[Case of cerebellar and spinal cord infarction presenting with acute brachial diplegia due to right vertebral artery occlusion].

A 73-year-old man was admitted for evaluation of sudden onset of dizziness, bilateral shoulder pain, and brachial diplegia. Neurological examination revealed severe bilateral weakness of the triceps brachii, wrist flexor, and wrist extensor muscles. There was no paresis of the lower limbs. His gait was ataxic. Pinprick and temperature sensations were diminished at the bilateral C6-C8 dermatomes. Vibration and position senses were intact. An MRI of the head revealed a right cerebellar infarction and occlusion of the right vertebral artery. An MRI of the cervical spine on T2 weighted imaging (T2WI) showed cord compression at the C3/4-C5/6 level secondary to spondylotic degeneration without any intramedullary signal changes of the cord. On the following day, however, high-signal lesions on T2WI appeared in the C5-C6 spinal cord, suggesting cord infarction. Unilateral vertebral artery occlusion does not usually result in cervical cord infarction because of anastomosis of arteries. Because of the long-term mechanical compression in our case, it was likely that cervical cord ischemia was present before the onset of symptoms. On the basis of chronic cord compression, our case suggests that occlusion of a unilateral vertebral artery could cause cervical cord infarction.

[Elderly hereditary hemorrhagic telangiectasia female with portosystemic encephalopathy].

We present a 71-year-old woman with hereditary hemorrhagic telangiectasia (HHT) who at age 69, had undergone total gastrectomy because of repeated upper gastrointestinal bleeding. A day prior to admission she began to demonstrate abnormal behavior. Examination showed she was restless and had higher brain dysfunction. Triphasic waves were seen on EEG, and a high signal in the globus pallidus on T1-weighted MRI. Plasma NH3 level was increased after a meal. Abdominal CT scan showed vascular anomalies including a portohepatic vein shunt. She was diagnosed with portosystemic encephalopathy. After treatment with a low-protein diet, lactitol, and branched chain-amino acids, her clinical condition, plasma NH3 level after a meal, and EEG returned to normal. Because portosystemic shunt is rare in HHT, there have been few reports of portosystemic encephalopathy with this condition. However, with aging, the possibility of portosystemic encephalopathy increases because of age-related increases in portosystemic shunt volume.

CADASIL-causing mutations do not alter Notch3 receptor processing and activation.

CADASIL is associated with mutations in the Notch3 gene but the causal mechanisms of the disorder remain unclear. We studied effects of widely established mutations on Notch3 receptor processing and ligand-mediated activation in stable lines of HEK293 and SH-SY5Y cells expressing either human wild-type or mutant Notch3 receptor. None of the four mutations (R90C, R133C, C185R and R449C) affected quantities of the full-length, amino-terminal or carboxyl-terminal fragments and did not impair intracellular trafficking in both cell types. The Jagged 1, Jagged 2 and Delta ligand-mediated S2 site cleavage and signal transduction were also observed to be similar in both wild-type and mutants, which exhibited similar rates of degradation of full-length, amino-terminal and carboxyl-terminal fragments. Our results suggest that the arteriopathy in CADASIL is caused by other mechanisms not necessarily involving Notch3 processing and activation.

[A case of MELAS presenting juvenile-onset hyperglycemic chorea-ballism].

We report herein the case of a 28-year-old man presenting with hyperglycemic chorea-ballism (HCB) in addition to mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). He was admitted to a local hospital due to weight loss, general fatigue and thirst. The patient had diabetes mellitus, with a blood glucose level of 738 mg/dl and HbA1c of 19.8%. Although insulin therapy improved hyperglycemia, he noticed involuntary movements in the right upper and lower limbs, which subsequently extended to the left side. The patient was thus transferred to our hospital. He displayed short stature (154 cm) and emaciation, and a maternal family history of diabetes mellitus was elicited. He had no history of stroke-like episode, headache, vomiting and seizure. Neurological examination revealed low intelligence (IQ 57), mild sensorineural deafness, and chorea-ballism in the extremities and head without ptosis or eye movement disturbance. Brain computed tomography (CT) demonstrated areas of high density, while T1-weighted magnetic resonance imaging (MRI) revealed extreme hyperintensity and T2-weighted MRI showed hyperintensity in bilateral caudate nuclei, putamina and globi pallidus. HCB was diagnosed. In, CSF, lactate level was increased to 43.9 mg/dl (n, 4-16), pyruvate level was 1.65 mg/dl (n, 0.3-0.9) and total protein concentration was 59 mg/dl. Histological examination of a biopsy sample from the biceps brachii muscle demonstrated ragged-red fibers. An A3243G point mutation in the tRNA(Leu(UUR)) gene was detected, indicating the presence of MELAS. Involuntary movements improved on treatment with haloperidol up to 4.5 mg/day. HCB usually appears in elderly individuals, and cases less than 40-years-old are very rare. The mitochondrial dysfunction in MELAS may accelerate development of HCB.

