Multiple Sclerosis Journal

Clinically significant depression can affect up to 50% of patients with multiple sclerosis over the course of their lifetime. It is associated with an increased morbidity and mortality and is regarded by patients as one of the main determinants of their quality of life. This review summarizes current perspectives relating to diagnosis, the utility of self report screening questionnaires, warning signs of suicidal intent and the biological and psychosocial variables implicated in mood change. In particular, the association between depression and structural brain abnormalities, including those derived from diffusion tensor imaging, is highlighted. Depression is treatable, as the results from randomized controlled trials of antidepressant medication, cognitive behavior therapy and mindfulness therapy, reveal. These positive findings are offset by data showing that depression in a neurological setting is often overlooked and under treated.

Background: Sardinia is a known high-risk area for multiple sclerosis (MS), but no data for south-western Sardinia (SWS) are available. SWS has a genetically homogeneous population, apart from St Peter Island, and represents a peculiar environment related to the industrial, mineralogical and military economy.

Objective: To estimate prevalence and incidence and to evaluate temporal trends and geographical distribution of MS in SWS.

Methods: MS prevalence was evaluated on 31 December 2007 and crude mean annual incidence rate was defined between 2003 and 2007. Temporal trend in MS incidence was assessed using the Armitage test. To identify MS clusters, Standard Morbidity Ratio (SMR) was calculated for each village and geographical distribution prevalence by means of a Bayesian hierarchical model.

Results: Total crude prevalence rate was 210.4 (95% CI 186.3–234.5): 280.3 (95% CI 241.4–319.3) for females, 138 (95% CI 110.1–165.8) for males. The crude mean annual incidence rate was 9.7/100,000 (95% CI 3.4–13.2): 4.7/100,000 (95% CI 2.4–17.0) and 14.6/100,000 (95% CI 11.8–34.8) for males and females respectively. MS incidence has increased over the last 50 years. Cluster analysis showed an SMR of 0.2 (95% CI 0.05–0.68, p = 0.002) on the island of San Pietro, and 2.0 (95% CI 1.35–2.95, p = 0.001) in Domusnovas. Spatial distribution of MS was confirmed by Bayesian geographical analysis.

Conclusions: Our data confirm Sardinia as a high-risk area for MS and support the relevance of genetic factors in MS, as evidenced in St Peter Island. However, we found an unexpectedly high MS prevalence in one village, in particular in males, suggesting an environmental influence on MS occurrence.

Background: Compared with quantitative observations, the search for qualitative changes that may characterize the immune response to Epstein–Barr virus (EBV) in multiple sclerosis (MS) has been less intense.

Objective: To examine the B-cell epitopes of antibodies against the Epstein–Barr nuclear antigen-1 (EBNA-1) and their relevance for MS, through a study in disease-discordant identical twins.

Methods: We evaluated the antibodies to all unique, maximally overlapping octapeptides of EBNA-1 in 12 pairs of monozygotic (MZ) twins (9 MS-discordant, 3 healthy), 3 non-twin patients and 2 healthy subjects. All except one of the patients were untreated. The EBV serology of these individuals had been assessed in advance using commercially available and in-house enzyme-linked immunosorbent assay (ELISA) kits, including assays for antibodies against select peptides of EBNA-1: EBNA-72 (GAGGGAGAGG) and EBNA-206 (EADYFEYHQEGGPDGE).

Results: The glycine–alanine rich domain of EBNA-1 was immunodominant in all subjects. Compared with healthy individuals, and similarly to what has been described in infectious mononucleosis (IM) patients, affected co-twins and non-twin patients had a significantly increased response to another EBNA-1 epitope (aa. 401–411).

Conclusion: In a study that controls for confounders, our data focus an EBNA-1 specificity that may be associated with MS pathogenesis.

Background: The existence of Epstein–Barr virus (EBV) strains specifically associated with multiple sclerosis (MS) is a matter of controversy. Little is also known about the prevalence of EBV types 1 and 2 in MS patients and the presence of co-infections by both strains.

Objective: To make EBV strain type assignment and compare the frequencies of types 1, 2 and co-infections by both in MS patients and healthy controls.

Methods: Blood samples from 75 consecutive MS patients and 186 controls were collected. EBV was simultaneously detected and typed using a polymerase chain reaction (PCR) which amplified a strain-specific sequence in the EBV nuclear antigen 2.

