Selective involvements of upper and lower motor neurons have been regarded as one of the most characteristic features of amyotrophic lateral sclerosis (ALS). However, evidences of more extensive involvements affecting the systems other than the pure motor systems have been accumulated since the discovery of ubiquitin-positive inclusions (UbIs) in ALS, ALS-dementia (ALS-D), and frontotemporal lobar degeneration (FTLD) with UbIs (FTLD-U). A breakthrough occurred in ALS research in October 2006, when TAR DNA-binding protein-43 (TDP-43) was identified as the core protein that is ubiquitinated in the cytoplasm, neurites and nucleus as UbIs. Antibody to phosphorylated TDP-43 selectively reacts to the inclusions and Western blotting demonstrates abnormal bands of phosphorylated TDP-43 in the brains of patients with ALS/FTLD-U. Similar findings were observed in ALS/parkinsonism-dementia complex (PDC) of Guam and Kii peninsula. These diseases are lumped in the "TDP-43 proteinopathy". In early 2008, several mutations of the TDP-43 gene were identified as the causative gene of autosomal-dominant familial ALS without SOD1 gene mutations. These findings suggest that abnormalities of TDP-43 directly or indirectly produce severe motor neuron degeneration. TDP-43 is thus one of the key proteins causing TDP-43 proteinopathies such as ALS, ALS-D, FTLD-U, and ALS/PDC of Guam and Kii. New revolutionary developments on ALS research for molecular mechanism and therapy are expected.
Purpose Swallowing difficulty is increased along with progression of respiratory disturbance in patients with Amyotrophic Lateral Scalerosis (ALS). To analyze the respiratory patterns during swallowing is important for the management of this disease. In this study, we evaluated apnea/hypopnea during water swallowing and the respiratory cycle at rest and after water swallowing. Method We evaluated respiratory patterns in swallowing in 10 ALS patients (66.0±7.1 years old), in 10 Myotonic dystrophy (MD) patients (46.5±12.2 years old), and in 10 healthy volunteers as control subjects (61.7±10.0 years old). The ALS and MD patients had consulted the Department of Neurology of Toneyama National Hospital or Tokushima National Hospital between April 2002 and July 2006. Respiratory patterns were evaluated by simultaneous recording of cervical swallowing sound in water swallow. A hypersensitive microphone measured cervical sound. A thermister was used for pneumography. The means of four continuous respiratory cycles at rest and after swallow of 3ml water were used for analysis. Respiration with amplitude of 1/2 or smaller than that of the pneumography at rest was defined as hypopnea, and the apnea/hypopnea duration was evaluated as the respiratory suppression time. Statistical Analysis All analyses were performed using SPSS 11.0J (SPSS Inc., Chicago, IL). Results In the ALS group, the respiratory cycle was 3.15±0.76sec (2.31-4.39sec) at rest, while after swallowing, it was 2.78±0.83sec (1.77-4.80sec) (p=0.1). In the MD group, the respiratory cycle was 2.56±0.46sec (1.91-3.67sec) at rest, while after swallowing, it was 2.94±0.60sec (2.03-4.29sec). In the control group, it was 3.46±0.57sec (3.18-4.34sec) at rest and 3.24±0.50sec (2.64-4.04sec) after swallowing. The apnea/hypopnea duration during water swallow was 14.33±8.89sec (2.50-30.68sec) in the ALS group, 3.66±1.58sec (1.78-6.42sec) in the MD group, and 3.64±1.00sec (2.34-5.56sec) in the control group. The apnea/hypopnea duration in the ALS group was significantly longer than that in MD and control groups (p=0.005, p=0.004 by the t-test). The ALS patients with severe respiratory failure or with aspiration in videofuoroscopy showed extended apnea/hypopnea duration. Conclusion Prolonged apnea/hypopnea was observed during water swallowing in ALS patients. We speculate that this prolongation is caused by severe swallowing disturbance and respiratory failure, which increases the risk of aspiration. The respiration of ALS patients should be closely monitored during eating.
To determine the frequency of cerebellar ataxia patients with autoantibodies for Hashimoto's disease, we analyzed 68 patients who were examined serum test for autoantibodies of Hashimoto disease among 178 cerebellar ataxia patients who visited our neurology clinic from January 2005 until December 2007. In these 68 patients, 8 had autoantibodies for Hashimoto's disease. Five of these 8 patients were diagnosed with hereditary spinocerebellar ataxia by genetic analysis. Moreover, one patient was diagnosed with probable multiple system atrophy by neurological examination. Cerebellar ataxic disease of known causes was ruled out for the remaining two cases; they were euthyroid and their cerebellar ataxia was slowly progressive and were diagnosed with cortical cerebellar atrophy. Although Hashimoto's disease may associate with cerebellar ataxia because cortical cerebellar atrophy is a heterogeneous condition, this association is not clear at present.
