Akihiko Ozaki

Combination of cyclosporine A with corticosteroids is effective for the treatment of neuromyelitis optica.

Neuromyelitis optica (NMO) and associated NMO spectrum disorders (NMOSDs) are neuroinflammatory diseases that frequently result in severe neurological disabilities. The aim of this study was to explore additional treatment options for NMO/NMOSD patients who are seropositive for anti-aquaporin 4 (AQP4) antibodies. We retrospectively evaluated the efficacy of immunosuppressants for NMO/NMOSDs by reviewing the clinical records of 52 patients confirmed as seropositive for anti-AQP4 antibodies. Of the 52 patients, 26 (23 women, three men) had received at least one kind of immunosuppressant other than corticosteroids. After eliminating ineligible cases, we evaluated the following 24 treatments in 22 patients (20 women, two men) that used azathioprine (AZA) (nxa0=xa09), cyclophosphamide (nxa0=xa01), cyclosporine A (CyA) (nxa0=xa09), tacrolimus (nxa0=xa02), methotrexate (nxa0=xa01), and mizoribine (nxa0=xa02). Both AZA and CyA treatments allowed us to decrease the median dose of the coadministered prednisone without affecting the expanded disability severity scale scores. In patients with relapsing-remitting courses, the annual relapse rate decreased from 1.7 (1.2–2.7) to 0.47 (0.36–0.59) after AZA treatments (nxa0=xa06, Pxa0=xa00.028), and also showed a significant decrease from 2.7 (1.8–4.3) to 0.38 (0–0.97) after CyA treatment (nxa0=xa08, Pxa0=xa00.012). These results indicate that CyA as well as AZA may help stabilize the disease activity in NMO/NMOSD patients seropositive for anti-AQP4 antibodies. This is the first case series study demonstrating the efficacy of CyA for the treatment of NMO/NMOSDs.

Idiopathic normal pressure hydrocephalus has a different cerebrospinal fluid biomarker profile from Alzheimer's disease.

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimers disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD.

Association of lipocalin-type prostaglandin D synthase with disproportionately enlarged subarachnoid-space in idiopathic normal pressure hydrocephalus

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Aβ) implicated in Alzheimer’s disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers.MethodsWe evaluated 22 patients (age: 76.4u2009±u20094.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Aβ42, Aβ40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score.ResultsL-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (pu2009=u20090.013 and pu2009=u20090.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman ru2009=u20090.753, pu2009<u20090.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman ru2009=u20090.602, pu2009=u20090.004), callosal angle (Spearman ru2009=u20090.592, pu2009=u20090.004), and ARWMC scores (Spearman ru2009=u20090.652, pu2009=u20090.001), but were negatively correlated with FAB scores (Spearman ru2009=u20090.641, pu2009=u20090.004).ConclusionsOur data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.

Clustering of multifocal cerebral infarctions in CADASIL: a case report

A 42-year-old Japanese man who suffered an accidental fall was admitted to our hospital and periventricular lucency was detected by head CT. Clinical manifestations were determined to include a 20-year history of alopecia and mood disorder without ischemic strokes or migraines. The patient reported having caught a cold 1 week before admission and subsequently decreased dietary intake in the preceding days. There was no history of consanguinity, but stroke and progressive dementia was documented in his mother with evidence of diffuse leukoencephalopathy on her MRI. His younger sister had a history of migraines and periventricular white matter lesions were recorded from her MRI. Upon examination, the patient’s core temperature was 37.1 C, blood pressure was 98/50 mmHg, and pulse was 83 beats/min. Neurological examination revealed mild abulia and cognitive impairment (Mini-Mental State Examination score, 20/30). Neither muscle weakness nor sensory disturbance could be detected. MRI-diffusion-weighted imaging (DWI) revealed multiple high intensities in the bilateral periventricular white matter and genu of the corpus callosum, accompanied by low apparent diffusion coefficient (ADC) values (Fig. 1a–d). Fluid-attenuated inversion recovery (FLAIR) images showed subcortical ischemic changes (Fig. 1e) N-isopropylp-[123 I]-iodoamphetamine single photon emission computed tomography (IMP-SPECT) showed global cerebral hypoperfusion (Fig. 1f). MR angiography, carotid ultrasonography, electrocardiography, echocardiography, and whole-body CT were all normal. Laboratory tests revealed elevated white blood cells (8,200/ll) and C-reactive protein (6.40 mg/dl). Hemostatic marker assays showed short prothrombin time (68.5%) and elevated fibrinogen level (522 mg/dl). Cardiovascular risk factors, collagen diseases, and metabolic abnormalities were not documented. These findings led us to perform a skin biopsy, which showed granular osmiophilic material (GOM) under ultrastructural examination (Fig. 1g, h). Direct sequencing analysis of whole blood sample revealed a Arg169Cys mutation caused by C?T transition at nucleotide position 583 within exon 4 of the NOTCH3 gene, establishing the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is a hereditary microangiopathy with recurrent transient ischemic attacks and strokes, migraines, mood disturbance, and progressive cognitive impairment [6]. Alopecia is known as a characteristic symptom of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) [5], while Yamada et al. has reported a CADASIL patient with alopecia [16]. A signal increase on MRI-DWI with low ADC values is highly accurate for the diagnosis of acute stroke [11]. Therefore, hyperintensity in DWI with low ADC values strongly indicate multiple ischemic lesions in the bilateral hemispheres. To our knowledge, these multifocal signal S. Saito A. Ozaki (&) M. Takahashi S. Matsumoto Department of Neurology, Kitano Hospital, The Tazuke Kofukai Medical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan e-mail: osk@kuhp.kyoto-u.ac.jp

Electrocardiography as the First Step for the Further Examination of Cardiac Involvement in Myasthenia Gravis

