Masaaki Hirayama

Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy

Characteristics of alcoholic neuropathy have been obscured by difficulty in isolating them from features of thiamine‐deficiency neuropathy. We assessed 64 patients with alcoholic neuropathy including subgroups without (ALN) and with (ALN‐TD) coexisting thiamine deficiency. Thirty‐two patients with nonalcoholic thiamine‐deficiency neuropathy (TDN) also were investigated for comparison. In ALN, clinical symptoms were sensory‐dominant and slowly progressive, predominantly impairing superficial sensation (especially nociception) with pain or painful burning sensation. In TDN, most cases manifested a motor‐dominant and acutely progressive pattern, with impairment of both superficial and deep sensation. Small‐fiber‐predominant axonal loss in sural nerve specimens was characteristic of ALN, especially with a short history of neuropathy; long history was associated with regenerating small fibers. Large‐fiber‐predominant axonal loss predominated in TDN. Subperineurial edema was more prominent in TDN, whereas segmental de/remyelination resulting from widening of consecutive nodes of Ranvier was more frequent in ALN. Myelin irregularity was greater in ALN. ALN‐TD showed a variable mixture of these features in ALN and TDN. We concluded that pure‐form of alcoholic neuropathy (ALN) was distinct from pure‐form of thiamine‐deficiency neuropathy (TDN), supporting the view that alcoholic neuropathy can be caused by direct toxic effect of ethanol or its metabolites. However, features of alcoholic neuropathy is influenced by concomitant thiamine‐deficiency state, having so far caused the obscure clinicopathological entity of alcoholic neuropathy. Ann Neurol 2003

Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease

Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinsons disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of approximately 50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinsons disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinsons disease.

Cardiac (123)I-meta-iodobenzylguanidine (MIBG) uptake in dementia with Lewy bodies: comparison with Alzheimer's disease.

Cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake was measured in 11 patients with dementia with Lewy bodies (DLB), 10 patients with Alzheimers disease (AD), and 10 age matched control subjects. The severity of cognitive impairment and duration of symptoms in patients with DLB matched that in the patients with AD. The heart/mediastinum (H/M) ratio of MIBG uptake in the patients with AD was indistinguishable from that in the control subjects. However, the H/M ratio in all patients with DLB was significantly lower than that in the patients with AD and control subjects (p<0.001). These findings indicate that local myocardial sympathetic nerves are affected in DLB and that cardiac 123I-MIBG scintigraphy may provide a means of differentiating DLB from AD.

Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status.

Background: Although polyneuropathy related to chronic alcoholism has been reported frequently, its clinical features and pathogenesis remain to be clarified. Objective: To determine the clinicopathologic features and pathogenesis of alcoholic polyneuropathy associated with pain in patients with normal thiamine status, particularly in comparison to beriberi neuropathy. Patients and methods: Clinical, electrophysiologic, and histopathologic findings were assessed in 18 patients with painful alcoholic polyneuropathy and normal thiamine status. Results: Symmetric sensory-dominant polyneuropathy predominantly involving the lower limbs was the major clinical pattern. Painful sensations with or without burning quality represented the initial and major symptom. Progression of symptoms usually was gradual, continuing over months or years. Electrophysiologic and pathologic findings mainly indicated an axonal neuropathy. Densities of small myelinated fibers and unmyelinated fibers were more severely reduced than the density of large myelinated fibers, except in patients with a long history of neuropathic symptoms and marked axonal sprouting. Conclusions: The clinicopathologic features of painful symptoms and small axon loss are distinct from those of beriberi neuropathy. Sensory-dominant involvement with prominent neuropathic pain is characteristic of alcoholic neuropathy when thiamine deficiency is not involved, supporting the view of direct neurotoxic effect by alcohol or its metabolites.

A radiological analysis of heart sympathetic functions with meta-[123I] iodobenzylguanidine in neurological patients with autonomic failure

Cardiac scintigraphy with meta-[123I]iodobenzylguanidine (MIBG) is used to assess cardiac sympathetic function. We performed [123I]MIBG scintigraphy in 7 patients with neurological diseases presenting orthostatic hypotension and other autonomic failures (AF), 22 neurological patients without AF, and 9 healthy subjects. Thallium scintigraphy and echocardiography were also performed in all subjects. In this series, patients with any evidence of cardiac dysfunction were excluded. No [123I]MIBG accumulation was observed in all patients with AF, and cardiac defects were noted in 7 patients (5 with Parkinsons disease [PD], 2 with spinocerebellar degenerations [SCD]), and in some patients without AF. In contrast, the distribution of [123I]MIBG was normal in all the healthy subjects. No decrease in [123I]MIBG accumulation was resulted from drug therapy (droxidopa, amezinium and thyrotropin-releasing hormone). In conclusion, reduced accumulation on [123I]MIBG scintigraphy may be due to myocardial beta-adrenoceptor dysfunction or reduced central sympathetic activity of the heart, or both.