A 69-year-old woman was admitted to our hospital because of disturbed consciousness. She awoke to a solid mass in her left breast, but it had been present for about 20 years. On arrival to our hospital, she was comatose, and Babinski's reflexes were present bilaterally. She had no paresis or neck stiffness. Her left breast contained a 10cm×12cm node with multiple ulcers. Blood analysis showed she was in a hypercoagulative state. Computed tomography of the brain demonstrated bilateral hypodensities in the thalamus and hyperdensities at the vein of Galen and at the straight sinus. Angiography showed an absence of flow in the inferior sagittal sinus, in the vein of Galen, and in the straight sinus. Thus, she was diagnosed as having a deep cerebral venous thrombosis. She was treated by continuous heparin infusion, and her consciousness improved gradually. The biopsy of her left breast confirmed the presence of a mucinous carcinoma. The hypercoagulative state associated with the carcinoma was considered to be the cause of her deep cerebral venous thrombosis. It is very rare to diagnose deep cerebral venous thrombosis in a cancer patient while the patient is still alive. In this case, computed tomography of the brain was useful for the diagnosis.
We reported a 23-year-old woman with distal myopathy and highly elevated serum creatine kinase (CK) caused by calpainopathy. Although muscle weakness was not evident, a muscle CT scan revealed replacement by adipose tissue in the medial head of the gastrocnemius. The gluteus maximus and biceps femoris were also affected to a lesser degree, but the lateral head of the gastrocnemius was preserved. A histological study of a biopsied specimen of the biceps brachii revealed obvious variation in fiber size and a few necrotic or regenerating fibers. Rimmed vacuoles or lobulated fibers were absent in vacuoles. Although the clinical features suggested Miyoshi's distal myopathy, gene analysis of calpain 3 revealed a c.802-9G>A mutation in intron 5 and a c.1319G>A (p.Arg440Gln) in exon 10. Mini-multiplex Western Blotting (MMW) of the patient's muscle showed no band in calpain 3 (p94) and calpain 3 30kDa fragments and immunoblotting did not reveal any dysferlin abnormalities. Calpainopathy should be also considered in patients with clinical manifestations of Miyoshi distal myopathy.
We reported two patients of cardioembolic stroke with stepwise progression. Magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) showed narrowing of the middle cerebral artery (MCA) in both patients at the acute phase of onset. Case 1 was classified as "undetermined" based on the TOAST classification although his electrocardiogram revealed atrial fibrillation. Case 2 was classified as "large artery atherosclerosis" with no evidence of cardioembolic source at the acute phase of onset. Follow-up MRA was performed at seventeen days after the onset in case 1 and ten days after the onset in case 2 respectively, which showed complete recanalization of the MCA in each case. The presence of cardioembolic source was also detected in both patients at that time, resulting in the final diagnosis of cardioembolic stroke. Cardioembolic stroke may occasionally present in a stepwise manner suggesting a thrombotic process. When MRA shows stenosis or occlusion of the arteries supplying the cortical areas at the acute phase of onset, it is advisable to examine recanalization of these arteries by follow-up MRA with simultaneous efforts to find out the possible embolic source.
We have reported a case of autosomal recessive juvenile parkinsonism PARK6 with a 30-year history. She developed tremor of right lower limb at the age of 23. At the age of 28, she received a clinical diagnosis of early-onset Parkinson's disease. She showed clinical improvements by the treatment with trihexyphenidyl, but symptoms showed slow progression over the subsequent years. L-DOPA therapy was introduced at the age of 42, and five years later, L-DOPA-induced dyskinesia developed. Dystonia, diurnal fluctuation and sleep benefit were absent. She carried a homozygous missense mutation in PINK1 gene, and was diagnosed as PARK6. The brain MRI did not show apparent abnormality. 18F-FDG-positron emission topography (PET) displayed normal uptake in the brain, suggesting normal glucose metabolism. PET imaging with a dopamine D2 receptor ligand 11C-raclopride revealed that postsynaptic 11C-raclopride uptake was normal in the bilateral putamen. After the introduction of pramipexisol, she showed clinical improvements. L-DOPA-induced dyskinesia disappeared with the gradual tapering and withdrawal of L-DOPA. In this PARK6 case, postsynaptic D2 receptors of the nigro-striatal dopaminergic neurons were thought to be maintained despite a long disease history.
A-58-year old man presented with fluctuating ptosis and dysphagia. When he was 53 years old, he developed oral candidiasis and serum human immunodeficiency virus (HIV) RNA was detected. After starting highly active antiretroviral therapy, serum HIV RNA became undetectable. Neurological examination revealed ptosis and bulbar symptoms. Myasthenia gravis was comfirmed by a positive edrophonium test, showing 20% decrement of the compound muscle action potential on repetitive stimulation. Anti-acetylcholine receptor antibodies were negative and anti-muscle specific tyrosine kinase (MuSK) antibodies were positive. The chest CT scan was normal. He experienced transient clinical remission with pyridostigmine bromide and prednisolone. However relapse occurred after he returned to work. Persistent clinical remission was first observed after cyclosporin administration. There are eleven reports in which patients had concomitant myasthenia gravis and HIV infection. Most of those cases were benign in clinical course and required only anticholinesterase therapy. In our case, however, anti-MuSK antibodies were positive, and symptoms of myasthenia gravis remained despite prednisolone administration. Cyclosporin is directly active against HIV, and thus, cyclosporine therapy may be helpful in patients with concomitant myasthenia gravis and HIV infection.