Patient-reported outcomes with subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: the PATH study.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) causes weakness which adversely impacts function and quality of life (QOL). CIDP often requires long-term management with intravenous or subcutaneous immunoglobulin. The Polyneuropathy and Treatment with Hizentra® (PATH) study showed that subcutaneous immunoglobulin (SCIG) was efficacious in CIDP maintenance. Here, patient-reported outcomes in patients on SCIG are assessed. METHODS: Subjects stabilized on intravenous immunoglobulin were randomly allocated to receive weekly 0.2 or 0.4 g/kg bodyweight of 20% SCIG (IgPro20) or placebo. Overall QOL/health status was assessed using the EuroQoL 5-Dimension (EQ-5D) health profile and visual analog scale, treatment satisfaction was assessed with the Treatment Satisfaction Questionnaire for Medicine (TSQM) and work-related impact was assessed with the Work Productivity and Activity Impairment Questionnaire for General Health (WPAI-GH). The EQ-5D health profile was assessed in terms of the percentage of subjects maintained or improved at week 25 of SCIG therapy on each of the EQ-5D domains versus baseline after intravenous immunoglobulin stabilization. TSQM and WPAI-GH were assessed by median score changes from baseline to week 25. RESULTS: In total, 172 subjects were randomized to placebo (n = 57), 0.2 g/kg IgPro20 (n = 57) and 0.4 g/kg IgPro20 (n = 58). Significantly higher proportions of IgPro20-treated subjects improved/maintained their health status on the EQ-5D usual activities dimension, and in additional dimensions (mobility and pain/discomfort) in sensitivity analyses. TSQM and WPAI-GH scores were more stable with IgPro20 treatment compared with placebo. CONCLUSIONS: IgPro20 maintained or improved QOL in most subjects with CIDP, consistent with the PATH study findings that both IgPro20 doses were efficacious in maintaining CIDP.

Acute disseminated encephalomyelitis in China, Singapore and Japan: a comparison with the USA.

BACKGROUND AND PURPOSE: Ethnicity-related differences in the incidence of acute disseminated encephalomyelitis (ADEM) and other demyelinating diseases including multiple sclerosis and neuromyelitis optica spectrum disorders have been reported. Little is reported on the influence of ethnicity and geographical location in ADEM. METHODS: Medical records of patients who presented with ADEM (ICD-9 323.61 and 323.81) at large referral hospitals in China, Singapore and Japan (years 1992-2015) were retrospectively reviewed and data were collected in a centralized database. Presenting features and outcomes of ADEM were compared between this multi-country Asian cohort and a uniformly collected US cohort using risk differences and risk ratios. Both cohorts were standardized to a 35% pediatric population to facilitate the comparison. RESULTS: There were 83 Asian patients (48 male, 16 pediatric) followed for a median of 2 (25th-75th percentile 1-10) months. Asian patients exhibited a 26% higher prevalence of spinal cord involvement on magnetic resonance imaging [95% confidence interval (CI) 0-52%; P = 0.05; 63% vs. 37%], a 39% lower prevalence of preceding events (95% CI 12-65%; P < 0.01; 33% vs. 72%) and a 23% lower prevalence of corpus callosum involvement (95% CI 7-39%; P < 0.01; 8% vs. 31%). No difference was observed between the two cohorts in the probability of relapse over the first year after disease onset. CONCLUSIONS: It is hypothesized that the high proportion of Asian patients with spinal cord lesions relates to genetic vulnerability or the higher incidence of neuromyelitis optica spectrum disorders in Asia or could be a spurious association. ADEM presentations most probably vary across geographical settings or ethnicities.

Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.

While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.

Muscle atrophy in chronic inflammatory demyelinating polyneuropathy: a computed tomography assessment.

BACKGROUND AND PURPOSE: Muscle atrophy is generally mild in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) compared with the severity and duration of the muscle weakness. Muscle atrophy was evaluated using computed tomography (CT) in patients with CIDP. METHODS: Thirty-one patients with typical CIDP who satisfied the diagnostic criteria for the definite CIDP classification proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society were assessed. The clinicopathological findings in patients with muscle atrophy were also compared with those in patients without atrophy. RESULTS: Computed tomography evidence was found of marked muscle atrophy with findings suggestive of fatty degeneration in 11 of the 31 patients with CIDP. CT-assessed muscle atrophy was in the lower extremities, particularly in the ankle plantarflexor muscles. Muscle weakness, which reflects the presence of muscle atrophy, tended to be more pronounced in the lower extremities than in the upper extremities in patients with muscle atrophy, whereas the upper and lower limbs tended to be equally affected in patients without muscle atrophy. Nerve conduction examinations revealed significantly greater reductions in compound muscle action potential amplitudes in the tibial nerves of patients with muscle atrophy. Sural nerve biopsy findings were similar in both groups. The functional prognoses after immunomodulatory therapies were significantly poorer amongst patients with muscle atrophy. CONCLUSIONS: Muscle atrophy was present in a subgroup of patients with CIDP, including patients with a typical form of the disease. These patients tended to demonstrate predominant motor impairments of the lower extremities and poorer functional prognoses.

