Saori Morozumi

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.

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.

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.

Systemic but asymptomatic transthyretin amyloidosis 8 years after domino liver transplantation

As familial amyloid polyneuropathy (FAP) is an adult-onset disease, a long period is expected between domino liver transplantation (DLT) and the occurrence of amyloidosis in recipients of a FAP liver. However, as time passes, and increased numbers of patients have undergone DLT, patients with symptoms suggesting amyloidosis have been reported. The authors describe, for the first time, pathological findings in an autopsy case of a recipient of a FAP liver. A male patient with primary sclerosing cholangitis received a liver graft from a FAP patient with the transthyretin (TTR) Tyr114Cys mutation when he was 30 years old. Although a recurrence of primary sclerosing cholangitis was detected at age 34, he had no symptoms indicating amyloidosis. He died from Burkitts lymphoma at 38 years of age. TTR immunoreactive amyloid was found in various organs including the heart, lung, gastrointestinal tract, pancreas, spleen, reproductive system and skeletal muscles. In the nervous system, TTR immunoreactive amyloid deposition was obvious in the sympathetic ganglia and the median nerve within the carpal tunnel, while loss of neurons or nerve fibres was not apparent. This case allows for the characterisation of amyloid deposition during the asymptomatic stage of FAP. Widespread amyloid deposition may occur before tissue damage in this disease.

The significance of carpal tunnel syndrome in transthyretin Val30Met familial amyloid polyneuropathy

Carpal tunnel syndrome (CTS) is frequently reported in association with amyloidosis. We determined the significance of CTS in transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) by comparing the electrophysiological indices of the median and ulnar nerves in 58 patients. As a whole, sensory nerve conduction velocity (SCV) was slowed and distal motor latency (DML) was prolonged to a similar extent in the median and ulnar nerves in these patients. The extent of abnormalities in the median nerve was almost similar to that in the ulnar nerve in both early-onset cases from endemic foci and late-onset cases from non-endemic areas. In age-matched idiopathic patients with CTS (20 patients, 27 hands), the slowing of SCV and the prolongation of DML in the median nerve were significant, while the slowing of motor conduction velocity was much less compared to FAP ATTR Val30Met patients. Although concomitant lesions in the ulnar nerve entrapment site at the wrist cannot be excluded, these findings indicate that CTS is not the sole distinctive feature in the majority of FAP ATTR Val30Met patients. The electrophysiological abnormality at the distal portion of the median nerve may be a consequence of polyneuropathy rather than an entrapment injury.

Differential, size-dependent sensory neuron involvement in the painful and ataxic forms of primary Sjögren's syndrome-associated neuropathy

Primary Sjögrens syndrome (pSS)-associated neuropathy manifests a wide variety of peripheral neuropathies that may show overlap among the neuropathic forms. In this report, we describe histopathological findings of two autopsy cases with pSS-associated neuropathy; one of them manifested the painful form and another showed ataxic form. The population of dorsal root ganglion (DRG) neurons and the density of myelinated fibers in the dorsal spinal root were variably reduced among spinal segments in both forms. In the painful form, there was a prominent reduction of small neurons, while in the ataxic form, large neurons were predominately lost. In accordance with the degree of the DRG cell loss, the modality of nerve fiber loss in the dorsal spinal roots and sural nerve correlated well with the corresponding DRG neuron loss. Prominent CD8+ T lymphocyte infiltration was present in the DRG, sympathetic ganglion, epineurial and perineurial space throughout the peripheral nerve trunks, and visceral organs, including the submandibular gland of both forms. Although the size of affected DRG neurons is different, these two forms share a similar causal mechanism, namely, cytotoxic autoimmunity to ganglion neurons, which may be one of a continuum of etiological factors. This hypothesis may have an impact on therapeutic approach.

Spatial Distribution of Nerve Fiber Pathology and Vasculitis in Microscopic Polyangiitis―Associated Neuropathy

We analyzed the 3-dimensional distribution of pathologic findings in 8 autopsied cases of neuropathy associated with microscopic polyangiitis. Necrotizing vasculitis was commonly and diffusely present in the epineurium of the sciatic/tibial and median nerves. Although findings of vasculitis were distributed diffusely in proximalto distal segments of the nerve trunks, marked loss of myelinated fibers occurred only from the middle to distal segments of thesenerves. Neurons of the sensory and sympathetic ganglia were well preserved, as were myelinated fibers of the anterior and posterior spinal roots. Central fascicular nerve fiber degeneration, suggesting direct ischemic damage, occurred in restricted segments of the proximal-middle portion of the sciatic/tibial and median nerve trunks. Vasculitis was also seen in various visceral organs in all patients, but its distribution differed among individual patients; the severity of vasculitis in the other organs did not correlate with that inthe peripheral nerves. The distinct spatial distribution pattern of nerve fiber degeneration, in contrast to the ubiquitous presence of vasculitis, suggested that the ischemic zone that directly damages nerve fibers is present in the proximal-middle portion of peripheral nerve trunks in microscopic polyangiitis.

Slowly progressive autonomic neuropathy with antiganglionic acetylcholine receptor antibody

The antiganglionic acetylcholine receptor (AChR) antibody is a serological marker for autoimmune autonomic ganglionopathy (AAG).1 2 Typical AAG cases show monophasic progression evolving to peak severity within a few days to weeks.1 3 Before the establishment of AAG as a disease entity, it was called acute pandysautonomia, autoimmune autonomic neuropathy, idiopathic autonomic neuropathy or subacute autonomic neuropathy.1 2 While most cases of AAG show an acute or subacute course to reach its nadir, similar to the somatic counterpart Guillain–Barre syndrome, the nosological position of AAG cases with a chronic course is obscure. In this report, we describe the clinical features and sural nerve biopsy findings in a case with slowly progressive autonomic neuropathy and positive for antiganglionic AChR antibody followed up for 15 years. A male patient noted faintness upon standing at age 61 (in 1994, 7 years before admission to our hospital). Not long afterwards, he felt palpitation, shortness of breath and dizziness during walking. He sometimes lost consciousness while walking after he felt such symptoms. He suffered from diarrhoea 4 years later. Family history was negative. As the loss of consciousness and diarrhoea gradually became frequent, he was admitted to a hospital at age 67, where hypohidrosis and dry …

Differential response to intravenous immunoglobulin (IVIg) therapy among multifocal and polyneuropathy types of painful diabetic neuropathy.

Peripheral neuropathy associated with diabetes mellitus often causes severe neuropathic pain that is difficult to alleviate. We evaluated the effect of intravenous immunoglobulin (IVIg) therapy on six patients with two phenotypes of painful diabetic neuropathy: three patients with multifocal neuropathy and three with symmetric polyneuropathy. All patients were treated with IVIg therapy and pain levels were evaluated on the Visual Analog Scale. Three patients were also assessed by quantitative sensory testing. All three patients with multifocal neuropathy showed a marked improvement in severe pain, while the patients with symmetric polyneuropathy did not respond to IVIg therapy. Pain associated with diabetic neuropathy is multifactorial and causative factors are heterogeneous. Our results show that IVIg therapy can alleviate pain in patients with multifocal diabetic neuropathy.