Results: EBV was detected in 70 out of 75 patients (93.3%) and in 123 of 186 controls (66.1%). Among positive cases, type 1 was found in 6 patients (8.6%) and 40 controls (32.5%), type 2 in 1 patient (1.4%) and 37 controls (30.1%), and dual-infections by both EBV types were detected in 63 patients (90%) and 46 controls (37.4%). Logistic regression models showed that MS was significantly associated with the presence of EBV (p < 0.001) and also with dual type infections (p < 0.001).

Conclusion: This study provides molecular evidence associating co-infection of type 1 and 2 EBV with MS.

Background: Inflammation triggers secondary neurodegeneration in multiple sclerosis (MS).

Objectives: It is unclear whether classical anti-inflammatory cytokines have the potential to interfere with synaptic transmission and neuronal survival in MS.

Methods: Correlation analyses between cerebrospinal fluid (CSF) contents of anti-inflammatory cytokines and molecular, imaging, clinical, and neurophysiological measures of neuronal alterations were performed.

Results: Our data suggest that interleukin-13 (IL-13) plays a neuroprotective role in MS brains. We found, in fact, that the levels of IL-13 in the CSF of MS patients were correlated with the contents of amyloid-β_1-42. Correlations were also found between IL-13 and imaging indexes of axonal and neuronal integrity, such as the retinal nerve fibre layer thickness and the macular volume evaluated by optical coherence tomography. Furthermore, the levels of IL-13 were related to better performance in the low-contrast acuity test and Multiple Sclerosis Functional Composite scoring. Finally, by means of transcranial magnetic stimulation, we have shown that GABAA-mediated cortical inhibition was more pronounced in patients with high IL-13 levels in the CSF, as expected for a neuroprotective, anti-excitotoxic effect.

Conclusions: The present correlation study provides some evidence for the involvement of IL-13 in the modulation of neuronal integrity and synaptic function in patients with MS.

Background: The ‘normal appearing white matter’ (NAWM) in multiple sclerosis (MS) is known to be abnormal using quantitative magnetic resonance (MR) techniques. The aetiology of the changes in NAWM remains debatable.

Objective: To investigate whether high-field and ultra high-field T₁-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) MRI enables detection of MS white matter lesions in areas defined as NAWM using high-field T₂-weighted fluid attenuation inversion recovery (FLAIR) MRI; that is, to ascertain whether undetected lesions are likely contributors to the burden of abnormality in similarly defined NAWM.

Methods: Fourteen MS patients underwent MRI scans using 3T FLAIR and MPRAGE and 7 Tesla (7T) MPRAGE sequences. Independent observers identified lesions on 3T FLAIR and (7T and 3T) MPRAGE images. The detection of every individual lesion was then compared for each image type.

Results: We identified a total of 812 white matter lesions on 3T FLAIR. Using 3T MPRAGE, 186 additional lesions were detected that were not detected using 3T FLAIR. Using 7T MPRAGE, 231 additional lesions were detected that were not detected using 3T FLAIR.

Conclusions: MRI with 3T and 7T MPRAGE enables detection of MS lesions in areas defined as NAWM using 3T FLAIR. Focal MS lesions contribute to the abnormalities known to exist in the NAWM.

Objectives: To identify associations between cognitive impairment and imaging measures in a cross-sectional study of patients with primary progressive multiple sclerosis (PPMS).

Methods: Neuropsychological tests were administered to 27 patients with PPMS and 31 controls. Patients underwent brain conventional magnetic resonance imaging (MRI) sequences, volumetric scans and magnetization transfer (MT) imaging; MT ratio (MTR) parameters, grey matter (GM) and normal-appearing white matter (NAWM) volumes, and WM T2 lesion load (T2LL) were obtained. In patients, multiple linear regression models identified the imaging measure associated with the abnormal cognitive tests independently from the other imaging variables. Partial correlation coefficients (PCC) were reported.

Results: Patients performed worse on tests of attention/speed of visual information processing, delayed verbal memory, and executive function, and had a worse overall cognitive performance index, when compared with controls. In patients, a lower GM peak location MTR was associated with worse overall cognitive performance (p < 0.001, PCC = 0.77). GM mean and peak height MTR showed the strongest association with the estimated verbal intelligence quotient (IQ) decline (p < 0.001, PCC = -0.62), and executive function (p < 0.001, PCC = 0.79). NAWM volume was associated with attention/speed of visual information processing (p < 0.001, PCC = 0.74), while T2LL was associated with delayed verbal memory (p = 0.007, PCC = -0.55).

