Haruki Koike

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

Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy

Background: Late-onset type I familial amyloid polyneuropathy (FAP TTR Met30) cases unrelated to endemic foci in Japan show clinical features setting them apart from early-onset cases in endemic foci. Objective: To compare pathologic features between the early- and late-onset types. Methods: Pathologic findings in FAP TTR Met30 with onset before age 50 in relation to endemic foci (11 cases) were compared with those in 11 later-onset cases unrelated to endemic foci. Results: Sural nerve biopsy specimens showed predominantly small-fiber loss in early-onset cases; variable fiber size distribution, axonal sprouting, and relatively preserved unmyelinated fibers characterized late-onset cases. Autopsy cases representing both groups showed amyloid deposition throughout the length of nerves and in sympathetic and sensory ganglia, but amounts were greater in early-onset cases. Amyloid deposition and neuronal cell loss were greater in sympathetic than dorsal root ganglia in early-onset cases; the opposite was true in late-onset cases. Size assessment of remaining neurons in these ganglia suggested predominant loss of small neurons in early-onset cases but loss of neurons of all sizes in late-onset cases. Transthyretin-positive, Congo red-negative amorphous material was more conspicuous in nerves from late- than early-onset cases. In extraneural sites, amyloid was more conspicuous in thyroid and kidney from early-onset cases and in heart and hypophysis from late-onset cases. In early-onset cases, cardiac amyloid deposition was prominent in the atrium and subendocardium but was conspicuous throughout the myocardium in late-onset cases. Conclusion: The pathology of early- and late-onset FAP TTR Met30 correlated well with differences in clinical findings.

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.

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.

Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas

Objective The objective of this study was to elucidate the natural history of late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) in non-endemic areas. Methods The authors retrospectively assessed the development of major clinical landmarks and abnormalities of nerve conduction and cardiac examination indices in 50 patients with an age of onset older than 50 years and no relationship to endemic foci. Results Once the neuropathic process was initiated, sensory and motor symptoms of both the upper and lower extremities appeared within a period of one and a half years. Digestive and orthostatic symptoms also tended to occur in the early phase of the disease, whereas urinary symptoms appeared in the middle of the disease progress. Along with pain in the extremities, these symptoms progressed over time and significantly disturbed the quality of life during the late phase of the disease, resulting in the need for wheelchair use. Although cardiomyopathy became clinically apparent only in the late phase of the disease, it was found to be the major cause of death. The mean duration of the disease onset to death was 7.3 years. Although values at the time of diagnosis were extremely variable, serial measurements of electrophysiological indices, the cardiothoracic ratio and interventricular septum thickness indicated a steady exacerbation in these outcomes among patients within a span of a couple of years. Conclusions The ages of onset of each clinical landmark were extremely variable between patients. However, once an initial symptom appeared, the chronological sequence of other clinical landmarks tended to be uniform, occurring within a relatively short time span.

Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals

Abstract  Mutations of the neurofilament‐light (NEFL/NF‐L) gene were examined in 124 unrelated Japanese patients with Charcot‐Marie‐Tooth disease (CMT) without known gene mutations, and 248 normal Japanese individuals. A new method, which can detect basepair mismatches with RNase cleavage on agarose gel electrophoresis, coupled with DNA sequencing, identified 8 novel sequence variations in the NF‐L gene. In these sequence variants, 5 variants were polymorphisms, including 3 single nucleotide polymorphisms (SNPs), and 3 other missense mutations (Pro22Thr, Asn97Ser and Ala148Val) were found in the patients with CMT phenotype. The variant alleles in the NF‐L gene could influence the developing process of CMT phenotype and also might cause CMT phenotype.

Spinal cord magnetic resonance imaging demonstrates sensory neuronal involvement and clinical severity in neuronopathy associated with Sjögren's syndrome.

