Biomedical subjects
J Kira
Publications and source records attributed to J Kira.
[A patient with probable dementia with Lewy bodies, who showed improvement of dementia and parkinsonism by the administratim of donepezil].
We present a 73-year-old man with probable dementia with Lewy bodies(DLB). At 65 years of age, he gradually developed bradykinesia, gait disturbance and mild amnesia. At 71 years of age, he noted resting tremor in bilateral hands, and amnesia and disorientation were exacerbated. He was diagnosed as having parkinsonism and took L-dopa/carbidopa at 100 mg/day. Since he developed hallucination and abnormal behavior 2 days after the initiation of the drug, he stopped taking L-dopa and was admitted to our hospital. A neurological examination on admission revealed moderate amnesia, disorientation, finger agnosia, constitutional apraxia, mask-like face, cogwheel rigidity, resting tremor in bilateral hands, and bradykinesia. Brain MRI showed mild brain atrophy, and single photon emission computerized tomography(SPECT) showed diffuse moderate hypoperfusion in bilateral cerebral cortex. As he had fluctuating cognitive dysfunction and parkinsonism, he was diagnosed to have probable DLB. As his dementia was exacerbated by trihexyphenidyl, an anti-cholinergic agent, at 2 mg/day, we treated him with donepezil, an anti-choline esterase agent, at 3-5 mg/day. His parkinsonism, including rigidity and bradykinesia, was markedly improved his dementia, consisting of amnesia and disorientation. Electroencephalography (EEG) improved in the organization of the dominant rhythm. The SPECT improved in the blood perfusion of the bilateral frontal lobe as well as cognitive function and parkinsonism were maintained by donepezil for 6 months after discharge. A therapeutic efficacy of donepezil for DLB has recently been reported. It is notable that donepezil was beneficial not only for cognitive dysfunction but also for parkinsonism in the present case with probable DLB.
[A patient with vitamin E deficient, myopathy presenting with amyotrophy].
We report a 61-year-old man with vitamin E deficiency, presenting with, myopathy as an only clinical symptom. In 1997, at 59 years of age, he noted mild proxymal-muscle weakness and atrophy in the four extremities, nine years after he received a Billroth II partial gastrectomy for a gastric ulcer. His muscle weakness slowly exacerbated, and he was admitted to our hospital in 1999. On admission, neurological examination confirmed mild proximal-muscle weakness and atrophy in the four extremities. Intelligence, cranial nerves, coordination, sensation and tendon reflexes were all normal. Laboratory examination showed normochromic anemia (Hb 9.9 g/dl, Ht 30.9%, MCV 97.5 fl, MCHC 31.2 pg), hypoproteinemia (5.0 g/dl), and hypocholesterolemia (107 mg/dl). The levels of serum CK, lactate and pyruvate were normal. The serum vitamin E level was markedly reduced (0.17 mg/dl; normal 0.75-1.41). Cerebrospinal fluid was normal. Nerve conduction, sensory evoked potentials (SEP), electromyography (EMG), head CT and electroencephalography (EEG) were all normal. Muscle biopsy from the right deltoid muscle showed both mild myogenic and neurogenic changes. Remarkably, type 1 muscle fiber predominance and granular accumulation of autofluorescent lipofuscin granules in the muscle fibers were found. These pathological findings were compatible with those of vitamin E-deficient myopathy. Thus, he was diagnosed as having vitamin E-deficient myopathy, which was confirmed by apparent effective supplementation of vitamin E. Interestingly, our present case did not show any other neurological manifestations such as deep sensory disturbance, sensory ataxia or polyneuropathy. A long-term workload due to hard physical labor and smoking in our patient may have accelerated oxidative muscle damage, resulting in amyotrophy mainly due to vitamin E deficient myopathy.
[A patient with restless legs syndrome/periodic limb movement successfully treated by wearing a lumbar corset].