Conclusions: The finding of strong associations between GM MTR, NAWM volume and T2LL and specific cognitive impairments suggests that models that predict cognitive impairment in PPMS should include comprehensive MRI assessments of both GM and WM. However, GM MTR appears to be the main correlate of overall cognitive dysfunction, underlining the role of abnormal GM integrity in determining cognitive impairment in PPMS.

Background: Incorporation of routine clinical testing for neutralizing antibodies (NAbs) to interferon (IFN)-β has remained problematic. With increasing treatment choice for patients, routine NAb testing should be incorporated to aid therapeutic decisions.

Objective: We sought to improve interpretation of NAb results by combining the luciferase NAb assay (luciferase gene expression assay under control of interferon-stimulated response element) and in-vivo biomarker (myxovirus A protein, MxA) induction in patients with MS.

Methods: Blood samples (serum and PAXGene^® for RNA) were obtained pre-injection and 12 hours post-injection of IFN-β from 144 subjects. Sera were tested for NAbs using the luciferase assay. MxA expression was quantified by real-time polymerase chain reaction (PCR).

Results: 26% of samples were NAb positive (titre > 20 NU). There was no difference in NAb titres in the pre- or post-dose sera (p = 0.643). MxA expression was inhibited in a dose-dependent fashion in NAb positive samples. Mean MxA level post-IFN-β: NAb negative 2330 (95% CI 1940–2719), NAb 20–99 NU 1533 (95% CI 741–2324), NAb 100–600 NU 832 (186–1478) and NAb > 600 NU 101 (95% CI 0–224). NAb titre and MxA level correlated strongly: MxA pre- (Spearman r = −0.72, p < 0.0001), MxA post- (Spearman r = −0.79, p < 0.0001) and MxA induction (Spearman r = −0.67, p = 0.0004).

Conclusion: A single, 12-hour post-injection sample should be used to test for NAbs using the luciferase assay and IFN-β bioactivity (MxA) in the clinical setting.

Background: Health-related quality of life (HRQoL) worsens with multiple sclerosis (MS) relapses and disease progression. Common symptoms including depression and fatigue may contribute to poor HRQoL.

Objectives: To report exploratory analyses assessing the impact of fingolimod (FTY720) on HRQoL and depression in a phase II study of relapsing MS.

Methods: The Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and Beck Depression Inventory second edition (BDI-II) scores were assessed during a 6-month, placebo-controlled study and optional extension.

Results: HAQUAMS total score improved with fingolimod and worsened with placebo. Mean score change from baseline to month 6 was −0.02 with fingolimod 1.25 mg (p < 0.05 versus placebo), −0.01 with fingolimod 5.0 mg and + 0.12 with placebo. Categorical data supported a clinically important effect of fingolimod on HRQoL. Fingolimod 1.25 mg was also beneficial over placebo in the fatigue/thinking HAQUAMS sub-domain (p < 0.05 versus placebo). Change in mean BDI-II scores from baseline to month 6 and the proportion of patients with BDI-II scores indicative of clinical depression favored fingolimod 1.25 mg over placebo (p < 0.05 for both). At month 4, mean BDI-II and HAQUAMS total scores appeared to be maintained in fingolimod-treated patients.

Conclusion: Fingolimod 1.25 mg may improve HRQoL and depression at 6 onths compared with placebo in patients with relapsing MS.

Background: Cognitive decline and fatigue are typical in multiple sclerosis (MS). However, there is no official medication for either of these symptoms.

Objective: The purpose of this study was to estimate the effects of a single dose of rivastigmine on processing speed and associated brain activity in patients with MS and subjective cognitive fatigue.

Methods: Fifteen patients with MS and subjective cognitive fatigue and 13 healthy controls (HCs) matched for age, gender and education performed a neuropsychological assessment and functional (f)MRI. A modified version of the Paced Visual Serial Addition Test (mPVSAT) was used as the behavioural task during fMRIs. After the first scanning session, both groups were randomly divided into two subgroups receiving either rivastigmine or placebo. A single dose of rivastigmine or placebo was administrated double-blindly and 2.5 hours later the scanning was repeated.

Results: At baseline, the patients with MS showed slower processing speed in mPVSAT compared with the HCs. They also demonstrated stronger bilateral frontal activation after sustained cognitive effort than the HCs. Performance improvement and a further activation increase in the left anterior frontal cortex and additional activation in the right cerebellum were observed in patients who received rivastigmine but not in patients on placebo, or in HCs with placebo or rivastigmine.

Conclusion: These preliminary findings suggest that rivastigmine may improve cognitive processing speed by enhancing compensatory brain activation in patients with MS.