OBJECTIVES To determine spinal cord MRI findings in neuronopathy associated with Sjögrens syndrome and their correlation with severity of sensory impairment. METHODS Clinical and electrophysiological features, pathological findings in the sural nerve, and hyperintensity on T2* weighted MRI in the spinal dorsal columns were evaluated in 14 patients with neuronopathy associated with Sjögrens syndrome. RESULTS Of 14 patients, 12 showed high intensity by T2* weighted MRI in the posterior columns of the cervical cord. High intensity areas were seen in both the fasciculus cuneatus and gracilis in nine patients, who showed severe and widespread sensory deficits in the limbs and trunk; these patients also had a high frequency of autonomic symptoms. Somatosensory evoked potentials often could not be elicited. Hyperintensity restricted to the fasciculus gracilis was seen in three patients, who showed sensory deficits restricted to lower limbs without trunk involvement, or with only partial limb involvement; no autonomic symptoms were noted. The two patients who did not show high intensity areas in the dorsal columns showed restricted sensory involvement in the limbs. All patients showed axonal loss predominantly affecting large fibres, without axonal sprouting. CONCLUSIONS High intensity areas on T2* weighted MRI in the spinal dorsal columns reflect the degree of sensory neuronal involvement in neuronopathy associated with Sjögrens syndrome; this finding could also be a helpful marker for estimating severity of this neuronopathy.

Clinicopathological features of neuropathy associated with lymphoma

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkins lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.

Paraneoplastic neuropathy: wide-ranging clinicopathological manifestations.

PURPOSE OF REVIEW Recent progress in serological screening for paraneoplastic autoantibodies and diagnostic imaging techniques to detect malignancies has resulted in a broadening of the concept of paraneoplastic neurologic syndromes through the characterization of nonclassical clinical features. The goal of this article was to review the recent literature describing the wide-ranging clinicopathological manifestations of paraneoplastic neuropathy. RECENT FINDINGS The classical feature of paraneoplastic neuropathy is subacute sensory neuronopathy; in addition, sensorimotor neuropathies, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, brachial plexopathy, and vasculitic neuropathy, are sometimes observed. Some studies also describe the occurrence of autonomic neuropathies, including autoimmune autonomic ganglionopathy and chronic gastrointestinal pseudo-obstruction. Whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) or FDG-PET/computed tomography may be helpful to detect malignancies that cannot be detected by conventional screening tests. The presence of paraneoplastic neuropathy should be considered in all patients with malignancy and can occur at any point in the disease, even during or after chemotherapy, radiation, or stem cell transplantation. The presence of paraneoplastic autoantibodies, especially anti-Hu and anti-CV2/CRMP-5 antibodies, may support the diagnosis of paraneoplastic neuropathy. Immunomodulatory treatment before, during, or after antineoplastic therapy may be of benefit for patients with paraneoplastic neuropathy and has been used even when the underlying malignancy cannot be identified. SUMMARY Recognition of the variable manifestations of paraneoplastic neuropathy is important, as diagnosis at an earlier stage facilitates prompt treatment and provides better chances of good outcomes.

Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome.

Objective: To reveal characteristic clinicopathological correlates of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. Methods: The clinical features of 22 patients with POEMS syndrome were investigated and correlated with the histopathological features of sural nerves and serum cytokine profiles. Results: More than half of the patients complained of pain in the lower extremities, which is closely related to hyperalgesia. Assessment of the total nerve fibre population using complete transverse sural nerve cross-sections, excluding the marked enlargement of endoneurial areas due to intrafascicular oedema, showed that myelinated fibres, especially small myelinated fibres, were reduced, whereas unmyelinated fibres were preserved. Uncompacted myelin lamellae and segmental demyelination were seen more frequently in the small, rather than the large, myelinated fibres. The presence of hyperalgesia was electrophysiologically associated with a reduction of sensory nerve action potentials in the sural nerve (p<0.05) and histopathologically associated with myelinated fibre loss (p<0.01). Serum levels of proinflammatory cytokines (interleukin-1β, interleukin-6 and tumour necrosis factor-α), but not their soluble receptors, were significantly elevated in patients with hyperalgesia (p<0.05–0.01). Conclusions: Hyperalgesia seen in patients with POEMS syndrome is closely related with a reduction in the myelinated, but not unmyelinated, fibre population. Elevation of proinflammatory cytokines is also correlated with hyperalgesia. The painful symptoms in POEMS syndrome may be generated by well-preserved unmyelinated C-fibres due to the lack of inhibitory myelinated A-fibres, along with cytokine sensitisation.