We report a 77-year-old woman with restless legs syndrome(RLS) and periodic limb movement(PLM). From 62 years of age, she was awakened by tingling and involuntary movement in her legs during sleep. There symptoms disappeared when she stood up and walked. She was treated with clonazepam (2.5 mg/day) and valproate (400 mg/day) at 77 years of age, and the symptoms clearly ameliorated. However, she developed mild truncal ataxia and was referred to our hospital. On admission, neurological examination revealed Babinski and Chaddock signs bilaterally with depressed tendon reflexes in the lower limbs, mild truncal ataxia and horizontal gaze nystagmus. She did not present with involuntary movement of the legs while taking the anti-epileptic drugs. Cessation of these drugs alleviated the truncal ataxia and nystagmus, but reexacerbated abnormal sensation with involuntary movement in her legs during sleep. The involuntary movements in her legs were slower than myoclonus and resembled a Babinski reflex (duration about 1 second), and they appeared periodically (around every 30 seconds) in I-II sleep stages. Neither brain MRI nor EEG detected any abnormality. Cervical MRI revealed focal compression of the spinal cord by osteophytes at C5-C6 (more severe on the left side). Motor evoked potentials with transcranial magnetic stimulation revealed a mild delay in the central conduction time (CCT), which was more prolonged on the left side. She was thus diagnosed as having RLS/PLM with involvement of the bilateral pyramidal tracts. Although nerve conduction studies did not detect any abnormality in the peripheral nerves, RLS/PLM of the left leg was induced by electric stimulation of the left tibial nerve. Because she did not want medication any more, we treated her with a lumbar corset, hoping that wearing a lumbar corset might induce contraction of the truncal muscles that would mimic standing and walking or might produce additional sensory input that would induce a 'sensory trick'. Consequently, her abnormal sensation and involuntary movement during sleep as well as the stimulation of the tibial nerve disappeared. Wearing a lumbar corset may inhibit the excitability of the spinal cord that generates RLS/PLM, though the level of sensory input by the corset was higher than the input level of abnormal sensation in her legs. A lumbar corset may be a useful alternative choice for patients with RLS/PLM, who cannot tolerate either anti-epileptic or dopaminergic drugs.
[An autopsy case of dementia with motor neuron disease accompanying Alzheimer's disease lesion].
We report the case of a 60-year-old man with autopsy-proven dementia with motor neuron disease (D-MND) and Alzheimer's disease lesion. The patient presented with clumsiness of his right hand at the age of 55 years old and subsequently developed dysarthria, weakness and atrophy of his upper limbs. He was unaffectionate towards his family, repeated the same phrase, and showed severe disorientation of time and place. Neurological examination on admission showed not only diffuse lower motor neuron signs, such as weakness, atrophy, fasciculation and areflexia in both upper limbs, but also dementia (HDS-R 9/30). He died of respiratory insufficiency. Neuropathological examination showed mild atrophy of the frontal and temporal lobes and anterior spinal roots. Microscopic examination of cortical sections revealed degenerative changes with simple atrophy and gliosis, and these changes were predominant in layers 1 and 2 of the frontal and temporal cortices. Using immunohistochemical staining, ubiquitin-positive but tau-negative inclusions were frequently found in neurons of the hippocampal granular cell layers and temporal lobes. Many senile plaques and neurofibrillary tangles were present in all sections of the brain. Our final diagnosis was dementia with motor neuron disease accompanying Alzheimer's disease lesion, because of hypoperfusion in the parietal lobe as well as the frontal lobe demonstrated by SPECT, and the presence of many senile plaques and neurofibrillary tangles in the cerebral cortex. Overlapping of pathologically-proven D-MND and Alzheimer's disease lesion is extremely rare, and this case may improve our understanding of the process of neurodegeneration.
[A patient with neuroborreliosis presenting gadolinium-enhanced MRI lesions in bilateral facial nerves].