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%–15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK–immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods: We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of Colq−/− mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice. Results: The in vitro overlay assay revealed that MuSK-IgG blocks binding of ColQ to the neuromuscular junction. The in vitro plate-binding assay showed that MuSK-IgG exerts a dose-dependent block of MuSK binding to ColQ by but not to LRP4. Passive transfer of MuSK-IgG to mice reduced the size and density of ColQ to ∼10% of controls and had a lesser effect on the size and density of AChR and MuSK. Conclusions: As lack of ColQ compromises agrin-mediated AChR clustering in Colq−/− mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients. Our experiments also predict partial AChE deficiency in MuSK-MG patients, but AChE is not reduced in biopsied NMJs. In humans, binding of ColQ to MuSK may be dispensable for clustering ColQ, but is required for facilitating AChR clustering. Further studies will be required to elucidate the basis of this paradox.

An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val)

OBJECTIVES AND METHODS Seven families were studied with an axonal form of Charcot-Marie-Tooth disease (CMT) associated with mutations in the peripheral myelin protein zero (MPZ) gene—Thr124Met or Asp75Val. RESULTS Patients with these mutations commonly showed relatively late onset sensorimotor neuropathy predominantly involving the lower limbs. Sensory impairment typically was marked, and distal muscle atrophy and weakness were also present in the legs. Adies pupil and deafness were often present, and serum creatine kinase concentrations were often raised irrespective of which MPZ mutation was present. Relatively well preserved motor and sensory nerve conduction velocities contrasted with reduced or absent compound muscle action potentials and sensory nerve action potentials. Axonal change with marked axonal sprouting was seen in sural nerve specimens. CONCLUSION The similar associated clinical findings suggest that patients with axonal CMT with an MPZ gene mutation share distinctive clinical features.

Postgastrectomy polyneuropathy with thiamine deficiency

OBJECTIVE Polyneuropathy has been reported after gastrectomy performed to treat various lesions. Although thiamine deficiency is a possible cause of this neuropathy, the pathogenesis still remains to be clarified. Seventeen patients with peripheral neuropathy with thiamine deficiency after gastrectomy are described. METHODS Seventeen patients with polyneuropathy after gastrectomy accompanied by thiamine deficiency were selected. Patients were restricted to those with total or subtotal gastric resection to treat ulcer or neoplasm. Patients who had undergone operations to treat morbid obesity were excluded. RESULTS Intervals between the operation and onset of neuropathy varied from 2 months to 39 years. Most patients did not seem malnourished. Serum concentrations of B vitamins other than thiamine were nearly normal. Symmetric motor-sensory polyneuropathy, predominantly involving the lower limbs, had progressed over intervals varying from 3 days to 8 years. Relative degrees of motor and sensory impairment also varied extensively. Some cases that progressed rapidly mimicked Guillain-Barré syndrome. Electrophysiological and pathological findings were those of axonal neuropathy. Substantial functional recovery from polyneuropathy was seen in most patients by 3 to 6 months after initiating thiamine supplementation. Motor recovery was better than sensory recovery. CONCLUSIONS Various symptoms were seen in patients with postgastrectomy neuropathy. Thiamine deficiency should be considered in the differential diagnosis of motor-sensory polyneuropathy after gastrectomy.

Onset age and severity of motor impairment are associated with reduction of myocardial 123I-MIBG uptake in Parkinson's disease

Objectives: To elucidate the factors associated with severity of cardiac sympathetic nerve involvement in idiopathic Parkinson’s disease (PD). Methods:123I-metaiodobenzylguanidine uptake was examined in 88 patients with PD. The ratio of the uptake in the heart (H) to that in the mediastinum (M) (the H/M ratio) was calculated and correlated with age at onset, age at examination, and disease severity and duration. Twenty five healthy people were also examined as a control. Results: There was a mild but significant negative correlation between H/M ratio and age at onset (early, r = −0.33, p = 0.002; delayed, r = −0.34, p = 0.001) and between Hoehn and Yahr (H-Y) stage (early, r = −0.30, p = 0.006; delayed, r = −0.32, p = 0.003). There was no significant correlation between disease duration and H/M ratio. When patients with PD were classified into four subgroups on the basis of age at onset (> 62 or < 62 years) and disease severity (H-Y > III or H-Y ⩽ II), the median H/M ratio of the older and more severe group was significantly lower than that of the younger and less severe group (p = 0.005). Conclusion: This study suggests that late onset, high severity PD is associated with myocardial sympathetic dysfunction.

Clinical and physiological characteristics of autonomic failure with Parkinson's disease

We analyzed the clinical and physiological features of autonomic failure with Parkinsons disease (AF-PD) in seven patients and compared them with those of autonomic failure with multiple system atrophy (AF-MSA). In AF-PD, parkinsonism was more gradually progressive than in AF-MSA, and symptoms were responsive to L-dopa. All seven patients with AF-PD had orthostatic hypotension, postprandial hypotension, and constipation, but no urinary retention. Of these, three had hypohidrosis and five had frequent urination; five patients had subnormal plasma norepinephrine (NE) concentrations. Supersensitivity to NE infusion was observed in all patients. Head-up tilting (HUT) test resulted in no increase of plasma NE concentrations in both groups, but a significant increase of the plasma arginine vasopressin (AVP) concentrations in the patients with AF-PD. Urodynamic studies revealed that urinary bladder function was relatively well preserved in AF-PD in contrast to AF-MSA. In conclusion, there exists some clinical and physiological differences in autonomic features between AF-PD and AF-MSA, and postganglionic involvement predominates in AF-PD.