[Successful treatment of Bing-Neel syndrome using combination therapy with fludarabine and rituximab].

Bing-Neel syndrome is known as Waldenström's macroglobulinemia with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells. A 74-year-old man was admitted because of progressive cognitive impairment. Serum immunoelectrophoresis showed a monoclonal IgM-kappa component. Bone marrow aspiration revealed 59% small lymphocytes showing plasmacytoid differentiation. Bone marrow flow cytometry disclosed a population of kappa light-chain positive lymphoid cells expressing CD19, CD20, CD38, and CD138. Magnetic resonance imaging of the brain demonstrated gadolinium-enhancement in the right temporo-parieto-occipital meninges with sulcal enhancement. Cerebrospinal fluid cytology showed a population of lymphoplasmacytoid cells, positive for CD19, CD20, CD25, and kappa light-chain. Based on these findings, Bing-Neel syndrome was diagnosed. Although combination chemotherapy consisting of intrathecal methotrexate and oral cyclophosphamide was started, his symptoms continued to worsen. Then, we initiated treatment with a regimen consisting of fludarabine/rituximab (FR). After 6 courses of this FR regimen, a complete remission was achieved. Our case suggests the FR regimen to potentially be an effective treatment option for Bing-Neel syndrome of the scattered type.

Micro-MRI improves the accuracy of clinical diagnosis in cerebral small vessel disease.

Even with postmortem pathological examination, only limited information is provided of the foci of in vivo clinical information. Cerebral small vessel disease, which is associated with ageing, dementia and stroke, highlights the difficulty in arriving at a definitive diagnosis of the lesions detected on in vivo radiological examination. We performed a radiological-pathological comparative study using ex vivo MRI to examine small cerebral lesions. Four patients with small vessel disease lesions detected on in vivo MRI were studied. Exact pathological findings of in vivo MRI-detected lesions were revealed. The ischaemic lesion after 17 days from onset showed positivity for peroxiredoxin, cluster of differentiation 204 and glial fibrillary acidic protein, indicating sterile inflammation and neuroprotective reaction. Cortical microinfarcts beneath the cortical superficial siderosis were associated with inflammation from the superficial layer in a patient with cerebral amyloid angiopathy; in this patient, a bilinear track-like appearance of the cortical superficial siderosis on the ex vivo MRI was compatible with iron deposition on the pia matter and within cortical layers II-III. An in vivo MRI-detected cerebral microbleed was revealed to be heterogeneous. An in vivo MRI-detected cerebral microbleed was revealed to be a venous angioma. Furthermore, a neuropathologically confirmed embolic cerebral microbleed was firstly detected using this method. Our results suggest that in vivo MRI-detected lobar cerebral microbleeds can be caused by non-cerebral amyloid angiopathy aetiologies, such as microembolism and venous angioma. Venous angioma and embolic microbleeds may mimic cerebral amyloid angiopathy markers on in vivo MRI. To clarify the clinical importance of these lesions, we should investigate their rate and frequency in a large cohort of healthy individuals and patients with cardiac risk factors. Thus, we provide evidence that ex vivo micro-MRI improves the clinical diagnosis of small vessel diseases.

["Tram-track" sign and "donut configuration" in Tolosa-Hunt syndrome].

We report unique MRI abnormalities seen in a patient with Tolosa-Hunt syndrome (THS). A 60-year-old woman was admitted for left eye symptoms, including periorbital pain, numbness around the left eyebrow, blurred vision, delayed light reflex and impairment of abduction. Laboratory studies were unremarkable except for elevated erythrocyte sedimentation rates. T1-weighted MRI showed a mass lesion in the left orbital apex. Fat-suppressed T2-weighted MRI showed a hyperintense parallel linear lesion on the left optic nerve and a ring lesion around it, producing the "tram-track" sign on the axial view and the "donut configuration" on the coronal view. A diagnosis of THS was made, and corticosteroid therapy was started. Symptoms were improved rapidly, and MRI abnormalities disappeared. Reevaluation of MRI which had been taken at the previous episode of the right eye symptoms two years before also showed the "tram-track" sign and the "donut configuration" on the right. These signs are easy to be recognized and well reflect the stage of the disease. They are thus useful for diagnosing THS and evaluating the effect of the treatment. One should pay attention not only to the cavernous sinus and orbital apex, but also to the optic nerve for the MRI diagnosis of THS.