Introduction. Cardiac involvement of myasthenia gravis (MG) accompanies a poor prognosis. In the present study, we aimed to investigate the relationship between ECG abnormality and cardiac involvement. Methods. Of 178 patients diagnosed with MG between 2001 and 2013 at our hospital, we retrospectively analyzed consecutive 58 patients who underwent both ECG and echocardiography and without underlying cardiovascular disease. ECG abnormalities were defined by computer-assigned Minnesota-codes. Cardiac damage was defined as either (1) ejection fraction (EF) <55% on echocardiography or (2) elevated E/e′, the ratio of mitral velocity to early diastolic velocity of the mitral annulus >8 on echocardiography. Results. Thirty-three patients (56.8%) had ECG abnormality. An elevated E/e′ was observed in patients with ECG abnormality compared to those without ECG abnormality (11.2 ± 3.2, 8.7 ± 2.2, resp., p = 0.03). Among patients with ECG abnormality, 14 of 15 patients showed cardiac damage. Among patients without ECG abnormality, 6 of 33 patients showed cardiac damage (p = 0.003). Reduced EF was observed in five patients (8.6%) with ECG abnormality and none in patients without ECG abnormality. Conclusions. ECG may aid as the first step for the further examination of cardiac damage in patients with MG.

Antidepressants for Depression, Apathy, and Gait Instability in Parkinson's Disease: A Multicenter Randomized Study

Objective Depression, apathy, and gait instability are cardinal symptoms in patients with Parkinson’s disease (PD). Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are used for treating the psychiatric symptoms of PD. This is the first prospective randomized study to compare the efficacy of an SNRI (duloxetine) with SSRIs (paroxetine, escitalopram) in improving depressive symptoms and apathy (primary) and freezing of gait (FOG; secondary) in patients with PD. Methods In this prospective, multicenter, open-label, randomized study, Japanese PD patients with a Quick Inventory of Depressive Symptomatology-Japanese (QIDS-J) score ≥6 were randomly assigned to receive an SSRI (27 enrolled, 25 analyzed) or duloxetine (28 enrolled, 27 analyzed) and were assessed at 6 and 10 weeks. Results The mean change (SD) in the QIDS J [SSRI -2.4 (3.6), p=0.015; SNRI -2.3 (3.9), p=0.029] and FOG-Questionnaire [SSRI -2.9 (4.2), p=0.012; SNRI -3.4 (4.7), p=0.010] scores (from baseline) at 10 weeks was statistically significant, while the mean change in the Apathy Scale scores was not [SSRI -2.7 (5.4), p=0.054; SNRI -1.5 (3.7), p=0.109]. No significant differences were observed between the SSRI and SNRI groups. The treatments were well-tolerated; however, gastrointestinal events were more common with SSRIs. Two SNRI-treated patients reported an exacerbation of tremor. Conclusion SSRIs and SNRIs improve the depressive symptoms and FOG in PD patients with mild to severe depressive symptoms. However, their effectiveness in treating apathy remains to be elucidated.

Interhemispheric Resting-State Functional Connectivity Predicts Severity of Idiopathic Normal Pressure Hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by a clinical triad (gait disturbance, dementia, and urinary incontinence), and by radiological findings of enlarged ventricles reflecting disturbance of central spinal fluid circulation. A diagnosis of iNPH is sometimes challenging, and the pathophysiological mechanisms underlying the clinical symptoms of iNPH remain largely unknown. Here, we used an emerging MRI technique, resting-state functional connectivity MRI (rsfcMRI), to develop a subsidiary diagnostic technique and to explore the underlying pathophysiological mechanisms of iNPH. rsfcMRI data were obtained from 11 patients with iNPH and 11 age-matched healthy volunteers, yielding rsfcMRI-derived functional connectivity (FC) from both groups. A linear support vector machine classifier was trained to distinguish the patterns of FCs of the patients with iNPH from those of the healthy volunteers. After dimensional reduction, the support vector machine successfully classified the two groups with an accuracy of 80%. Moreover, we found that rsfcMRI-derived FC carried information to predict the severity of the triad in iNPH. FCs relevant to the classification of severity were mainly based on interhemispheric connectivity, suggesting that disruption of the corpus callosum fibers due to ventricular enlargement may explain the triad of iNPH. The present results support the usefulness of rsfcMRI as a tool to understand pathophysiology of iNPH, and also to help with its clinical diagnosis.

Folate deficiency in dementia patients

Background: Folate deficiency and vitamin B12 deficiency could worsen dementia. The clinical character of folate deficiency was investigated serially in our department. Methods: The patients with dementia were assessed by mini-mental state examination (MMSE), category fluency, serum folate, vitamin B12, and homocysteine. Cut-off value was 3.1ng/ml for folate deficiency. 180pg/ml for vitamin B12 deficiency, 14.1nmol/ml for hyperhomocysteinemia. They were also assessed with brain MRI or CT. The degree of atrophy in hippocampus was measured by voxel-based analysis. These parameters were compared between patients with folate deficiency and those with normal serum folate. Results: 90 patients were assessed, 35 men and 55 women. The average age was 78.5. Median duration between first symptom and assessment, was 2 years and 2 months. Median score of MMSE was 21.0. 54% of the patients were clinically diagnosed as Alzheimer’s disease, 15% as vascular dementia. 16 patients (18%) had folate deficiency. 9 patients (10%) had vitamin B12 deficiency. 30 patients (33%) had hyperhomocysteinemia. Inverted correlation was found in serum folate and homocysteine. Patients with folate deficiency showd no differences in score of MMSE, category fluency, and degree of atrophy in hippocampus, compared with patients with normal serum folate.Conclusions: Folate deficiency was sometimes detected in dementia patients. It might influence cognitive function independently.