We report a 33-year-old man with bilateral facial paralysis due to neuroborreliosis. About three weeks after rhinorrhea and fever lasting four days, he noticed fatigue in the legs and paresthesia in all four extremities. Another week later, he developed paresthesia in his tongue and bilateral facial muscle weakness, and was admitted to our hospital. On admission, neurological examination revealed moderate bilateral facial muscle weakness, mild paresthesia in the tongue and four extremities, and decreased Achilles tendon reflex bilaterally. Mild pleocytosis and increased protein were found in the cerebrospinal fluid (CSF). IgM antibodies that reacted with the antigens of Borrelia garinii and Borrelia afzelii were found in his serum. Clinically and serologically, he was thus diagnosed as having neuroborreliosis. Brain MRI revealed gadolinium-enhanced lesions of the bilateral facial nerves in the facial nerve canal portion. After three weeks of treatment with 100 mg/day doxycycline and 2 g/day ceftriaxone sodium, his symptoms and CSF abnormalities were rapidly improved. Although facial nerve paralysis is a major symptom of neuroborreliosis, the present report is the first to detect the inflammatory lesions of the facial nerves in the facial nerve canal portion by MRI.
[Mite allergy and neural damage].
The number of adult patients with atopic disorders is increasing in Japan. We recently reported the occurrence of myelitis in patients with atopic diathesis (atopic myelitis). The characteristic features of myelitis with atopic diathesis are: (1) paresthesia/dysesthesia as the predominant symptom, (2) mild and infrequent, if any, muscle weakness, (3) preferential involvement of the cervical cord, (4) persistence of neurologic symptoms and MRI lesions, (5) hyperIgEaemia, (6) mite antigen-specific IgE in serum, and (7) normal cerebrospinal fluid findings. The spinal cord lesions show eosinophilic inflammation on biopsy. We also found an association of Hirayama disease, juvenile muscular atrophy of the distal upper limb, with atopic diathesis. In children, poliomyelitis-like illness following asthma attacks is well known as Hopkins syndrome. These three conditions suggest a link between atopic diathesis and the development of spinal cord disease.
Vergence disorders in patients with spinocerebellar ataxia 3/Machado-Joseph disease: a synoptophore study.
Diplopia, a common symptom in spinocerebellar ataxia 3/Machado-Joseph disease (SCA3/MJD) cases, is not always due to asymmetric ophthalmoplegia. We found a Japanese SCA3/MJD family, in which three patients clearly had an impairment of divergence eye movement. We thus quantitatively examined the vergence ranges in eight Japanese SCA3/MJD cases using the synoptophore test. An impairment of the vergence eye movements was found in all patients, and the vergence impairment pattern, but not the ophthalmoplegia pattern, was found to be compatible with the diplopia pattern. The diplopia in SCA3/MJD cases is, therefore, attributed, at least in part, to the impairment of the vergence eye movements.
Selective increase in cellular A beta 42 is related to apoptosis but not necrosis.
Amyloid beta protein ending at 42 (A beta 42) plays an important role in the pathology of Alzheimer's disease (AD). Here we show an increase in cellular A beta 42 in damaged neurons, with both ELISA and immunocytochemistry. The cellular A beta 42 increase was caused by 3-day treatments with H2O2, etoposide or melphalan, all of which induce genotoxic apoptosis, but not by treatment with sodium azide, which causes necrosis. Secreted A beta was similarly decreased with all these treatments. The cellular A beta 42 increase appeared even with minimal damage (ELISA) and A beta 42-positive cells were TUNEL negative (double staining), indicating that any early apoptosis mechanism may induce the cellular A beta 42 increase. Thus, neuronal apoptosis and cellular A beta 42 increase may be linked in a way that contributes importantly to AD pathology.
Lovastatin does not correct the accumulation of very long-chain fatty acids in tissues of adrenoleukodystrophy protein-deficient mice.
