell/µl increase). Conclusions Blood biomarkers associated with atherosclerotic processes seem to be an indication for symptomatic worsening, and the number of CD34+ cells may help to predict three-month functional outcome in patients with penetrating artery territory infarction.

Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients.

The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9, known as CYP2C93, and then examined an association of these genotypes with warfarin maintenance doses (mean+/-SD=2.96+/-1.06 mg/day). We found an association of effective warfarin dose with the -1639G>A (p=0.004) and 3730G>A genotypes (p=0.006) in VKORC1, the 8016G>A genotype in GGCX (p=0.022), and the 42613A>C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.

Apparent diffusion coefficient reduction might be a predictor of poor outcome in patients with posterior reversible encephalopathy syndrome.

It is thought that posterior reversible encephalopathy syndrome (PRES) is both clinically and radiologically reversible. However, its reversible nature has been challenged based on reports of permanent neurological impairments. The factors that predict the development of irreversible neurological impairment are still unclear. In the present study, we investigated clinical manifestations, laboratory findings, and neuroradiological images to identify predictors of functional outcomes in PRES. We investigated 23 PRES patients. Apparent diffusion coefficient (ADC) reduction was observed in 4 patients in the poor outcome group, whereas no patients presented ADC reduction in the favourable outcome group (p<0.01). Further studies are warranted to evaluate the association between ADC reduction and functional outcome after PRES.

Visualization of the Intimal Flap in Intracranial Arterial Dissection Using High-Resolution 3T MRI.

BACKGROUND AND PURPOSE: Presence of an intimal flap is a critical imaging finding in diagnosing intracranial artery dissection (ICAD). Recent reports showed that high-resolution magnetic resonance imaging (MRI) was better at identifying intimal flaps as compared with routine MRI techniques used in clinical settings. However, no current standardized sequence for high-resolution MRI without gadolinium enhancement produces images of satisfactory quality with clinically tolerable scanning times. This study evaluated a nonenhanced high-resolution fast spin echo (HR-FSE) MRI sequence for visualizing intimal flaps in patients with ICAD. SUBJECTS AND METHODS: Three patients with ICAD underwent plain MRI examination using a 2-dimensional T2-weighted FSE imaging sequence optimized for our 3T system (in-plane pixel size, .23 mm × .23 mm; slice thickness 3 mm with no interslice gap), as well as scanning with conventional modalities, including CT angiography, magnetic resonance angiography, and digital subtraction angiography. We assessed whether these imaging methods could visualize an intimal flap and/or double lumen sign in the participants and compared the results between HR-FSE and the other modalities. RESULTS: HR-FSE images clearly showed intimal flaps and double lumen signs in all 3 patients, whereas the conventional modalities identified a double lumen sign in only 2 of the 3 patients. CONCLUSIONS: The present method of optimized HR-FSE imaging with a 3T system improved visualization of intimal flaps and should thus be considered for assessing patients with suspected ICAD that cannot be definitively diagnosed by conventional imaging modalities.

[A case of multiple sclerosis with pathological laughing caused by pontine base lesions].

We report a case of multiple sclerosis (MS) with pathological laughing for which lesions in pontine bases are considered to be responsible. A 30-year-old man was diagnosed as having MS based on left hemiparesis, and pathological laughing, and MRI findings showing a plaque in the right pontine base as well as several plaques in the bilateral periventricular deep white matter. After remission for 6 years, his pathological laughing exacerbated in association with development of right hemiparesis. A new lesion in the left pontine base was demonstrated by MRI studies in addition to a few supratentorial lesions. Steroid pulse therapy was effective for both pathological laughing and right hemiparesis. We speculate that the anatomical lesion responsible for the pathological laughing is located in the pontine base.

[A case suspected of acute gas poisoning by carbon monoxide (CO), presenting with progressive diffuse leukoencephalopathy associated with marked brain edema].

A 51-year-old man was found comatose in a decerebrate posture in a cottage. Brain MRI showed diffuse high-signal-intensity areas in the white matter on T 2-weighted and FLAIR images, and diffusion-weighted images showed marked diffuse high intensity areas in the white matter. Initially inflammatory demyelinating diseases were suspected and methylprednisolone pulse therapy was administered. However, no improvement was noted. On close inspection of the cottage, a gas generator was discovered in the poorly ventilated room. He was therefore suspected to have suffered from gas intoxication, including carbon monoxide (CO). Hyperbaric oxygen therapy was administered, but without any improvement. The diffuse white matter lesions and brain edema progressed with time and the patient died of cerebral herniation. Autopsy revealed no inflammatory processes. Most cases with CO intoxication show hyperintense lesions in the globus pallidus on both sides in T 2-weighted images, and some cases show lesions only in the white matter without any involvement of the globus pallidus. The progressive clinical course, diffuse leukoencephalopathy and brain edema may be due to apoptosis of oligodendrocytes. CO intoxication is thus important in the differential diagnosis of diffuse white matter lesions of the cerebrum.