Kimitoshi Hirayanagi

Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift FUS Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment.

A 24-year-old Japanese woman developed anterocollis, weakness of the proximal arms, and subsequent cognitive impairment. A neurological examination revealed amyotrophic lateral sclerosis (ALS) without a family history. Systemic muscle atrophy progressed rapidly. Cerebral MRI clearly exhibited high signal intensities along the bilateral pyramidal tracts. An analysis of the FUS gene revealed a heterozygous two-base pair deletion, c.1507-1508delAG (p.G504WfsX515). A subset of juvenile-onset familial/sporadic ALS cases with FUS gene mutations reportedly demonstrates mental retardation or learning difficulty. Our study emphasizes the importance of conducting a FUS gene analysis in juvenile-onset ALS cases, even when no family occurrence is confirmed.

Bilateral striatal necrosis caused by a founder mitochondrial 14459G > A mutation in two independent Japanese families

Bilateral striatal necrosis (BSN) has many causes and is characterized by unique clinical and neuroradiological features. Herein, we report a clinical and genetic analysis of three BSN cases from two independent Japanese families harboring a mitochondrial DNA (mtDNA) 14459G>A mutation located in a coding region of the NADH dehydrogenase subunit 6 gene. In the first family, two male siblings from non-consanguineous parents exhibited similar phenotypes, with infantile-onset generalized dystonia. A third sporadic case involved a male patient with a comparatively milder phenotype characterized by juvenile-onset mild truncal ataxia and parkinsonism. Cerebral magnetic resonance imaging of these cases revealed abnormal signal intensities along the bilateral putaminal area and enlarged lateral ventricle anterior horns caused by caudate nuclear atrophy, particularly in the sibling pair. The sibling-pair cases shared a homoplasmic 14459G>A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A>G single nucleotide polymorphism, which was previously reported as a rare synonymous variation (4.3%) in a Japanese population. Plasmid sequencing revealed a genetic linkage of these two DNA substitutions, suggesting that the three patients shared a genetic founder. Although our mtDNA analysis was only accessible using leukocytes, clinical severity might be associated with homoplasmy or heteroplasmy. In summary, it is important to evaluate potential mtDNA defects in BSN cases, regardless of familial occurrence.

Encephalopathy with amyloid angiopathy and numerous amyloid plaques with low levels of CSF Aβ1–40/Aβ1–42

A middle-aged male suffering from encephalopathy with cerebral amyloid angiopathy (CAA) with amyloid beta (Aβ) presented with initial symptoms of transient consciousness disturbance and left visual field photophobia. Lesions with aberrantly high signal on T2-weighted magnetic resonance imaging (MRI) of the brain appeared in the right temporal lobe posterior to the occipital lobe and spread to other areas. Brain biopsy revealed Aβ deposits in vascular walls and numerous diffuse plaques in parenchymal areas. Based on MRI findings, Initial corticosteroid therapy with beta methasone effectively improved the neurological symptoms of consciousness disturbance and motor deficits. After corticosteroid therapy was stopped at 4 weeks, recurrence occurred. Additional corticosteroids did not improve clinical symptoms and the patient progressed to a bed-ridden state with a severe consciousness disturbance. Notably, CSF Aβ1–42 and CSF Aβ1–40 decreased while the recurrent encephalopathy worsened. After intense deterioration, the patient became stable. CSF Aβ1–42 increased but remained at a very low level. This case of CAA encephalopathy with apolipoprotein E ϵ4/ϵ4 homozygosity showed Aβ deposits in vascular walls and numerous diffuse plaques in parenchymal areas. The clinical course suggests that reduction of CSF Aβ1–42 and Aβ1–40 might be related to clinical deterioration in cases of encephalopathy.

An Autopsy Case of Fulminant Hepatitis in a Patient with Multiple Sclerosis Treated by Interferon-Beta-1a

A 44-year-old woman with multiple sclerosis (MS) receiving interferon (IFN)-beta-1a treatment was admitted to a local hospital for severe icterus and liver injury. She was transferred to our university hospital because fulminant hepatitis (FH) was suspected. She was diagnosed with acute-type FH based on hepatic coma, severe liver injury and liver failure, and she received plasma exchange and continuous hemodiafiltration therapy. On hospital day 6, she died from liver failure despite intensive care. An autopsy revealed histological findings consistent with FH. Physicians should monitor the hepatic function of MS patients receiving IFN-beta-1a treatment, as serious events can occur in rare cases.

A case of neurolymphomatosis presenting extended involvement of spinal nerve roots

A 56-year-old man suffered from diffuse large B-cell lymphoma (DLBCL) originated from the stomach. He received R-CHOP therapy, and had a complete remission. However, at age 57, he experienced left shoulder pain and weakness of left arm, and his muscle weakness and sensory disturbance subacutely progressed to other limbs. Cervical and lumbosacral MRI showed enhanced extended lesions of cervical, thoracic, lumbar, and sacral nerve roots and cauda equina. Cerebrospinal fluid analysis revealed a sustained low glucose level. Nerve conduction study showed abnormalities of measurement parameters of F-waves in all limbs. A diagnosis of recurrent DLBCL presenting neurolymphomatosis could be established by repeated cytology of cerebrospinal fluid. He received high dose methotrexate therapy, but his symptoms were worsened to tetraplegia. It should be noticed that DLBCL can involve spinal nerve roots extensively.

Reversal of leukoencephalopathy induced by liposomal amphotericin B in a patient with cryptococcal meningitis.

• This is the first reported case of reversible leukoencephalopathy associated with liposomal amphotericin B (AMB).

Putaminal iron deposition precedes MSA-P onset by 2 years

Changes in putaminal MRI signals are important imaging biomarkers for the diagnosis of multiple system atrophy with predominant parkinsonism (MSA-P). However, there exists little data on the first occurrence of these changes in the natural history of the disorder.

Response to the letter to the editor regarding an article “Bilateral striatal necrosis caused by a founder mitochondrial 14459G>A mutation in two independent Japanese families”

We thank Finsterer and a colleague for inquiries about our reports [1]. Mitochondrial disorders including bilateral striatal necrosis (BSN) are characterized by multisystem involvement. Regarding multi-organ dysfunctions of three presented cases, our intensive investigations revealed that the affected organ is confined to the brain. As for the initial symptom of foot dragging in Patient A-1, we speculated it was due to dystonia occurred in lower limb muscles but not muscle weakness because manual muscle test on each muscles confirmed full scores without muscle atrophy. Tendon reflexes were normal in all limbs. Serum creatine kinase level was 122 IU/L (normal range: 62 to 287). Both the needle electromyogram and the nerve conduction studies in all limbs showed no pathological findings and each measurement was within normal limits, indicating complicating neuropathy and myopathy were unlikely. Based on clinical similarities between DOPA-responsive dystonia and Patient A-1, levodopa was administered to him with unsuccessful outcome. The pathogenesis of BSN is heterogeneous, and diagnosis of previous BSN cases was usually made by clinical findings, typical neuroradiological findings, and genetic evaluations. We do not believe pathological confirmation is necessarily when we consider the diagnosis of BSN. Bilateral putaminal hypoperfusion found by SPECT analysis in Patient A-1 will not indicate ischemia or vascular pathogenesis of this disorder, but possibly the result after the neuronal loss in these regions. Magnetic resonance spectroscopy was performed in Patient A-1, and found that there was no abnormal changes of metabolites including lactate. In mitochondrial disorders, it had been reported that the same mutation can represent heterogeneous phenotype and severity [2,3]. As already described in the Discussion section of our report [1], the differences in clinical severity between patients from Families A and B might be attributable to the respective presence of homoplasmy or heteroplasmy. However, previous reports have described asymptomatic homoplasmic 14459GNA mutation carriers [4–6]. Thus the differences in clinical severity between patients from Families A and B will not be explained only by the heteroplasmic mutation state of leukocyte DNAs. We had already described in our report that it is necessary to consider that tissue heteroplasmy might affect the penetrance of the 14459GNA

Progressive Pseudolithiasis Associated with the Intravenous Administration of Ceftriaxone in Patients with Central Nervous System Infections

We report four adult cases of ceftriaxone (CTRX)-induced pseudolithiasis and nephrolithiasis. With the exception of case 1, none of our cases showed abdominal symptoms. Our patients, who had central nervous system (CNS) infections, had been treated with CTRX (4 g/day) for 35-69 days. CTRX-induced pseudolithiasis and nephrolithiasis can appear depending on the total dose of CTRX and the duration for which it is administered. Patients with bacterial CNS infections who are treated with CTRX are typically treated with higher doses for longer periods. It should be recognized that these patients are at higher risk of developing CTRX-induced pseudolithiasis and nephrolithiasis.

MICROBLEEDS IN CLINICAL SUBTYPES OF ALZHEIMER'S DISEASE ON CSF AND NEUROIMAGING MARKERS

(BMI) is associated with reduced risk for future development of Alzheimer’s Diseases (AD), particularly in older subjects (Emmerzaal et al., 2015). Therefore, we sought to investigate how BMI in late middle aged and elderly subjects relates to regional cerebral metabolic rate of glucose (rCMRgl) and whether this relationship is influenced by the status of APOEε4 allele, a genetic risk for AD, or age. Methods: 197 cognitively healthy, non-diabetic subjects (59M/138F; age 61.066.3y; BMI 27.364.9kg*m), including homozygous (n1⁄440) and heterozygous (n1⁄458) carriers of the APOEε4 allele, underwent quantification of rCMRgl using 2-[F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography. Voxelwise multiple regression analyses across the whole brain and within specific regions of interest (ROI) including precuneus, posterior cingulate, parietal, temporal, prefrontal, and occipital brain regions were employed to investigate associations of BMI with rCMRgl and potential interactions with APOEε4 carrier status, age and gender. Furthermore, we applied the hypometabolic convergence index (HCI; Chen et al., 2011) in order to explore the relationship between BMI and AD typical hypometabolic patterns. Results:We found extensive and exclusively positive associations of BMI with rCMRgl in regions known to be affected by AD such as occipital, parietal, temporal (including the bilateral hippocampal region), and other brain regions (i.e. cerebellum, frontoinsular and subcortical regions). Confirmatory results were found for specific ROIs. A significant BMI by gender interaction was observed with stronger associations within the right temporal and the right orbitofrontal cortex in males. However, no significant BMI by APOEε4 carrier status interaction or BMI by age group interaction was detected. Additionally, BMI was negatively correlated with HCI, indicating less convergence to AD typical hypometabolic patterns in subjects with high BMI measures. Conclusions: BMI is positively associated with rCMRgl in healthy late middle aged and elderly subjects, including brain regions that are typically affected by AD, thus providing a potential explanation for the proposed beneficial effects of higher BMI with respect to AD development. These associations seem to be modified by gender, possibly as the result of differences in body composition, but not by APOEε4 genotype or age.