Shinichi Shirai

Thrombotic microangiopathy after treatment with bortezomib and dexamethasone in a patient with multiple myeloma

Bortezomib (Bz) is extensively used for treating patients with multiple myeloma. There has been an accumulation of information on its efficacy and safety. Thrombotic disorders after treatment with Bz are rare, except for complication caused by tumor lysis syndrome. Here, we report a rare case of thrombotic microangiopathy (TMA) after treatment with Bz and dexamethasone (Dexa) in a patient with multiple myeloma. A 54-year-old Japanese man with refractory IgAjtypemultiple myeloma was treated with Bz (1.3 mg/m, days 1, 4, 8, and 11 in 21-day cycles) and Dexa (20 mg/body, days 1, 2, 4, 5, 8, 9, 11, and 12) in November 2007. He had received high-dose melphalan with autologous peripheral blood stem cell transplantation in May 2005 and allogeneic bone marrow transplantation after a reduced-intensity conditioning regimen [fludarabine, busulfan, and 4 Gy of total body irradiation (TBI)] in November 2006. He had dry skin and bronchiolitis obliterans organizing pneumonia (BOOP) caused by chronic graft-versus-host disease (GVHD), and he was treated with oral tacrorimus (1.2 mg/ day) and prednisolone (10 mg/day) and showed improvement. He had not had TMA, thrombotic thrombocytoprnic purpura (TTP), hemolytic uremic syndrome (HUS) or veno-occlusive-disease (VOD). The patient complained of chest pain and dyspnea on the fifth day in the first course of treatment with Bz and Dexa. His oxygen saturation (SpO2) was 88% in room air. Computed tomography of the chest showed ground glass opacities throughout the bilateral upper and middle lobes (Fig. 1). He suffered from severe interstitial pneumonia (IP). Since we thought that Bz was the cause of his pneumonia, we administered methylpredonisolone at 1,000 mg/ body intravenously for 3 days and stopped the treatment with Bz and Dexa. His pneumonia improved rapidly and did not recur despite steroid tapering off. Three days after the onset of IP (first course, day 8), he had scattered petechiae and suggillation. His consciousness was clear and vital signs were normal. Results of laboratory tests are shown in Tables 1 and 2. Anemia and thrombocytopenia had progressed, and aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and indirect bilirubin were elevated and haptoglobin was decreased. Coombs test results were negative. Erythrocyte fragmentation ratio was 12.7% (Fig. 2). These data suggested microangiopathic hemolytic anemia. Decreased fibrinogen and extended prothrombin time observed by coagulation tests appeared 2 days before this event. Activity of ADAMTS-13 was slightly low (Table 2) and an inhibitor of ADAMTS-13 was not detected. Cytomegalovirus antigens were not detected, and beta-D-glucan, candida antigens and aspergillus antigens were normal. Bacterial cultures in sputa, stools, and urine were negative. We thought he suffered from TMA and administered fresh frozen plasma (240 ml/day) and haptoglobin (2,000 U/day). His symptoms improved gradually. Within 20 days, his laboratory data returned to the levels before treatment with Bz and Dexa. TMA is thought to be caused by endothelial damage derived from high-dose chemotherapy, TBI, GVHD, immunosuppressive agents and opportunistic infections in R. Morita (&) S. Hashino S. Shirai N. Fujita M. Onozawa K. Kahata T. Kondo M. Asaka Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan e-mail: r-mori@f3.dion.ne.jp

Quantitative evaluation of gait ataxia by accelerometers.

An appropriate biomarker for spinocerebellar degeneration (SCD) has not been identified. Here, we performed gait analysis on patients with pure cerebellar type SCD and assessed whether the obtained data could be used as a neurophysiological biomarker for cerebellar ataxia. We analyzed 25 SCD patients, 25 patients with Parkinsons disease as a disease control, and 25 healthy control individuals. Acceleration signals during 6 min of walking and 1 min of standing were measured by two sets of triaxial accelerometers that were secured with a fixation vest to the middle of the lower and upper back of each subject. We extracted two gait parameters, the average and the coefficient of variation of motion trajectory amplitude, from each acceleration component. Then, each component was analyzed by correlation with the Scale for the Assessment and Rating of Ataxia (SARA) and the Berg Balance Scale (BBS). Compared with the gait control of healthy subjects and concerning correlation with severity and disease specificity, our results suggest that the average amplitude of medial-lateral (upper back) of straight gait is a physiological biomarker for cerebellar ataxia. Our results suggest that gait analysis is a quantitative and concise evaluation scale for the severity of cerebellar ataxia.

Novel GNE compound heterozygous mutations in a GNE myopathy patient.

Introduction: Molecular studies have revealed that some patients with myopathies with rimmed vacuoles have pathogenic mutations in the UDP‐N‐acetylglucosamine‐2‐epimerase/N‐acetylmannosamine kinase (GNE) and Z‐band alternatively spliced PDZ motif‐containing protein (ZASP) genes. Methods: We investigated a patient with distal myopathy with rimmed vacuoles by muscle biopsy and sequenced 6 candidate genes. Results: The patient carried GNE compound heterozygous missense mutations (p.V421A and p.N635K) and a ZASP variant (p.D673N). This patient also presented with distal weakness sparing the quadriceps muscles and had atypical results for Z‐band‐associated protein immunostaining. This finding indicates that the GNE mutations are pathogenic, and the diagnosis is compatible with GNE myopathy. Conclusions: By combining pathological studies and candidate gene screening, we identified a patient with GNE myopathy due to novel GNE compound heterozygous mutations. Muscle Nerve 48: 594–598, 2013

Rare frequency of downbeat positioning nystagmus in spinocerebellar ataxia type 31

Spinocerebellar ataxia type 31 (SCA31) and spinocerebellar ataxia type 6 (SCA6) are the most frequent types of spinocerebellar degeneration in Japan. Previous reports described that it was difficult to distinguish SCA6 and SCA31 in clinical situations. There is not much difference except that the onset age of SCA31 is slightly higher than that of SCA6. Therefore we surveyed our medical records retrospectively, and then compared clinical symptoms of SCA6 and SCA31. As previously stated, the onset age of SCA31 is higher than that of SCA6. Gaze-evoked nystagmus is more frequent in SCA6 than in SCA31. The percentage in downbeat positioning nystagmus (DPN) is as high as 63% in SCA6. In contrast, DPN in SCA31 is rare and subtle. Our study suggests that the presence of DPN is an important sign that can differentiate SCA6 from SCA31 clinically.

Usefulness of 11C-methionine-positron emission tomography for the diagnosis of progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disease of the brain caused by the JC virus that occurs mainly in immunocompromised patients. The prognosis is very poor. As the lesion looks like non- specific leukoencephalopathy, making a diagnosis at the early stage is very difficult. We report three PML cases in which there was a mismatch between 11C-methionine-positron emission tomography (MET-PET) uptake and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake. All three cases demonstrated the hyper-uptake of MET around the white matter lesions and hypo-uptake of FDG inside the lesions. We speculate that the infection had ended inside the white matter lesions of these patients, while JC virus infection was ongoing around the lesions, resulting in the increase of methionine metabolism, and the glucose metabolism was reduced or intermediate because inflammatory cells infiltrate PML lesions rarely. Two patients who were diagnosed and treated with mefloquine while the JC virus was at a low level in the cerebrospinal fluid are still alive. We suggest the usefulness of MET-PET for the early diagnosis of PML and early treatment with mefloquine.

Frontotemporal dementia and progressive supranuclear palsy-like syndrome with a novel TARDBP mutation

TARDBP mutation has been shown to cause frontotemporal dementia and progressive supranuclear palsy‐like disease. In this case study, we present the first reported Japanese case of frontotemporal dementia and progressive supranuclear palsy‐like syndrome caused by a novel TARDBP mutation. A 63‐year‐old man was diagnosed with frontotemporal dementia and progressive supranuclear palsy‐like disease. An older brother of the patients deceased father showed similar symptoms. Genetic analysis showed a novel TARDBP heterozygous mutation (c.715 A > G, p.I239V). This mutation is not found in databases of the 1000 genome project and Human Genomic Variation, but is identified as a pathogenic mutation by Mutation Taster. Although the hot cross bun sign as a result of frontotemporal dementia and progressive supranuclear palsy has been reported only rarely, brain magnetic resonance imaging of this patient showed the hot cross bun sign and T2‐hyperintensity of the middle cerebellar peduncles along with frontotemporal and midbrain tegmentum atrophy.

Neuromyelitis optica spectrum disorders accompanying subarachnoid hemorrhage and reversible white matter lesions

A 48‐year‐old man was admitted to Tomakomai City Hospital, Tomakomai, Japan, because of intractable hiccups and nausea, and orthostatic hypotension. Brain magnetic resonance imaging findings showed a dorsal medullary lesion. Respiratory failure occurred, and he underwent tracheotomy and mechanical ventilation when magnetic resonance imaging showed subarachnoid hemorrhage in addition to enlarged medullary lesions. Serum anti‐aquaporin‐4 antibody was positive and the cerebrospinal fluid was bloody. We diagnosed meuromyelitis optica spectrum disorders complicating subarachnoid hemorrhage. He was treated with a steroid. Although extensive white matter lesions occurred transiently, the patient was discharged from the hospital when he became able to walk with the use of the walker on the 52nd day. We suggest that the subarachnoid hemorrhage and transient white matter lesions were associated with vascular damage associated with the meuromyelitis optica spectrum disorders.

Hashimoto's encephalopathy mimicking a brain tumor and its pathological findings: A case report

Hashimotos encephalopathy is characterized by the presence of anti-thyroid antibodies with no alternative cause. Patients with Hashimotos encephalopathy present with various clinical symptoms and magnetic resonance imaging (MRI) findings. To our knowledge, this is the first documented report of Hashimotos encephalopathy with MRI findings mimicking a brain tumor. The patient was a 41-year-old woman with a history of Hashimotos disease. She experienced gradually worsening Parkinsonism and an MRI revealed a brain tumor-like lesion at the left caudate nucleus. She underwent a brain biopsy that revealed diffuse gliosis and perivascular lymphocyte infiltration with CD3+ T-cell predominance. No pathological signs of a brain tumor were found. Hashimotos encephalopathy was suspected based on the patients history and the presence of anti-thyroid antibodies. Her symptoms and the MRI findings improved with glucocorticoid treatment. Although there exist only a few studies on the pathology of Hashimotos encephalopathy, our findings were consistent with those of previous reports. Our findings suggest cerebral vasculitis as an underlying etiology of Hashimotos encephalopathy. We also emphasize the importance of considering Hashimotos encephalopathy as a differential diagnosis of brain tumors.

Tremor during orthostatism as the initial symptom of Machado–Joseph disease

A 60-year-old man was admitted to our hospital. He had mild tremor in his four extremities when supine or sitting, which was markedly exacerbated when standing. We diagnosed him with Machado-Joseph disease according to the genetic test. His tremor improved with clonazepam, trihexyphenidyl, and a rotigotine patch.

Pseudodystonia in sarcoid myopathy

We describe a 61‐year‐old woman with difficulty extending her left ring finger and little finger caused by sarcoid myopathy. As her symptom temporarily improved with carpal flexion or forearm pronation, we once misdiagnosed her as having dystonia of the upper limb. Her symptom gradually worsened, and muscle biopsy specimen revealed sarcoid myopathy. Muscle magnetic resonance imaging of the left forearm showed abnormal signals in the quadriceps femoris and biceps brachii muscles, and the area surrounding the flexor digitorum profundus and supinator muscles. Treatment with prednisolone was effective, and stopped progression of the symptom. Adhesion of the supinator muscle and flexor digitorum profundus as a result of inflammation might have caused limited extension of the flexor digitorum profundus.