Lovastatin, an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase, normalizes the very long-chain fatty acids (VLCFA) concentrations in fibroblasts and plasma from patients with X-linked adrenoleukodystrophy (X-ALD). The effects of lovastatin on the accumulation of VLCFA in tissues of adrenoleukodystrophy protein (ALDP)-deficient mice were assessed. ALDP-deficient mice were fed chow with 0.01-0.1% lovastatin for 4-8 weeks. The VLCFA concentrations in the plasma, brain, spinal cord, liver and kidneys were measured. Treatment with 0.1% lovastatin significantly reduced body weight and total cholesterol in the plasma of ALDP-deficient mice. Treatment with lovastatin, however, did not correct the accumulation of VLCFA in the plasma or tissues, including the brain and spinal cord. Lovastatin does not affect the accumulation of VLCFA in ALDP-deficient tissues in mice.
Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors.
The purpose of this study was to clarify the association of HLA-DRB1 and -DPB1 alleles with multiple sclerosis (MS) in Japanese, to determine whether optico-spinal MS (OS-MS) and conventional MS are immunogenetically distinct, and to verify the role of gender difference in HLA associations of MS. We studied HLA-DRB1 and -DPB1 polymorphisms in 166 Japanese patients with MS. Forty-seven patients were classified as having the optico-spinal MS (OS-MS) and 119 as having conventional MS. A lack of DPB1*0301 and a higher frequency of DPB1*0501 compared with controls (corrected P<0.0074; odds ratio=9.48) were found in OS-MS. By contrast, we found for the first time an association of DPB1*0301 with conventional MS in Japanese (corrected P=0.0444; odds ratio=3.28). Logistic analysis, adjusted for sex and age, revealed independent associations of DPB1*0301 (P=0.0004, adjusted odds ratio (aOR)=4.70), DPB1*0501 (P=0.0081, aOR= 2.50) and DRB1*1501 (P=0.0252, aOR=2.21) with conventional MS. However, the frequencies of DRB1*1501 and DPB1*0501 in male patients with conventional MS were equal to those in male controls while the DPB1*0301 frequency was increased in both male and female patients. We did not find any association of these HLA alleles with disease course and severity. In conclusion, OS-MS is a DPB1*0501-associated distinct subtype of MS, and DPB1*0301 is the most strongly associated allele with conventional MS in Japanese. In addition, gender plays an important role in HLA association with MS.
Familial Creutzfeldt-Jakob disease with D178N-129M mutation of PRNP presenting as cerebellar ataxia without insomnia.
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Acute myelitis after asthma attacks with onset after puberty.
A poliomyelitis-like illness after asthma attacks has been found and is called asthmatic amyotrophy (Hopkins' syndrome). All of the previously reported cases were under 13 years of age. Three patients are described who developed acute myelitis after asthma attacks at 15, 22, and 73 years of age. All of them showed acute flaccid monoparesis, and needle EMG disclosed denervation potentials in the relevant muscles. In addition, in the two adult patients the sensory or pyramidal tracts were involved, and evoked potential studies confirmed an involvement of the pyramidal tracts in one of them. This 22 year old patient showed a second episode of monoparesis in the other limb after another asthma attack. All three patients had no significant changes in their antiviral antibody titres, whereas every patient had hyperIgEaemia and allergen specific IgE. These findings suggest that asthmatic amyotrophy can develop after puberty and that patients who develop this disease in adulthood seem to show both a widespread involvement of the spinal cord and a more varied course.
Very-long-chain fatty acid metabolism in adrenoleukodystrophy protein-deficient mice.
X-linked adrenoleukodystrophy (X-ALD) is characterized by progressive mental and motor deterioration, with demyelination of the central and peripheral nervous system. Its principal biochemical abnormality is the accumulation of very-long-chain fatty acids (VLCFAs) in tissues and body fluids, caused by the impairment of peroxisomal beta-oxidation. The authors have generated a line of mice deficient in ALD protein (ALDP) by gene targeting. ALDP-deficient mice appeared normal clinically, at least up to 12 mo. Western blot analysis showed absence of ALDP in the brain, spinal cord, lung, and kidney. The amounts of C26:0 increased by 240% in the spinal cord. VLCFA beta-oxidation in cultured hepatocytes was reduced to 50% of normal. The authors investigated the roles of ALDP in VLCFA beta-oxidation using the ALDP-deficient mice. Very-long-chain acyl-CoA synthetase (VLACS) is functionally deficient in ALD cells. The impairment of VLCFA beta-oxidation in the ALDP-deficient fibroblasts was not corrected by over-expression of VLACS only, but was done by co-expression of VLACS and ALDP, suggesting that VLACS requires ALDP to function. VLACS was detected in the peroxisomal and microsomal fractions of the liver from both types of mice. Peroxisomal VLACS was clearly decreased in the ALDP-deficient mouse. Thus, ALDP is involved in the peroxisomal localization of VLACS.