[Posterior-predominant leukoencephalopathy which was caused by methylenetetrahydrofolate reductase deficiency and successfully treated with folic acid].

A 35-year-old woman was admitted with subacute intellectual deterioration. Laboratory studies showed elevated total homocysteine and decreased folic acid. MRI revealed leukoencephalopathy with a posterior predominance, and hyperintensity in the pyramidal tracts on T2-weighted and FLAIR images. The enzyme assay showed a deficiency of methylenetetrahydrofolate reductase (MTHFR) activity with low residual activity of 4.2% of the mean control value in cultured fibroblasts. Sequence analysis of the MTHFR gene demonstrated two homozygous missense mutations, c.677C>T (p.Ala222Val) and c.685A>C (p.Ile225Leu). c.677C>T (p.Ala222Val) is known as a common polymorphism and c.685A>C (p.Ile225Leu) is considered to be a novel polymorphism. A diagnosis of MTHFR deficiency was made. Treatment with folic acid, vitamin B12 and B6 made significant improvement of intellectual deterioration and reduction in the total homocysteine level. They also made marked resolution of leukoencephalopathy. Posterior-predominant leukoencephalopathy was found to be an excellent marker of MTHFR deficiency, and may help to establish the diagnosis.

[A case of hypomyelinating leukodystrophy with new homozygous mutation in POLR3A].

We describe a 34-year-old man with hypomyelination, hypogonadotropic hypogonadism, ataxia, and myopia without hypodontia. He was born to non-consanguineous parents, and had an elder brother who showed a similar phenotype. Laboratory studies demonstrated low level of LH, FSH and testosterone. MRI showed hypomyelination, atrophy of the cerebellum and the hypoplastic corpus callosum. Homozygous missensze mutation c.2350G>A (p.Gly784Ser) was found in POLR3A,which codes for the largest subunit of RNA polymerase III. Since PolIII-related leukodystrophies shows various combination of neurologic and non-neurologic features, additional reports will help to confirm the mechanism of this disease.

Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis.

Recently, a hexanucleotide repeat expansion in C9orf72 was identified as the most common cause of both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Western populations. We analyzed 563 Japanese patients with ALS (552 sporadic and 11 familial) using fluorescent fragment-length analysis of C9orf72 and repeat-primed polymerase chain reaction analysis. Haplotype analysis was performed for 42 single nucleotide polymorphisms in patients with C9orf72 repeat expansion. C9orf72 repeat expansion was found in 2 patients with sporadic ALS (2/552 = 0.4%) and no patients with familial ALS (0/11 = 0%). In the probands' families, 1 primary progressive aphasia patient and 1 asymptomatic 76-year-old individual exhibited C9orf72 repeat expansion. All of the patients with the C9orf72 repeat expansion carried the 20-single nucleotide polymorphism consensus risk haplotype. The frequency of the C9orf72 repeat expansion among Japanese patients is much lower than in Western populations. The existence of a 76-year-old asymptomatic carrier supported the notion of incomplete penetrance. The C9orf72 mutation should be analyzed in sporadic ALS patients after determining their family histories not only of frontotemporal dementia but also of primary progressive aphasia.

Antidiabetic effect of Lactobacillus GG in streptozotocin-induced diabetic rats.

Neonatally streptozotocin-induced diabetic (n-STZ) rats were given food containing Lactobacillus GG cells (GG) or a control diet (control), from 9 to 18 weeks of age. The GG cells significantly lowered the blood hemoglobin A(1C) (HbA(1C)) level and improved glucose tolerance in n-STZ rats (p<0.05). In the GG group, the serum insulin level at 30 min after glucose loading was significantly higher than in the control group (p<0.05).