In clinical practice it is not uncommon for patients with adrenomyeloneuropathy or female carriers of adrenoleucodystrophy to have a presenting history and examination compatible with multiple sclerosis. This suggests that there may be an under-diagnosis of adrenoleucodystrophy and its variants in the multiple sclerosis population. We measured levels of very long chain fatty acids, which are typically elevated in the plasma of patients with adrenoleucodystrophy, in a large cohort of patients diagnosed clinically with multiple sclerosis. We tested serum samples from patients with either a first degree relative with multiple sclerosis or those with a primary progressive phenotype. No elevations in very long chain fatty acids were found in the cohort. This study suggests that the number of cases of adrenomyeloneuropathy or adrenoleucodystrophy amongst patients diagnosed clinically with multiple sclerosis is likely to be extremely low. This has important diagnostic implications.

Anxiety and depression are widely distributed symptoms among multiple sclerosis patients and in the general population. We assessed the prevalence of anxiety and depression in the multiple sclerosis population in Nord-Trøndelag County, Norway compared with Norway’s general population. The Hospital Anxiety and Depression Scale questionnaire was completed by 172 MS patients and 56,000 controls. A cut-off of ≥8 was used to define significant symptoms of anxiety and depression. Fatigue was measured using Krupp’s Fatigue Severity Scale, with a mean cut-off of >4. Among men, 31.1% of the multiple sclerosis patients reported anxiety, while only 12.1% of the control population reported this symptom (p = 0.002). For women, the prevalence of anxiety was 29.7% versus 17.4% (p < 0.001). Depression was reported by 26.2% of the men with multiple sclerosis compared with 10.8% of the controls (p < 0.001). The corresponding figures for women were 25.2% versus 10.4% (p < 0.001). Anxiety and depression were not correlated with duration of disease or disability measured by the Expanded Disability Status Scale. Among women, fatigue was associated with anxiety (p ≤ 0.010) and depression (p = 0.007). No such association was found among men. Anxiety and depression occur more frequently in multiple sclerosis patients than in the general population. Fatigue was associated with these neuropsychiatric manifestations in only women.

We previously reported that the prevalence of multiple sclerosis (MS) in the Tokachi Province of Hokkaido increased from 8.6 to 13.1 per 100,000 individuals between 2001 and 2006. Here, we study the frequency of MS patients who fulfill the Barkhof criteria and identified their common features. All 47 subjects in our previous study, who fulfilled Poser’s criteria, were included in this study. Of these, 33 satisfied the Barkhof criteria. In 2006, 9.2 per 100,000 MS patients fulfilled the Barkhof criteria; the percentage of patients who fulfilled these criteria was significantly higher among patients born after 1960 than among those born before 1960 (84.3% and 40.0%, respectively). The proportion of patients with conventional MS (C-MS) who fulfilled the Barkhof criteria was higher than that of patients with opticospinal MS (OS-MS) who fulfilled these criteria (93.9% and 71.4%, respectively). Longitudinally extensive spinal cord lesions (LESCLs) were not associated with the brain lesions defined in the Barkhof criteria (Barkhof brain lesions). In Tokachi Province, the increased percentage of MS patients who fulfill the Barkhof criteria was associated with increased C-MS incidence and an increase in the proportion of C-MS patients with Barkhof brain lesions among people born after 1960.

Gray matter (GM) magnetic resonance imaging (MRI) T2 hypointensity, a putative marker of iron deposition, is a frequent finding in patients with clinically definite (CD) multiple sclerosis (MS). The objective of this study was to assess: (a) how early deep GM T2 hypointensity occurs in MS, by studying patients with clinically isolated syndromes (CIS) suggestive of MS, and (b) whether they contribute to predict subsequent evolution to CDMS. Dual-echo scans using two different acquisition protocols were acquired from 47 CIS patients and 13 healthy controls (HC). Normalized T2-intensity of the basal ganglia and thalamus was quantified. Patients were assessed clinically at the time of MRI acquisition and after three years. During the observation period, 18 patients (38%) evolved to CDMS. At the baseline, only the GM T2-intensity of the left caudate nucleus was significantly reduced in CIS patients in comparison with the HC (p = 0.04). At the baseline, the T2 intensity of the left caudate nucleus was significantly lower (p = 0.01) in CIS patients with disease dissemination in space (DIS), but not in those without DIS, compared to the HC. The baseline T2 lesion volume, but not GM T2 hypointensity, was associated with evolution to CDMS (hazard ratio = 1.60, 95% confidence interval (CI) = 1.05–2.42; p = 0.02). In CIS patients, deep GM is not spared, suggesting that iron-related changes and neurodegeneration occurs early. The magnitude of such damage is only minor and not associated with an increased risk of evolution to CDMS.

