Masahiro Iijima

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.

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.

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.

Distinct characteristics of amyloid deposits in early- and late-onset transthyretin Val30Met familial amyloid polyneuropathy

Late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) cases unrelated to endemic foci in Japan show different clinicopathological features from the conventional early-onset cases in endemic foci. We compared the characteristics of amyloid deposits in early-onset FAP ATTR Val30Met cases in endemic foci and late-onset cases in non-endemic areas. Amyloid deposits in three early-onset cases from endemic foci and five late-onset cases from non-endemic areas were systematically examined post-mortem. Amyloid deposits in early-onset cases were highly congophilic and showed strong apple-green birefringence with Congo red staining and had long, parallel fibrils in most organs. On the other hand, those in late-onset cases were generally weakly congophilic and showed faint apple-green birefringence with Congo red staining and had short, haphazard fibrils. In the renal glomus and adrenal gland of early-onset cases, the characteristics of amyloid deposits were similar to those observed in late-onset cases. Analysis of cardiac amyloid using surface enhanced desorption/ionization time-of-flight mass spectrometry indicated that most transthyretin (TTR) was variant in early-onset cases, while more than half was composed of wild-type TTR in late-onset cases. Although characteristics of amyloid deposits may differ among individual organs of respective cases, especially in early-onset cases, the pattern was distinct between early- and late-onset cases. Amyloid deposition in late-onset cases may be similar to that observed in senile systemic amyloidosis with wild-type TTR deposition, suggesting that aging may play an important role in these cases.

Diagnosis of sporadic transthyretin Val30Met familial amyloid polyneuropathy: a practical analysis

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP and is now prevalent in areas other than those seen within conventional endemic foci. We investigated 15 patients with FAP ATTR Val30Met without a family history of FAP who were referred for sural nerve biopsy. Initial symptoms included somatic neuropathy in all patients, while sensory dissociation and autonomic symptoms were apparent only in two and seven patients, respectively. Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients. Small-fiber predominant loss was observed in a minority of patients. In terms of cardiac involvement, findings suggestive of subclinical cardiomyopathy due to amyloid deposition, such as cardiomegaly on chest X-ray, thickening of the interventricular septum, and granular sparkling echo on echocardiography, were seen alone or in combination in 11 of 14 examined patients. In conclusion, clinicians should consider the possibility of FAP ATTR Val30Met in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis. Detecting subclinical cardiac involvement may help to diagnose late-onset FAP ATTR Val30Met in those without a family history of the disease.

Clinicopathologic features of nonsystemic vasculitic neuropathy and microscopic polyangiitis-associated neuropathy: a comparative study.

OBJECTIVE To compare clinicopathologic findings in nonsystemic vasculitic neuropathy (NSVN) and microscopic polyangiitis-associated neuropathy (MPAN). METHODS Patients clinicopathologically confirmed to have NSVN (n=23) or MPAN (n=40) were compared with respect to clinical, electrophysiologic, and histopathologic features. RESULTS Clinical features of neuropathy such as initial symptoms, progression, and distribution of sensory and motor deficits were similar in both groups, while functional compromise was greater in MPAN than NSVN. Abnormalities of laboratory data including those reflecting severity and extent of inflammation such as C-reactive protein were more conspicuous in MPAN than NSVN. Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) were positive in two-thirds of patients with MPAN but negative in all NSVN. Electrophysiologic and histopathologic findings indicated axonal neuropathy in both groups, whereas the reduction of compound muscle action potentials in the tibial nerve and sensory nerve action potentials in the median nerve was significantly more profound in MPAN than NSVN. As for the epineurial perivascular infiltration, frequencies of cell-specific markers for T lymphocytes, macrophages, and B lymphocytes among cells infiltrating the vasculitic lesions were essentially similar between groups. CONCLUSIONS Clinicopathologic profiles and vascular pathology were similar between NSVN and MPAN but the age at onset, severity, and presence of p-ANCA were clearly different. Further study is needed to clarify the pathogenesis of NSVN and its place in the vasculitic spectrum of diseases.

Clinicopathological features of acute autonomic and sensory neuropathy

Acute autonomic and sensory neuropathy is a rare disorder that has been only anecdotally reported. We characterized the clinical, electrophysiological, pathological and prognostic features of 21 patients with acute autonomic and sensory neuropathy. An antecedent event, mostly an upper respiratory tract or gastrointestinal tract infection, was reported in two-thirds of patients. Profound autonomic failure with various degrees of sensory impairment characterized the neuropathic features in all patients. The initial symptoms were those related to autonomic disturbance or superficial sensory impairment in all patients, while deep sensory impairment accompanied by sensory ataxia subsequently appeared in 12 patients. The severity of sensory ataxia tended to become worse as the duration from the onset to the peak phase of neuropathy became longer (P<0.001). The distribution of sensory manifestations included the proximal regions of the limbs, face, scalp and trunk in most patients. It tended to be asymmetrical and segmental, rather than presenting as a symmetric polyneuropathy. Pain of the involved region was a common and serious symptom. In addition to autonomic and sensory symptoms, coughing episodes, psychiatric symptoms, sleep apnoea and aspiration, pneumonia made it difficult to manage the clinical condition. Nerve conduction studies revealed the reduction of sensory nerve action potentials in patients with sensory ataxia, while it was relatively preserved in patients without sensory ataxia. Magnetic resonance imaging of the spinal cord revealed a high-intensity area in the posterior column on T(2)*-weighted gradient echo image in patients with sensory ataxia but not in those without it. Sural nerve biopsy revealed small-fibre predominant axonal loss without evidence of nerve regeneration. In an autopsy case with impairment of both superficial and deep sensations, we observed severe neuronal cell loss in the thoracic sympathetic and dorsal root ganglia, and Auerbachs plexus with well preserved anterior hone cells. Myelinated fibres in the anterior spinal root were preserved, while those in the posterior spinal root and the posterior column of the spinal cord were depleted. Although recovery of sensory impairment was poor, autonomic dysfunction was ameliorated to some degree within several months in most patients. In conclusion, an immune-mediated mechanism may be associated with acute autonomic and sensory neuropathy. Small neuronal cells in the autonomic and sensory ganglia may be affected in the initial phase, and subsequently, large neuronal cells in the sensory ganglia are damaged.

Sjögren’s syndrome associated painful sensory neuropathy without sensory ataxia

Sensory neuropathy with prominent ataxia reflecting kinesthetic sensory impairment is a well recognised form of neuropathy associated with Sjogren’s syndrome.1–4 Pathologically, T cell invasion of dorsal root ganglia, loss of large sensory neurons, and secondary large fibre degeneration is seen in this neuropathy.4 However, a form of neuropathy associated with Sjogren’s syndrome, presenting with pain and superficial sensory involvement without sensory ataxia has been described anecdotally5 and in a case report.6 Clinicopathological details of the second form of neuropathy have not been elucidated. In this report we describe seven patients with Sjogren’s syndrome showing painful sensory neuropathy without sensory ataxia. Patients studied were referred for painful neuropathy to Nagoya University Hospital and its affiliated institutions. All seven patients fulfilled diagnostic criteria for Sjogren’s syndrome by the American-European Consensus Group7 and showed painful peripheral neuropathy (table 1). Patients included six women and one man, ranging from 25 to 72 years old. In all patients initial symptom of neuropathy was paraesthesia or painful dysaesthesia in the most distal portions of the extremities, later extending proximally to involve the entire legs and arms. The trunk became involved in three patients, and the trigeminal nerve was impaired in three patients. Asymmetry in sensory impairment was present in four patients. None of the patients showed sensory ataxia in the initial phase. Most patients retained essentially normal muscle strength, but patient 1 showed slight weakness in distal limb muscles. …

Clinicopathologic features of folate-deficiency neuropathy

Objective: The clinical significance and characteristics of neuropathy caused by folate deficiency remain to be established. Methods: We examined the clinicopathologic features of 18 consecutive patients with neuropathy caused by folate deficiency who presented with low serum folate levels but normal blood thiamine and serum cobalamin levels in the absence of chronic alcoholism. Results: Symptoms were relatively uniform, characterized by slowly progressive polyneuropathy with predominant involvement of the lower extremities, with a tendency to manifest as sensory rather than motor neuropathy and predominant deep rather than superficial sensory loss. The electrophysiologic features were consistent with axonal neuropathy. The histopathologic features of sural nerve biopsy specimens indicated large fiber–predominant axonal loss without segmental demyelination. Although macrocytosis was found in 7 patients, only 3 patients exhibited hemoglobin levels less than 10 g/dL. During the same study period, we found 12 patients who had low blood thiamine levels but normal serum folate and cobalamin levels without chronic alcoholism. Compared with patients who had thiamine-deficiency neuropathy, patients with a folate deficiency showed significantly slower progression (p < 0.01), a tendency to manifest sensory neuropathy (p < 0.05), predominant deep sensory loss (p < 0.01), and preservation of biceps tendon reflexes (p < 0.05). Conclusions: Folate-deficiency neuropathy was characterized by a slowly progressive and sensory-dominant pattern, which was different from thiamine-deficiency neuropathy (i.e., beriberi neuropathy). This study demonstrates the importance of folate deficiency in the differential diagnosis of neuropathy, particularly in countries where folic acid fortification has not yet been practiced.