[MRI and SPECT findings in a case of metronidazole-induced reversible acute cerebellar ataxia].

A 69-year-old man was referred to our department because of acute onset nausea, vomiting, dysphagia, dysarthria and gait disturbance. He had a 50-day-history of amebic dysentery and had been treated with 1,500 mg metronidazole per day. Neurological examination revealed dysphagia, ataxic speech, ataxia of the left extremities and the trunk, and hyperactive deep tendon reflexes in all extremities. Sensory impairment of all modalities was apparent in a glove and stocking pattern, with mild paresthesia. Brain MRI showed T2 high signal lesions in the bilateral cerebellar dentate nuclei, more markedly on the left. On brain SPECT, obvious low blood perfusion was observed in the left cerebellar hemisphere. These findings well explained the ataxia of the left limbs. One month after discontinuing metronidazole, the cerebellar ataxia, dysphagia and MRI abnormalities completely cleared. Therefore, central nervous system damage induced by metronidazole is considered reversible. In spite of the presence of the MRI lesion in the right dentate nucleus, the patient had no ataxia of the right extremities and there was no hypoperfusion in the right cerebellar hemisphere. Thus, metronidazole does not appear to have a direct neurotoxic effect on the central nervous system. On the other hand, nerve conduction studies showed axonal polyneuropathy, which was not improved one month after cessation of the drug; thus metronidazole seems to exert more damage on peripheral nerves.

[Primary progressive multiple sclerosis as a differential diagnosis of ALS: a case report].

A 44-year-old man was admitted to our hospital because of a five year history of chronic progressive gait disturbance. Neurological examination revealed mild weakness and atrophy of the upper extremities, but severe of the lower ones, and without sphincter disturbance or apparent sensory impairment. Hyperreflexia and positive pathological reflexes of the lower extremities were apparent. EMG showed a reinnervation pattern and decreased number of motor units in the extremities, suggesting ALS. However, multiple plaques on the head and spinal MRI, a prolonged central conduction time of MEP and SEP, a delayed P100 latency of VEP, and a increased IgG index in the CSF indicated primary progressive type multiple sclerosis. After receiving steroid pulse therapy, the weakness of the lower extremities showed slight improvement. Diffuse inflammation in the spinal cord involving not only the pyramidal tract but also the anterior horn cells/intramedullary ventral roots explained the ALS-like clinical picture.

Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis.

We have examined Notch3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose samples were submitted to us in Japan. The subjects were composed of 21 Japanese, 1 Iranian, 1 Korean and 1 Canadian families. Mutations in the Notch3 gene were found in 7 of 24 families examined. These were R133C in two unrelated Japanese families, and R213K, C174F and R169C in each Japanese family. In addition, we have found R90C in an Iranian family and C174R in a Korean family. Thus, contribution of Notch3 gene mutations is less than one fourth of Japanese CADASIL families, suggesting the existence of other causative genes in CADASIL. It is also of interest to know that Notch3 mutant CADASIL exists in other Asian countries. We next examined the localization of Notch3 protein in the tissue by immunohistochemistry. It was restricted to the wall of arterioles in the brain and other organs. In the brain, there was no difference in the staining pattern among arterioles in the cortex, white matter and meninges. The staining was negative in the venule and capillaries as well as in neurons and glial cells. From the staining pattern, it was recognized to be expressed in the vascular smooth muscle cells in the adult tissue. In an autopsy case with R213K mutation, we could see numerous cerebral infarcts and arteriole wall degeneration with deposits of granular osmiophilic material (GOM). However, it is interesting to note that occlusion of arterioles was rarely observed and the GOM was negative for Notch3 staining. These findings suggest that hemodynamic abnormalities due to smooth muscle cell degeneration may be important in the pathogenesis of CADASIL.