There are two distinct subtypes of multiple sclerosis (MS) in Asians: opticospinal (OSMS) and conventional (CMS). OSMS has similar features to neuromyelitis optica (NMO) and half of OSMS patients have the NMO-Immunoglobulin G (IgG)/anti-aquaporin-4 (AQP4) antibody. We reported that Helicobacter pylori (H. pylori) infection was significantly less common in CMS patients than controls. To reveal the immune responses to the H. pylori neutrophil-activating protein (HP-NAP) in Japanese MS patients, according to anti-AQP4 antibody status, sera from 162 MS patients, 37 patients with other inflammatory neurological diseases (OIND), and 85 healthy subjects were assayed for anti-H. pylori antibodies, anti-HP-NAP antibodies, and myeloperoxidase (MPO) by enzyme immunoassays. H. pylori seropositivity rates were significantly higher in anti-AQP4 antibody-positive MS/NMO (AQP4 + /MS) patients (19/27, 70.4%) than anti-AQP4 antibody-negative CMS (AQP4 - /CMS) patients (22/83, 26.5%). Among H. pylori-infected individuals, the anti-HP-NAP antibody was significantly more common in AQP4 + /MS and AQP4 - /OSMS patients than healthy subjects (36.8%, 34.6% versus 2.8%). Among the AQP4 + /MS patients, a significant positive correlation between anti-HP-NAP antibody levels and the final Kurtzke’s Expanded Disability Status Scale scores was found, and MPO levels were higher in anti-HP-NAP antibody-positive patients than anti-HP-NAP antibody-negative ones. Therefore, HP-NAP may be associated with the pathology of anti-AQP4 antibody-related neural damage in MS/NMO patients.

The objective of this article was to assess the association between apolipoprotein E (APOE)-4 and cognitive impairment (CI) in relapsing–remitting multiple sclerosis (RRMS). The APOE genotype was assessed in 85 RRMS cases (58 females, mean age 43 ± 8.4 years, mean disease duration 15.8 ± 9.6 years, mean Expanded Disability Status Scale (EDSS) 1.7 ± 1.0). Cognitive functioning was evaluated in the whole sample using Rao’s Brief Repeatable Battery (BRB). Performance on each test was assessed by applying the normative values for the Italian population. In a subgroup of 50 patients, a brain magnetic resonance (MR) study was performed including measurement of T2 lesion volumes (T2LV), neocortical volume (NCV) and normalized brain volume (NBV). The relationship between APOE genotype, CI and MR variables was assessed through univariate and multivariate logistic regression models. CI, most commonly involving complex attention and verbal memory tasks, was found in 28 cases (33%). We identified a total of 19 4carriers (22.4%), who did not differ from non-carriers regarding clinical and demographic characteristics. The presence of the 4 genotype was associated with neither CI (p = 0.28) nor impairment on each neuropsychological test (p > 0.32; corrected for age, gender, disease duration, EDSS, depression and fatigue). The APOE genotype and CI were also not related in the subgroup of younger patients (age < 45 years; p > 0.9). Moreover, CI was related to higher T2LV (p = 0.008) and lower NCV (p = 0.006). In conclusion, in our sample CI was associated with higher subcortical damage and cortical atrophy but not with APOE-4 genotype. The role of APOE-4 as a possible biomarker in multiple sclerosis is still questionable.

Neutralizing antibodies against interferon-beta are associated with a reduction of the efficacy of this drug. Continuing treatment leads to a decline or even loss of neutralizing antibodies over years. No strategies are currently available to shorten the period of neutralizing antibody positivity. The objective of this study was to investigate the effect of switching between high and low immunogenic interferon-beta products on neutralising antibody titres. Twenty-four patients treated with the subcutaneously administered interferon-beta 1b or 1a and high titres of neutralizing antibodies were included. At baseline interferon-beta therapy was interrupted for 3 months and two pulses of high dose methylprednisolone were applied. Patients were then randomized to receive either the previous interferon-beta preparation or the low immunogenic intramuscular interferon-beta 1a. The primary end-point was the change of neutralizing antibody titres 12 months after randomization. Twelve patients were switched to interferon-beta 1a intramuscularly and 12 patients remained on previous treatment. Median neutralizing antibody titres were 846 NU at baseline and 196 NU at the end of the study. The median change of neutralizing antibody titres did not differ significantly between therapy switchers and non-switchers. Baseline and final neutralizing antibody titres correlated significantly. In conclusion, neither switching nor continuous therapy with any subcutaneous interferon-beta preparation significantly changed neutralizing antibody titres.