A novel feature disclosed in opticospinal multiple sclerosis in Asians.
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Hyperprolactinemia in optico-spinal multiple sclerosis.
OBJECTIVE: To clarify the clinical features of MS patients with hyperprolactinemia. SUBJECTS AND METHODS: The serum prolactin level was measured in 67 Japanese patients (19 men and 48 women) with multiple sclerosis (MS) and in 16 patients (4 men and 12 women) with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) using a two-site immunoradiometric assay. RESULTS: In the MS patients, 32 were classified as having Asian type MS showing a selective involvement of the optic nerves and spinal cord, while the other 35 were classified as having Western type MS which displayed disseminated central nervous system involvement. In women, the serum prolactin level was found to be significantly higher only in Asian type MS (mean=23.1 ng/ml, n=25) than in HAM/TSP (mean=6.9 ng/ml, n=12) (p=0.0297), while it did not differ significantly in men among the three groups. Hyperprolactinemia was significantly associated with acute relapse involving the optic nerves. All MS patients with hyperprolactinemia (7 women with Asian type MS and 2 women with Western type MS) showed recurrent opticomyelitis either throughout or in the early course of the disease, and also had a higher age of onset, a higher Expanded Disability Status Scale score, a greater visual impairment, and higher cell counts and protein contents in the cerebrospinal fluid than did the normoprolactinemic patients. CONCLUSION: Hyperprolactinemia may be one of the characteristic features of Asian patients with MS who preferentially show the optic nerve involvement.
Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.
Hyperornithinemia, hyperammonemia and homocitrullinuria (HHH) syndrome presents with various neurological symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma caused by hyperammonemia. We report three novel mutations in the mitochondrial ornithine transporter gene (ORNT1) of Japanese patients with HHH syndrome: a nonsense mutation (R179X) associated with exon skipping and a frameshift, a missense mutation (G27E), and an insertion of AAC between codons 228 and 229, leading to an insertion of the amino acid Asn. The ORNT1 gene consists of at least six exons, and all exon-intron junction sequences conform to the GT/AG rule. All 3 patients were homozygous for their respective mutations. This study confirms that defects in the ORNT1 gene cause the HHH syndrome and that the genetic basis in Japanese patients is heterogeneous.
[A case of diabetic polyneuropathy complicated with entrapment neuropathy of the bilateral ulnar nerves due to osteoarthrosis at the elbow].
We report a 61-year-old man with diabetic polyneuropathy and bilateral ulnar nerve palsy due to osteoarthrosis in the elbow. He was diagnosed as having non-insulin dependent diabetes mellitus (DM) at 40 years of age. At 56 years of age, he developed muscle atrophy and weakness predominantly in the distal parts of his upper limbs. A neurological examination showed him to have severe atrophy and weakness in the muscles innervated by the ulnar nerve bilaterally. He also had paresthesia on the distal parts of all four limbs. Superficial and deep sensory deficits were observed in the lower limbs. A motor nerve conduction study showed a marked reduction in the motor conduction velocity as well as in the amplitude of the action potentials of both ulnar nerves. Roentgenograms of the elbow joints and grooves for the ulnar nerve revealed marked osteophyte formation bilaterally. The bilateral ulnar nerve palsy was thus considered to be due to the entrapment of the nerve by the osteophyte. Since several studies have suggested the existence of a relationship between DM and osteoarthropathy, it is important to check for the possible presence of osteoarthrosis in cases of diabetic neuropathy complicated with entrapment neuropathy.