Yuichi Kawagashira

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.

Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP

Objective: Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by immune-mediated peripheral demyelination. Although corticosteroid, IV immunoglobulin (IVIg) and plasma exchange have been established as the most effective therapeutics, subpopulations of patients show little or no response to either of these therapies. In this study, we examined whether particular genetic factors influence the therapeutic responsiveness of patients with CIDP. Methods: One hundred Japanese patients categorized as responders or nonresponders to IVIg therapy participated in our study. We performed an association analysis with single nucleotide polymorphisms (SNPs) and haplotype studies between the IVIg responders and nonresponders. Results: Two separate SNPs, corresponding to TAG-1 (transient axonal glycoprotein 1) and CLEC10A (C-type lectin domain family 10, member A), showed strong significant differences between responders and nonresponders. Haplotype analysis of a series of expanded SNPs, from TAG-1 or CLEC10A, showed that only TAG-1 included a significant haplotype within 1 linkage disequilibrium block, which accommodates IVIg responsiveness. Diplotype analysis of TAG-1 also supported this observation. Conclusions: Transient axonal glycoprotein 1 is a crucial molecule involved in IV immunoglobulin responsiveness in Japanese patients with chronic inflammatory demyelinating polyneuropathy.

Intravenous immunoglobulin treatment for painful sensory neuropathy associated with Sjögren's syndrome

BACKGROUND Patients with painful sensory neuropathy associated with Sjögrens syndrome-associated neuropathy often show severe neuropathic pain which is not relieved by conventional treatments. OBJECTIVE To evaluate the effect of intravenous immunoglobulin (IVIg) therapy in the treatment of neuropathic pain associated with Sjögrens syndrome. PATIENTS AND METHODS We examined 5 patients affected by painful sensory neuropathy associated with Sjögrens syndrome. All patients were treated with IVIg (0.4 g/kg/day for 5 days) and pain rating was assessed by the Visual Analogue Scale (VAS). RESULTS All five patients showed a remarkable improvement in neuropathic pain following IVIg therapy. Pain, assessed by the determination of mean VAS score, was reduced by 73.4% from days 2-14 following treatment. The observed clinical improvement persisted for 2 to 6 months. One patient, examined by quantitative sensory testing (QST), showed an improvement of superficial sensory deficit accompanied by pain relief. CONCLUSION IVIg might be an effective treatment for pain in Sjögrens syndrome-associated neuropathy. Further studies should be done in a controlled, blind study.

Electrophysiological features of late-onset transthyretin Met30 familial amyloid polyneuropathy unrelated to endemic foci.

BackgroundThrough the development of gene diagnostic techniques, late-onset transthyretin Met30-associated familial amyloid polyneuropathy (FAP TTR Met30) has been shown to be more prevalent than is generally believed.ObjectiveTo examine the electrophysiological features of late-onset FAP TTR Met30 unrelated to endemic foci.MethodsNerve conduction findings in 44 cases with an onset of more than 50 years of age in a non-endemic area were assessed and compared with findings from 21 earlier-onset cases related to endemic foci.ResultsThe extent of the reduction of the compound muscle action potential and, especially, the sensory nerve action potential was more profound in the late-onset group even when the decline of these indices with aging in normal control subjects was taken into account. The feature of predominant lower-limb involvement seemed to be more conspicuous in the late-onset group. Electrophysiological indices tended to be aggravated as the duration of neuropathic symptoms increased in the early-onset group, while most of these indices in the lateonset group did not show this correlation. A slowing of conduction velocity and a prolongation of distal latency, which suggests demyelination, were conspicuous in some patients. Pathologically, a predominant loss of small-fibers was not conspicuous in sural nerve biopsy specimens from late-onset patients. Large myelinated fiber density showed a negative correlation with the disease duration in early-onset cases, but not in late-onset cases.ConclusionsElectrophysiological differences between late- and early-onset cases were present, probably reflecting the different underlying pathogenic mechanisms of neuropathy. The demyelinating feature does not exclude the possibility of this disease.

Rapidly developing weakness mimicking Guillain-Barré syndrome in beriberi neuropathy: Two case reports

OBJECTIVE We examined the diagnostic difficulty in thiamine deficiency. METHODS We report on two patients with polyneuropathy associated with thiamine deficiency (i.e., beriberi neuropathy) that presented with acute motor symptoms mimicking Guillain-Barré syndrome. RESULTS The cause of the thiamine deficiency was associated with gastrectomy to treat cancer in a 46-y-old man and with dietary imbalance in a 33-y-old man. The thiamine deficiency was not related to alcohol intake in either patient. In both patients, the upper and lower extremities showed a rapidly progressive weakness over the course of 1 mo. Muscle weakness in the first patient progressed even after admission to the hospital, and urinary retention, Wernickes encephalopathy, lactic acidosis, paralytic ileus, and heart failure appeared subsequently. Clinical symptoms in both patients showed improvement after initiation of thiamine administration, although some residual deficit remained. CONCLUSION Thiamine deficiency must be actively considered as a possible cause of polyneuropathy, and variability in its clinical features should be taken into consideration.

IgM MGUS anti‐MAG neuropathy with predominant muscle weakness and extensive muscle atrophy

We report a patient with anti–myelin‐associated glycoprotein (MAG) neuropathy, predominantly exhibiting severe motor symptoms, accompanied by extensive muscle atrophy mimicking Charcot–Marie–Tooth disease. Nerve conduction studies revealed mild retardation of motor conduction velocities and significant prolongation of distal latency. Sural nerve biopsy revealed widely spaced myelin and positive staining of myelinated fibers with an IgM antibody. Predominant motor symptoms with muscle atrophy can be one of the clinical manifestations of anti‐MAG neuropathy. Muscle Nerve, 2010

Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy.

To characterize the morphological progression of neuropathy associated with immunoglobulin M-monoclonal gammopathy ofundetermined significance with anti-myelin-associated glycoprotein antibody, we assessed histopathologic features of sural nerve specimens from 15patients, emphasizing widely spaced myelin (WSM), demyelination, and tomaculous changes. The frequency of WSM correlated with that of demyelination and tomaculous appearance in teased-fiber preparations. Inlongitudinal sections at nodes of Ranvier and paranodal regions, thespaces between terminal myelin loops, particularly those adjacent to the node of Ranvier, were widened, indicating an early change before demyelination, and there was concomitant swelling of terminal myelin loops. Some conspicuously swollen terminal myelin loops were detached from the paranodal axolemma, thereby widening the nodes ofRanvier. Tomacula coexisted frequently with redundant myelin loops and WSM, particularly in the outermost layer of myelin sheaths, suggesting that loosening of the outer layers contributes to their formation. By immunofluorescence microscopy, immunoglobulin M and myelin-associated glycoprotein were colocalized in paranodal regions and Schmidt-Lanterman incisures. Confocal analysis revealed colocalization of immunoglobulin M and complement product C3d corresponding to the area of WSM. Thus, morphological changes in terminal myelin loops, formation of WSM at paranodes, and subsequent dissociation from paranodal axolemma (which may be associated with activation ofthe complement pathway) likely contribute to demyelination in thiscondition. Loosening of compact myelin seems to contribute to tomacula formation.