Detecting clinically significant symptoms of depression and anxiety in medically ill patients using self-report rating scales presents a challenge because of somatic confounders. The Hospital Anxiety and Depression Scale (HADS) was developed with this in mind, but has never been validated for a multiple sclerosis population. Our objective was to validate the HADS for multiple sclerosis patients. Multiple sclerosis patients were interviewed for the presence of major depression (n = 180) and anxiety disorders (n = 140) with the Structured Clinical Interview for DSM-IV disorders. A receiver operating characteristic (ROC) analysis was undertaken to assess which HADS cut-off scores give the best yield with respect to diagnoses of major depression and all anxiety disorders defined by the Structured Clinical Interview for DSM-IV. A threshold score of 8 or greater on the HADS depression subscale provides a sensitivity of 90% and specificity of 87.3% (ROC area under the curve 0.938). The same cut-off score gives a sensitivity of 88.5% and a specificity of 80.7% on the anxiety subscale (ROC area under the curve 0.913), but for generalized anxiety disorder only. The study confirms the usefulness of the HADS as a marker of major depression and generalized anxiety disorder, but not other anxiety disorders, in multiple sclerosis patients.

Fatigue and quality of life are significant concerns in adult multiple sclerosis (MS) but little is known about these factors in pediatric MS. The present investigation evaluates fatigue and quality of life in 51 pediatric MS patients to determine the rate of fatigue and reduced quality of life and assesses the relations between these variables and clinical factors. Fatigue and quality of life were assessed by self- and parent-report via the PedsQL Multidimensional Fatigue Scale and the PedsQL Quality of Life Scale. One-sample t-tests determined if scores were below published data for healthy individuals. Moreover, scores falling one standard deviation from norms were considered mildly affected, with severe difficulties being defined as scores falling two or more standard deviations from norms. Associations between self- and parent-reported difficulties and clinical factors were examined via Pearson correlation analyses. In comparison with healthy samples, pediatric MS patients reported greater difficulties with respect to fatigue, sleep, cognition, physical limitations, and academics. In addition to significant difficulties on these factors, parents reported problems with respect to emotional functioning, and tended to report greater fatigue, sleep, and cognitive difficulties than were self-reported. Expanded Disability Status Scale score was the only neurologic variable significantly related to fatigue or quality of life scores. Fatigue was significantly correlated with reports of sleep difficulties, cognitive problems, and quality of life variables. These findings suggest that fatigue and poorer quality of life is a clear concern in pediatric MS, and is related to overall physical disability.

Association of HLA class II with multiple sclerosis (MS) has been widely studied in both Western and Oriental populations. However, such an association is not well documented in Chinese. The objective of this study was to examine the association between the susceptibility to conventional MS in Southern Chinese with HLA-DRB1,-DPB1 alleles and putative DRB1-DPB1 haplotypes. Genotyping of HLA-DRB1 and -DPB1 alleles was performed in 60 patients with conventional MS and 95 controls. Allele frequencies were compared between patients and controls to identify MS-associated alleles. Relative predisposing effect method was used to compare haplotype frequencies in patients and controls and to identify possible predisposing DRB1-DPB1 haplotypes, which were further examined for differences in haplotype carriage rates between the two groups. We found that the allele frequency of DRB1*1501 was not different between patients (18.3%) and controls (21.1%) (p = 0.837). In contrast, frequency of the DPB1*0501 allele was significantly higher in patients (90%) than in controls (67.4%) (odds ratio = 4.36, p = 0.0013, pcorr = 0.025). DRB1-DPB1 linkage disequilibrium was confirmed in both controls and patients. The frequency of the DRB1*1602-DPB1*0501 haplotype in patients (8.33%) was significantly higher than in controls (0%) (p < 0.0001) and the carriage rate of this haplotype was significantly increased in patients (15%) as compared with controls (0%) (p = 0.00013, pcorr = 0.003). Combined, these results suggest that HLA-DRB1*1501 is not associated with susceptibility to conventional MS in Southern Chinese. Instead, both the DPB1*0501 allele and the DRB1*1602- DPB1*0501 haplotype are strong predisposing factors for conventional MS in this population. Our results establish that the HLA profiles of MS in Southern Chinese are distinct from other populations.