A new disorder of praxis in neurodegenerative disease that may be part of Alzheimer's disease.

Apraxia is a well-known disorder of praxis and is caused mainly by damage to the left parietal lobe. We presented two cases of neurodegenerative disease with a distinct disorder of praxis, predominantly involving left parietal lobe. While both patients could understand what they should do, they were not able to initiate action and often stopped during execution of actions. They had no apraxia and no temporal and spatial errors on praxis. Magnetic resonance imaging of both patients showed atrophy of the left parieto-occipital and temporo-occipital lobes, and single photon emission computed tomography showed hypoperfusion in the same lobes. Moreover, one of our cases, using [11C] PIB PET, demonstrated increased uptake in the cerebral cortices, suggesting Alzheimer's disease. The symptoms described are different from other disorders of praxis and similar to bradyphrenia or freezing.

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.

Endothelial and inflammatory markers in relation to progression of ischaemic cerebral small-vessel disease and cognitive impairment: a 6-year longitudinal study in patients with type 2 diabetes mellitus.

BACKGROUND: Progression of silent brain infarctions (SBIs) and white-matter lesions (WMLs) seen on brain MRI is associated with an increased risk of cognitive impairment, but their relation to endothelial and inflammatory markers is unknown in type 2 diabetes mellitus. METHODS: In 190 type 2 diabetic outpatients (mean age 62.7 years), the authors related baseline levels of soluble intercellular adhesion molecule-1 (sICAM-1) and high-sensitivity C-reactive protein (hs-CRP) to subsequent brain MRI findings and cognitive function. The authors assessed incident SBIs and changes in periventricular and subcortical WMLs (PVWMLs and SCWMLs) on MRI performed at baseline and 3 and 6 years. Neuropsychological tests were administered to 83 patients older than 65 years at 6 years. This present study represents an extension of the authors' previously published study. RESULTS: SBIs were observed in 46 patients (24.2%), PVWMLs in 93 (48.9%) and SCWMLs in 87 (45.8%) on baseline MRI. After adjustment for age, gender, hypertension, duration of diabetes, baseline MRI findings and medication use, the relative odds associated with a 1SD increase in sICAM-1 levels at baseline were 1.67 (95% CI 1.02 to 3.05) for SBI progression and 2.17 (95% CI 1.29 to 3.62) for PVWML progression at 6 years. In contrast, baseline hs-CRP levels were significantly associated with SBI progression only at 3 years. Significant trends were observed between quartiles of sICAM-1 at baseline and scores in Digit Symbol substitution (p for trend=0.01). CONCLUSIONS: The findings suggest that higher sICAM-1 levels are associated with SBI and PVWML progression, and may predict impairment in psychomotor function in type 2 diabetes.

Schwann cell galactocerebroside induced by derivatives of adenosine 3',5'-monophosphate.

Indirect immunofluorescence was used to show the presence of galactocerebroside (galC), a lipid found in myelin, on the surface of about half of the Schwann cells isolated from neonatal rat sciatic nerves and cultured for 1 day without neurons. By day 4 in vitro, the Schwann cells had all lost their surface galC. Three days after beginning treatment with 10(-3) molar 8-bromo-adenosine 3',5'-monophosphate (8-bromo cyclic AMP) or N6,O2'-dibutyryl adenosine 3',5'-monophosphate (dibutyryl cyclic AMP), galC reappeared on the Schwann cells, and 2 days later 48 percent of the cultured Schwann cells showed surface galC. Tritium from tritiated D-galactose was incorporated into galC by the 8-bromo cyclic AMP-and dibutyryl cyclic AMP-treated cultures at a rate 15 times the control rate.

Cognitive impairment in spinocerebellar degeneration.