Background: Few high-quality trials have examined the effects of progressive resistance training (PRT) on people with multiple sclerosis (MS).

Objective: To determine the effectiveness of PRT for people with MS, focusing on improving the gait deficits common in this population.

Methods: Using a single blind randomized controlled trial, people with relapsing–remitting MS were randomly allocated to either a PRT program targeting the lower limb muscles twice a week for 10 weeks (n = 36), or usual care plus an attention and social program conducted once a week for 10 weeks (n = 35). Outcomes were recorded at baseline, week 10 and week 22.

Results: Participants attended 92% of training sessions, with no serious adverse events. At 10 weeks, no differences were detected in walking performance. However, compared with the comparison group PRT demonstrated increased leg press strength (16.8%, SD 4.5), increased reverse leg press strength (29.8%, SD 12.7), and increased muscle endurance of the reverse leg press (38.7%, SD 32.8). Improvements in favor of PRT were also found for physical fatigue (Mean difference −3.9 units, 95%CI −6.6 to −1.3), and the physical health domain of quality of life (Mean difference 1.5 units, 95%CI 0.1 to 2.9). At week 22 almost no between-group differences remained.

Conclusion: PRT is a relatively safe intervention that can have short-term effects on reducing physical fatigue, increasing muscle endurance and can lead to small improvements in muscle strength and quality of life in people with relapsing–remitting MS. However, no improvements in walking performance were observed and benefits do not appear to persist if training is completely stopped.

Background: Benign multiple sclerosis (BMS) is typically defined using the Expanded Disability Status Scale (EDSS), which relies heavily on ambulation. We set out to examine important psychosocial and cognitive outcomes in patients with longstanding BMS compared with patients who had recently progressed to ‘no longer benign’ (NLB).

Methods: A previously reported cohort of BMS (EDSS ≤3 at 20 years disease duration) were re-assessed 25–30 years post-onset. Patients remaining benign (EDSS ≤3 at re-assessment) were compared with those NLB for: depression (Beck Depression Inventory), fatigue (Modified Fatigue Impact Scale), health-related quality of life (MSQoL-54), cognition (Rao’s Neuropsychological Screening Battery), and employment status.

Results: A total of 75% (66/88) of the original cohort were located. A total of 61 patients were re-assessed. Twenty-five patients (41%) had progressed in EDSS and were NLB. Compared with benign patients, those NLB were more likely to have: significant fatigue (15/36 [42%] vs. 18/25 [72%], p = 0.019); poorer physical functioning (mean MSQoL-54 = 67.30 vs. 50.89, p = 0.002); an MS-related negative change in employment status (13/36 [36%] vs. 21/25 [84%], p < 0.0001) and cognitive impairment (3/28 [11%] vs. 5/19 [26%]; trend only, p = 0.317). Depression and mental health quality if life differed little between the benign and NLB patients (p > 0.6).

Conclusions: Despite remaining benign for 20 years, a significant proportion of patients progressed with further follow up. While neither depression nor patient-reported mental health quality of life was associated with EDSS progression, patients with longstanding ‘benign’ MS (EDSS ≤3 for 25+ years) had less fatigue, better physical quality of life and employment outcomes and infrequent cognitive impairment. Remaining benign over the long term, as defined by the EDSS, carried some advantages beyond ambulation.

We discuss a forgotten report by the famous British neuroanatomist, neuropathologist and neurologist Jacob Augustus Lockhart Clarke (1817–1880) about a 17-year-old girl with bilateral optic neuritis and longitudinally extensive transverse myelitis. This report, which appeared in 1865, i.e. 15 years prior to Wilhelm Erb’s much-cited paper on the coincidence of optic neuritis and acute myelitis, represents the first known account of a case of Devic’s syndrome or neuromyelitis optica in the English-language medical literature.

Oral fingolimod (Gilenya) is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapses and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). We report a patient with MS who developed asystole and sustained bradycardia 21 hours after the first dose of fingolimod.

Glatiramer acetate (Copaxone^®) is an immunomodulatory polypeptide used in patients with relapsing–remitting multiple sclerosis. It represents a safe treatment option with mild side effects. In this study, we look at a 39-year-old woman who received glatiramer acetate as subcutaneous injections for two months and developed contact dermatitis. The drug had to be stopped, and treatment with topical prednisone was initiated. Prick/scratch testing was negative but the lymphocyte transformation test was highly positive for glatiramer acetate. This is the first report on contact dermatitis induced by glatiramer acetate injections. The treatment consisted of local topical steroids and cessation of the drug.