Masayuki Minami

Nested polymerase chain reaction for assessing the clinical course of tuberculous meningitis

The authors examined the usefulness of nested PCR (N-PCR) to detect Mycobacterium tuberculosis (MTB) DNA in CSF for assessing the clinical course of tuberculous meningitis (TBM). N-PCR successfully detected MTB DNA in all nine CSF samples from patients with suspected TBM. During anti-tuberculosis treatments, N-PCR results converted from positive to negative, correlating with the improvement of the patient’s clinical condition.

Lower motor neuron disease caused by a novel FUS/TLS gene frameshift mutation

A 26-year-old Japanese man (patient 1, Fig. 1a) suffered from distal weakness of the right leg. After a few months, he began to stumble frequently and gradually developed distal weakness of the right upper limb. He was then admitted to our hospital. On physical examination, he was alert and his mental status was normal. He had no cognitive abnormalities. He had distal dominant muscular atrophy and weakness in the right extremities. His ocular movements were normal, and he did not display any signs of dysarthria, dysphasia, facial weakness, or tongue abnormalities. Muscle tonus was normal, no fasciculation was seen in any of the extremities and the deep tendon reflex was decreased to absent. He had no urinary or bowel disturbance, and no sensory impairment nor cerebellar ataxia. A nerve conduction study revealed a decrease in F-wave frequency in the right extremities. Electromyography (EMG) demonstrated denervation and renervation potentials in all extremities but fasciculation potentials were absent in all extremities. Routine blood analysis, cerebrospinal fluid analysis and spine MRI revealed no abnormalities. Approximately 6 months after the onset of symptoms, muscle weakness and atrophy had spread to all extremities symmetrically. Muscle weakness and atrophy increased rapidly without upper motor neuron signs, and the patient died of respiratory failure about 1 year after onset. Autopsy was not performed. The mother of patient 1, who was 52 years old (patient 2, Fig. 1a), and the maternal aunt, who was 42 years old (patient 3, Fig. 1a), both experienced weakness and wasting of the right leg in the first decade, and came to walk with dragging of the right leg. Neurological examinations revealed them to be objectively normal except for weakness and wasting of the right leg and a dragging gait. However, EMG demonstrated evidence of mild renervation potentials in all extremities. After progressing for several years, their subjective symptoms remained unchanged until their current ages, which were 52 years old in patient 2 and 42 years old in patient 3, respectively. We routinely performed the mutation analysis of superoxide dismutase 1 (SOD 1) gene, TAR-DNA binding protein 43 (TARDBP) gene and fused in sarcoma/translocation in liposarcoma (FUS/TLS) gene in all patients suspected of familial motor neuron disease with informed consent. Genetic analysis of patient 1 was thus performed. DNA extraction and genotyping were performed using standard protocols as described elsewhere [1]. No mutation of the SOD 1 gene and TARDBP gene was confirmed. We also sequenced all exons of FUS/TLS gene. The allelespecific cloning of the FUS/TLS gene was performed after cloning of the genomic DNA of both alleles, and we identified a novel heterozygous c.1420_1421insGT missense mutation located in exon 14 encoding the RNA-recognition motif (Fig. 1b), and result in an amino acid exchange from Glycine to Valine at protein 472, which is followed by reading frameshift at this point (p.Gly472ValfsX57). Exon 14 of the FUS/TLS gene was sequenced in 100 Japanese healthy controls and no mutation like this case was detected. No expansion of the androgen receptor CAG repeat number and no elongation M. Hara M. Minami (&) S. Kamei Division of Neurology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo 173-8610, Japan e-mail: mm@med.nihon-u.ac.jp

Pathological study of pseudohypertrophy of the inferior olivary nucleus

There have been only a few reports about the immunohistochemical study of pseudohypertrophy of the inferior olivary nucleus (PH‐IO). We therefore performed the detailed immunohistochemical study of 10 PH‐IOs in 8 patients to clarify the mechanism of neuronal degeneration and its related phenomenon of PH‐IO. We used various antibodies to αB‐crystallin (αBC), synaptophysin (SYP), microtubule‐associated protein 2 (MAP2), Lys‐Asp‐Glu‐Leu (KDEL) receptors, heat shock protein (HSP) 27 as well as SMI‐31. We found αBC‐positive neurons on the ipsilateral side of 10 PH‐IOs. SMI‐31‐positive neurons were also observed in 6 PH‐IOs. Confocal laser microscopy showed co‐localization of αBC and SMI‐31 in some neurons. However, there were no HSP27‐positive neurons or astrocytes in any of the 10 PH‐IOs. MAP2 immunostaining showed MAP2‐positive hypertrophic thick neurites around hypertrophic neurons on the ipsilateral side of 7 PH‐IOs and demonstrated “glomeruloid structures” in 3 PH‐IOs. In addition, fine granular SYP‐immunoreactivity was decreased in the neuropils on the ipsilateral side of all 10 PH‐IOs. SYP‐immunoreactive dots were scattered in the neuropils and on the neuronal cell bodies on the side of 7 PH‐IOs, and the aggregation of SYP‐immunoreactive dots scattered in the neuropils was shown in 3 PH‐IOs. Double‐immunostainings using anti‐MAP2 and anti‐SYP antibodies demonstrated frequent SYP‐immunoreactive dots along the MAP2‐positive hypertrophic thick neurites and their cell bodies. Periphery‐stained KDEL‐positive neurons were also found on the side of 7 PH‐IOs. We showed that the change of the distribution of presynaptic terminals correlated well to the hypertrophic thick neurites in PH‐IO. Our immuohistochemical stainings demonstrated various changes which occurred to the neurons in PH‐IO, and their neurites and presynaptic terminals. We considered that αBC was expressed in the neurons in PH‐IO, induced by cellular stress. Such a detailed immunohistochemical investigation has not been reported previously.

Open-label study to evaluate the pharmacodynamics, clinical efficacy, and safety of meropenem for adult bacterial meningitis in Japan

The aim of this study was to assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid when meropenem (2 g every 8 h) was administered to Japanese adult patients with bacterial meningitis. Five Japanese patients (mean age 60.6 years [range 35-71]) were enrolled. Infection with Streptococcus pneumoniae (three patients), Streptococcus salivarius (one patient), and Staphylococcus aureus (one patient) was confirmed by cerebrospinal fluid culture. Meropenem (2 g every 8 h) was administered to all five patients. Treatment duration ranged from 14 to 28 days (mean 22.6 days). All the patients were successfully treated. The concentration of meropenem in cerebrospinal fluid ranged from 0.27 to 6.40 μg/ml up to 8.47 h and was over 1 μg/ml 3 h after starting meropenem infusion. In each patient, the present study confirmed for the first time that the concentration of meropenem in cerebrospinal fluid exceeded the minimal inhibitory concentration for these pathogens. Eleven clinical and laboratory adverse events considered to be related to meropenem were observed in all patients, but no serious adverse event and no discontinuance of treatment due to adverse events occurred. Thus meropenem appeared to be a well-tolerated and effective agent for Japanese adult patients with bacterial meningitis. 2 g every 8 h of meropenem was delivered to CSF and its concentration was exceed in MICs for the detected pathogens.

Case of acute cerebellitis as a result of varicella zoster virus infection without skin manifestations

Kiyohito Okumiya received funding for the Project D-03 of Research Institute for Humanity and Nature from Japanese Ministry of Education, Science and Culture. The project was conceived and designed by Kiyohito Okumiya, Masayuki Ishine, Taizo Wada, Ryota Sakamoto, Kuniaki Otsuka and Kozo Matsubayashi. All authors participated in the medical surveys in Tosa in Japan. Kiyohito Okumiya, Ryota Sakamoto and Kozo Matsubayashi engaged in analysis and interpretation of data, and in the preparation of the manuscript.

Hospital-based study of the distribution of pathogens in adult bacterial meningitis with underlying disease in Tokyo, Japan

Therapeutic management of bacterial meningitis worldwide has been established based on the patient age and risk factors.

A healthy, 81-year-old woman with toxoplasmic encephalitis

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