It has been reported that patients with spinocerebellar degenerations (SCDs) have cognitive dysfunction as well as limb and truncal ataxia, dysarthria and dysphagia. We review cognitive dysfunction in common types of SCD, including spinocerebellar ataxia types 1, 2, 3, 6, and 17, dentatorubral-pallidoluysian atrophy, Friedreich's ataxia, and multiple system atrophy. There are few studies that address cognitive function in SCD. Although there are few comparison studies among the various SCDs, cognitive dysfunction may be more common and severe in spinocerebellar ataxia type 17 and dentatorubral-pallidoluysian atrophy. While cognitive dysfunction in SCD appears to represent frontal dysfunction, the mechanisms of cognitive dysfunction have not been directly clarified. Nevertheless, various lesions, including those in the cerebrocerebellar circuitry, cortico-striatal-thalamocortical circuitry, and the frontal lobe, may influence cognitive function to various degrees for each disease.

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-1beta, interleukin-6 and tumour necrosis factor-alpha), 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.

Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population.

OBJECTIVE AND METHODS: To characterise the epidemiological features of chronic inflammatory demyelinating polyneuropathy (CIDP) in the Japanese population, this study performed a nationwide assessment of the prevalence and incidence rates in Japan. RESULTS: The prevalence rate per 100 000 was 1.61 in the total population; 2.01 in males and 1.23 in females. The age dependent prevalence rates were 0.23 in juveniles (<15 years old), 1.50 in young adults (15-55 years) and 2.31 in elderly adults (>55 years). The sex and age dependent prevalence rates were 0.22 in males and 0.24 in females in juveniles, 1.81 in males and 1.19 in females in young adults, and 3.12 in males and 1.64 in females in elderly adults. The annual incidence rate per 100 000 was 0.48 in the total population, 0.58 in males and 0.38 in females. The age dependent incidence rate was 0.06 in juveniles, 0.40 in young adults and 0.73 in elderly adults. The sex and age dependent incidence rate was 0.05 in males and 0.08 in females in juveniles, 0.50 in males and 0.30 in females in young adults, and 0.93 in males and 0.58 in females in elderly adults. Both the prevalence and incidence rates were very similar throughout the eight geographical areas studied, from the northern to the southern parts of Japan. CONCLUSIONS: The prevalence and incidence rates were similar to those reported in the Caucasian population. The pathogenic background is suggested to be common throughout the different races and geographic areas, while gender and age effects should be taken into account in the pathogenesis of CIDP.

Cognitive impairment in spinocerebellar ataxia type 6.

OBJECTIVE: The aim of this study was to evaluate cognitive impairment in patients with spinocerebellar ataxia type 6 (SCA6) and to verify the role of cerebellar involvement in intellectual abilities. METHODS: Cognitive function was examined in 18 patients with genetically confirmed SCA6 and in 21 age and education matched controls using a test battery for attention, verbal and visuospatial memory, as well as executive function. RESULTS: Verbal fluency and immediate visual memory task were markedly impaired in SCA6 compared with the control group (p = 0.007, 0.004 and 0.014, respectively). The results of the Rule Shift Cards Test was reduced in patients with SCA6, but the reduction was not significant. These cognitive dysfunctions did not correlated with CAG repeat length, age at onset, ataxic motor dysfunctional scale or depression. CONCLUSIONS: Our results demonstrate that specific cognitive deficits occur in patients with SCA6, independent of ataxic motor dysfunction. These deficits may reflect disruption of cortico-cerebellar circuits.

Prefrontal hypoperfusion and cognitive dysfunction correlates in spinocerebellar ataxia type 6.

OBJECTIVE: The aim of this study is to evaluate the correlation between brain perfusion and cognitive dysfunction in spinocerebellar ataxia type 6 (SCA6) patients. METHODS: Thirteen genetically confirmed SCA6 patients and 21 age- and education-matched control subjects were subjected to single photon emission computed tomography (SPECT) and neuropsychological tests. Brain perfusion was examined with SPECT analysis, while general cognition, verbal and visual memory, attention, visuospatial ability, language, executive function, depression, and anxiety were examined with the neuropsychological tests. RESULTS: SCA6 patients showed prefrontal hypoperfusion, and impairments of visual memory, verbal fluency, and executive function compared to control subjects. These neuropsychological impairments in SCA6 patients were significantly correlated with a decrease in prefrontal perfusion. This relation was not correlated to other factors, such as age, education and severity of cerebellar ataxia, which are possible relevant factors associated with cognitive performance. CONCLUSIONS: SCA6 patients have mild cognitive impairment, and correlating prefrontal hypoperfusion. These results indicate cognitive impairment in SCA6 patients resulting from prefrontal hypoperfusion.

Intravenous immunoglobulin therapy markedly ameliorates muscle weakness and severe pain in proximal diabetic neuropathy.

A 57-year-old man with type 2 diabetes mellitus for 10 years showed progressive loss of muscle strength in both legs, pain and muscle atrophy in the femoral region and significant weight loss. On admission, he could not stand alone and used a wheelchair. He also complained of severe pain in the lower extremities. He was diagnosed with proximal diabetic neuropathy (PDN) by characteristic clinical and electrophysiological features. Intravenous immunoglobulin therapy (IVIg 0.4 g/kg x 5 days) markedly reduced the severe pain and muscle weakness in the legs. Eventually, pain assessed by the Visual Analogue Scale was relieved by 80% and muscle strength was also well recovered, thereby enabling the patient to walk with a cane. The present case suggests that IVIg therapy may be effective for the relief of pain in PDN.

Intravenous immunoglobulin treatment in painful sensory neuropathy without sensory ataxia associated with Sjögren's syndrome.

Patients having neuropathy associated with Sjögren's syndrome may present with pain and superficial sensory involvement in the absence of sensory ataxia. Treatment for this form of associated neuropathy has not been established. The case of a patient with painful sensory neuropathy associated with Sjögren's syndrome, whose symptoms, particularly pain, responded well to intravenous immunoglobulin both at onset and in a relapse, is reported. Other patients with painful sensory neuropathy associated with Sjögren's syndrome may also be candidates for intravenous Ig treatment.

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.

Nerve growth factor receptors on dissociated neurofibroma Schwann-like cells.

Neurofibromatosis is a disorder which predominantly involves cellular elements of peripheral neural sheaths. Little is known about the regulation of differentiation and proliferation of cells comprising neurofibromas. Because nerve growth factor-like activity may be present in neurofibromas and the cells comprising neurofibromas are neural crest derivatives, we have investigated whether nerve growth factor (NGF) receptors are present on cells from dissociated dermal neurofibromas. Using 125I-NGF to measure binding to cultured cells in suspension and for autoradiography, we identified a population of cells having characteristics of Schwann cells which exhibited saturable 125I-NGF binding. This binding is characteristic of the "fast" (low affinity) NGF receptor, having a Kd of approximately 1 nM and a Bmax of at least 120 fmol/10(6) cells. Less than 20% of the bound 125I-NGF (5 ng/ml) is not displaced when transferred to 0 degrees C by an excess of unlabeled NGF (10 micrograms/ml) and is therefore bound to either "slow" (high affinity) sites or is rapidly internalized. NGF receptors with characteristics of fast sites have recently been reported on Schwann-like cells from chick dorsal root ganglia [Zimmerman, A., and Sutter, A. Beta nerve growth factor (beta NGF) receptors on glial cells. Cell-cell interaction between neurones and Schwann cells in culture of chick sensory ganglia. EMBO J., 2: 879-885, 1983]. The identification of NGF receptors on both fetal chick dorsal root ganglia and neurofibroma Schwann-like cells suggests that NGF may have a role in the regulation of Schwann cell function in both normal development and in neurofibromatosis.

Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype.

We investigated the transforming activity of the ret proto-oncogene with a mutation in cysteine 609, 611, 618, 620, 630, or 634 detected in patients with multiple endocrine neoplasia type 2A (MEN 2A), familial medullary thyroid carcinoma (FMTC), or Hirschsprung's disease. Of these cysteine mutations, codon 634 mutations are known to be correlated with the development of MEN 2A, whereas codon 609, 618, or 620 mutations were detected in two-thirds of FMTCs and in several cases of Hirschsprung's disease. Analysis of a total of 18 mutant genes revealed that codon 634 mutations have the highest transforming activity. The activity of ret with a codon 609, 611, 618, or 620 mutation and with a codon 630 mutation was approximately 3- to 5-fold and 2-fold lower than that of ret with a codon 634 mutation, respectively. In addition, different amino acid substitutions for the same cysteine displayed comparable transforming activity. The expression of the cell surface form of Ret with codon 609, 611, 618, or 620 mutation was very low compared with that of Ret with codon 634 mutation, indicating that the former four mutations might impair transport of Ret to the plasma membrane, as observed for several Hirschsprung mutations affecting the Ret extracellular domain. These results thus suggest that mutations in cysteine 609, 611, 618, or 620 may have the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC.