Hydroxychloroquine for Primary Progressive Multiple Sclerosis.

OBJECTIVE: Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The antimalarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro. METHODS: We conducted a single-arm, phase II futility trial of 200 mg oral HCQ twice daily for 18 months. In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening magnetic resonance imaging (MRI). The primary end point was ≥20% worsening on the timed 25-foot walk measured between 6 and 18 months of follow-up. RESULTS: Based on original trial data, 40% of the cohort were expected to worsen. We used a Simon 2-stage design to compare a null hypothesis of 40% of the cohort worsening against the one-sided alternative of 20%. Using a 5% type 1 error rate and 80% power, HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary end point, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well-tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use. INTERPRETATION: HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials. ANN NEUROL 2021;90:940-948.

Minocycline treatment in clinically isolated syndrome and serum NfL, GFAP, and metalloproteinase levels.

BACKGROUND: In the trial of Minocycline in Clinically Isolated Syndrome (MinoCIS), minocycline significantly reduced the risk of conversion to clinically definite multiple sclerosis (CDMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in MS, and minocycline modulates matrix metalloproteinases (MMPs). OBJECTIVE: To assess the value of blood NfL and GFAP as a biomarker of baseline and future disease activity and its utility to monitor treatment response in minocycline-treated patients with clinically isolated syndrome (CIS). METHODS: We measured NfL, GFAP, and MMPs in blood samples from 96 patients with CIS from the MinoCIS study and compared biomarkers with clinical and radiologic characteristics and outcome. RESULTS: At baseline, NfL levels correlated with T2 lesion load and number of gadolinium-enhancing lesions. Baseline NfL levels predicted conversion into CDMS at month 6. GFAP levels at baseline were correlated with T2 lesion volume. Minocycline treatment significantly increased NfL levels at 3 months but not at 6 months, and decreased GFAP levels at month 6. Minocycline decreased MMP-7 concentrations at month 1. DISCUSSION: Blood NfL levels are associated with measures of disease activity in CIS and have prognostic value. Minocycline increased NfL levels at month 3, but reduced GFAP and MMP-7 levels.

Multiple Sclerosis Clinic Utilization is Associated with Fewer Emergency Department Visits.

OBJECTIVE: Alberta is a Canadian province with a high prevalence of multiple sclerosis (MS). In this ecological study, we examined group differences in health care utilization among persons with MS (pwMS) living within different regions of the province. METHODS: pwMS were identified from provincial administrative databases spanning 2002-2011. Utilization of health care services was determined for a 2-year period (April 2010-March 2012). Residential postal codes placed patients into their provincial health care zones. As data were provided to the investigators in an aggregated form, tests of statistical significance and confounding were not performed. RESULTS: In total, 11,721 pwMS were identified. During the 2-year observation period, 96.2% of pwMS accessed a family physician and 57.1% accessed a neurologist. Nearly all (99.0%) pwMS who received neurologist care in Calgary visited an MS clinic, in contrast to Edmonton where a larger proportion (34.8%) received solely community neurologist care. More pwMS living in Edmonton accessed the ED (41.1%) compared to Calgary (35.7%), and the rate of visits per pwMS was higher in Edmonton (1.07/pwMS) than in Calgary (0.81/pwMS). The frequency of inpatient admissions was similar. CONCLUSIONS: Over 2 years, most pwMS accessed primary care and over half saw a neurologist. Despite a similar frequency of inpatient admissions, the frequency of ED visits by pwMS was higher in Edmonton compared to Calgary, where more patients received MS clinic care. Although this exploratory study is subject to several limitations, our findings suggest that specialized MS clinics may reduce costly ED visits.

An enrichment strategy for clinical trials in SPMS.

BACKGROUND: We recently compared clinical outcomes in secondary progressive MS (SPMS) clinical trials and found an association of timed 25 foot walk (T25FW) worsening events and baseline disability scores. It is unclear whether disability worsening in clinical trials is comparable to that seen in clinical practice. OBJECTIVE: The objective of this study is to compare disability worsening between the IMPACT and ASCEND data sets and data from the Calgary MS clinic and to characterize the association of baseline T25FW and expanded disability status scale (EDSS) scores with disability worsening. METHODS: We combined the three data sets and investigated the impact of baseline characteristics on disability worsening with a logistic regression model. We calculated T25FW, EDSS, and 'EDSS or T25FW' worsening events as a function of ascending cut-off baseline disability scores. RESULTS: Data source was not associated with T25FW worsening at 12 months. There was a strong association of baseline T25FW and EDSS cut-off scores with T25FW worsening. No such association was present for the EDSS and 'EDSS or T25FW'. CONCLUSION: Our results suggest that it is possible to 'enrich' a trial cohort for expected T25FW worsening events using specific baseline T25FW and EDSS cut-off scores. These analyses inform the selection of inclusion criteria for clinical trials in SPMS.

The Canadian prospective cohort study to understand progression in multiple sclerosis (CanProCo): rationale, aims, and study design.

BACKGROUND: Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (MS). Although there are a handful of disease-modifying treatments approved for use in progressive phenotypes of MS, there are no treatments that substantially modify the course of clinical progression in MS. Characterizing the determinants of clinical progression can inform the development of novel therapeutic agents and treatment approaches that target progression in MS, which is one of the greatest unmet needs in clinical practice. Canada, having one of the world's highest rates of MS and a publicly-funded health care system, represents an optimal country to achieve in-depth analysis of progression. Accordingly, the overarching aim of the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) is to evaluate a wide spectrum of factors associated with the clinical onset and rate of disease progression in MS, and to describe how these factors relate to one another to influence progression. METHODS: CanProCo is a prospective, observational cohort study with investigators specializing in epidemiology, neuroimaging, neuroimmunology, health services research and health economics. CanProCo's study design was approved by an international review panel, comprised of content experts and key stakeholders. One thousand individuals with radiologically-isolated syndrome, relapsing-remitting MS, and primary-progressive MS within 10-15 years of disease onset will be recruited from 5 academic MS centres in Canada. Participants will undergo detailed clinical evaluation annually over 5 years (including advanced, app-based clinical data collection). In a subset of participants within 5-10 years of disease onset (n = 500), blood, cerebrospinal fluid, and research MRIs will be collected allowing an integrated, in-depth evaluation of factors contributing to progression in MS from multiple perspectives. Factors of interest range from biological measures (e.g. single-cell RNA-sequencing), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and micro and macro-environmental factors. DISCUSSION: Halting the progression of MS remains a fundamental need to improve the lives of people living with MS. Achieving this requires leveraging transdisciplinary approaches to better characterize why clinical progression occurs. CanProCo is a pioneering multi-dimensional cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Multiple sclerosis-related fatigue: the role of impaired corticospinal responses and heightened exercise fatigability.

It is unclear whether motor fatigability and perceived fatigue share a common pathophysiology in people with multiple sclerosis (PwMS). This cross-sectional investigation explored the relationship between the mechanisms of motor fatigability from cycling and fatigue severity in PwMS. Thirteen highly fatigued (HF) and thirteen nonfatigued (LF) PwMS and thirteen healthy controls (CON) completed a step test until volitional exhaustion on an innovative cycle ergometer. Neuromuscular evaluations involving femoral nerve electrical stimulation and transcranial magnetic stimulation were performed every 3 min throughout cycling. One-way ANOVA at baseline and exhaustion uncovered evidence of consistently smaller motor evoked potential (MEP) amplitudes (P = 0.011) and prolonged MEP latencies (P = 0.041) in HF as well as a greater decline in maximal voluntary contraction force (HF: 63 ± 13%; LF: 75 ± 13%; CON: 73 ± 11% of pre; P = 0.037) and potentiated twitch force (HF: 35 ± 13%; LF: 50 ± 16%; CON: 47 ± 17% of pre; P = 0.049) in HF at volitional exhaustion. Hierarchical regression determined that fatigue severity on the Fatigue Severity Scale was predicted by prolonged MEP latencies (change in r2 = 0.389), elevated peripheral muscle fatigability (change in r2 = 0.183), and depressive symptoms (change in r2 = 0.213). These findings indicate that MS-related fatigue is distinguished by disrupted corticospinal responsiveness, which could suggest progressive pathology, but fatigability from whole body exercise and depressive symptoms also influence perceptions of fatigue in PwMS.NEW & NOTEWORTHY The etiology of fatigability from whole body exercise was examined for the first time to accurately elucidate the relationship between fatigue and fatigability in multiple sclerosis (MS). Compromised corticospinal responsiveness predicted fatigue severity, providing a novel, objective indicator of fatigue in MS. Although the impaired corticomotor transmission did not aggravate muscle activation in this group of people with multiple sclerosis (PwMS) of lower disability, heightened muscle fatigability was seen to contribute to perceptions of fatigue in PwMS.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Biomarkers of intestinal barrier function in multiple sclerosis are associated with disease activity.

BACKGROUND: Recent evidence suggests a role for the gut-brain axis in the pathophysiology of multiple sclerosis (MS). MATERIALS AND METHODS: We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured. RESULTS: Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood-brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad- subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS. CONCLUSIONS: People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut-brain axis modulates neuroinflammation in MS.

A Pacchionian Puzzle.

A 73-year-old male with a history of chronic ataxia presented with transient facial droop to the Emergency Department. A CT angiogram and MRI with diffusion weighted imaging (DWI) were negative for stroke. However, incidental note was made of numerous giant arachnoid granulation pits in the posterior fossa predominantly involving the left occipital bone (Figure 1). These arachnoid pits demonstrated multiple foci of herniation of the adjacent cerebellar parenchyma into the pits with gliosis of the herniated parenchyma and focal encephalomalacia of the subjacent cerebellar parenchyma. Review of bone windows on a remote CT brain performed almost 13 years earlier confirmed this to be a longstanding abnormality (Figure 2). The patient's physical exam was suggestive of cerebellar ataxia with left-sided dysmetria on finger to nose testing and a wide-based unsteady gait.

Gestational bisphenol-A exposure lowers the threshold for autoimmunity in a model of multiple sclerosis.

Environmental and hormonal factors are implicated in dysimmunity in multiple sclerosis. We investigated whether bisphenol-A, a prominent contaminant with endocrine-disrupting capabilities, altered susceptibility in an inflammatory model of multiple sclerosis. We found that gestational, but not adult, exposure to bisphenol-A increased the development of experimental autoimmune encephalomyelitis in adulthood in male, but not female, mice when a suboptimal disease-inducing immunization was used. Gestational bisphenol-A in male mice primed macrophages in adulthood and raised granulocyte-colony stimulating factor and neutrophil counts/activity postsuboptimal immunization. Neutralizing granulocyte-colony stimulating factor blocked susceptibility to disease in bisphenol-A mice. Early life exposure to bisphenol-A may represent an environmental consideration in multiple sclerosis.

The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics.

Biological barriers are essential for the maintenance of homeostasis in health and disease. Breakdown of the intestinal barrier is an essential aspect of the pathophysiology of gastrointestinal inflammatory diseases, such as inflammatory bowel disease. A wealth of recent studies has shown that the intestinal microbiome, part of the brain-gut axis, could play a role in the pathophysiology of multiple sclerosis. However, an essential component of this axis, the intestinal barrier, has received much less attention. In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, and content of the intestinal microbiome entering into the circulation can impact the functions of CNS microglia. We highlight currently available studies suggesting that there is intestinal barrier dysfunction in multiple sclerosis. Finally, we address the mechanisms by which commonly used disease-modifying drugs in multiple sclerosis could alter the intestinal barrier and the microbiome, and we discuss the potential of barrier-stabilizing strategies, including probiotics and stabilization of tight junctions, as novel therapeutic avenues in multiple sclerosis.

Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease?

BACKGROUND: Most multiple sclerosis (MS) patients succumb to a progressive phenotype. Continued lymphocyte activity in the brain, microglia-mediated injury, iron deposition, and oxidative stress are characteristics of progressive MS. OBJECTIVE: As minocycline and hydroxychloroquine have been shown to inhibit microglia, we evaluated their effects on other outcomes relevant for progression. METHODS: Medications were evaluated in culture and in mice with acute and chronic experimental autoimmune encephalomyelitis (EAE). RESULTS: Both medications individually reduced iron neurotoxicity and a combination effect was not observed. Hydroxyl radical scavenging activity was manifested by minocycline only. Minocycline reduced T-cell proliferation more prominently than hydroxychloroquine; an aggregate effect occurred at low but not high concentrations. B-cell proliferation was mitigated to a greater extent by hydroxychloroquine and an additive effect was not evident. In EAE, suboptimal doses of minocycline and hydroxychloroquine individually delayed onset of clinical signs, while their combination suppressed clinical manifestations until treatment was stopped. In Biozzi ABH mice, a model of progressive MS, the chronic phase was beneficially altered using the combination. CONCLUSION: While minocycline and hydroxychloroquine did not manifest additive effects in most culture assays, their combination at suboptimal doses in EAE unexpectedly exceeded their individual activity. Minocycline and hydroxychloroquine combined are candidate treatments for progressive MS.

Discriminative ability of quality of life measures in multiple sclerosis.

BACKGROUND: Though many people with multiple sclerosis (MS) have comorbidities, the use of generic and disease-specific health related quality of life (HRQOL) scales to discriminate the effects of comorbidity has not been established. The utility of these scales to discriminate differences between persons with varying levels of disability is also unknown. METHODS: Using online questionnaires, a convenience sample of Albertans with MS was recruited between July 2011 and March 2013. Participants completed demographic questions, a validated comorbidity questionnaire, a self-reported disability scale, and the following HRQOL scales: the Short Form (SF)-36, SF-6D, Health Utilities Index-Mark III (HUI-III), and Multiple Sclerosis Quality of Life-54 (MSQOL-54). The ability of each HRQOL scale to distinguish between comorbidity groups was assessed using a one-way analysis of covariance, adjusting for age, sex, disease course, and disability level. RESULTS: Five hundred sixty three participants completed all relevant questionnaires. All HRQOL measures distinguished between persons with or without depression, while none were able to distinguish between participants with or without hypertension, thyroid disease, irritable bowel syndrome, or osteoporosis. The SF-36 physical scale, SF-6D, HUI-III, and MSQOL-54 physical scales were able to distinguish between all disability groups, though the HUI-III was better able to distinguish between individuals with moderate versus severe disability. CONCLUSIONS: Disease-specific measures would discriminate better between those with and without comorbidities than generic-specific measures and the HUI-III would discriminate best between persons with differing severities of disability. Generic or disease-specific measures may be useful in future studies examining the effects of comorbidity in MS and the effects of treatment of comorbidities in MS.

Multi-scale MRI spectrum detects differences in myelin integrity between MS lesion types.

BACKGROUND: Lesions with different extents of myelin pathology are found at autopsy in multiple sclerosis (MS), but the differences are not discernible in magnetic resonance imaging (MRI). OBJECTIVE: To determine whether analysis of the local spectrum in MRI is sensitive to lesion differences in myelin integrity. METHODS: We imaged fresh brain slices from 21 MS patients using 1.5T scanners. White matter lesions were identified in T2-weighted MRI, matched to corresponding specimens, and then classified into five categories in histology: pre-active (intact myelin); active, chronic active, chronic inactive (complete demyelination); and remyelinated lesions. Voxel-based frequency spectrum was calculated using T2-weighted MRI to characterize lesion structure (image texture). RESULTS: MRI texture heterogeneity resulting from all spectral scales was greater in completely demyelinated lesions than in myelin-preserved lesions (p = 0.02) and normal-appearing white matter (p < 0.01). Moreover, the spectral distribution pattern over low-frequency scales differentiated demyelinated lesions from remyelinated and pre-active lesions (p < 0.01), where different lesion types also showed distinct texture scales. CONCLUSION: Using multi-scale spectral analysis, it may be possible for standard MRI to evaluate myelin integrity in MS lesions. This can be critical for monitoring disease activity and assessing remyelination therapies for MS patients.

Medical Tourism for CCSVI Procedures in People with Multiple Sclerosis: An Observational Study.

BACKGROUND: Many Canadians with multiple sclerosis (MS) have recently travelled internationally to have procedures for a putative condition called chronic cerebrospinal venous insufficiency (CCSVI). Here, we describe where and when they went and describe the baseline characteristics of persons with MS who participated in this non-evidence-based medical tourism for CCSVI procedures. METHODS: We conducted a longitudinal observational study that used online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following procedures for CCSVI. A convenience sample of all Albertans with MS was recruited between July 2011 and March 2013. RESULTS: In total, 868 individuals enrolled; 704 were included in this cross-sectional, baseline analysis. Of these, 128 (18.2%) participants retrospectively reported having procedures for CCSVI between April 2010 and September 2012. The proportion of participants reporting CCSVI procedures declined from 80 (62.5%) in 2010, to 40 (31.1%) in 2011, and 8 (6.3%) in 2012. In multivariable logistic regression analysis, CCSVI procedures were independently associated with longer disease duration, secondary progressive clinical course, and greater disability status. CONCLUSIONS: Although all types of people with MS pursued procedures for CCSVI, a major driver of participation was greater disability. This highlights that those with the greatest disability are the most vulnerable to unproven experimental procedures. Participation in CCSVI procedures waned over time possibly reflecting unmet expectations of treated patients, decreased media attention, or that individuals who wanted procedures had them soon after the CCSVI hypothesis was widely publicized.

Prolactin in combination with interferon-ß reduces disease severity in an animal model of multiple sclerosis.

Previous work has demonstrated that the hormone prolactin promotes oligodendrocyte precursor proliferation and remyelination following lysolecithin-induced demyelination of the mouse spinal cord. Prolactin, however, can elicit pro-inflammatory responses, and its use in the prototypical demyelinating and inflammatory condition, multiple sclerosis (MS), should thus be approached cautiously. Here, we sought to determine whether recombinant prolactin could alter the course of experimental autoimmune encephalomyelitis (EAE), an inflammatory animal model of MS. Consistent with previous literature, we found that prolactin activated leukocytes in vitro. Daily treatment with prolactin from around the time of onset of clinical signs, for 9 (days 9 to 17) or 25 (days 9 to 33) days did not increase clinical or histological signs of EAE over that of vehicle-treated mice. Instead, the combination of prolactin and a suboptimal dose of recombinant murine interferon-ß resulted in (days 9 to 17 group) or trended towards (days 9 to 33 group), a greater amelioration of clinical signs of EAE, compared to either treatment alone or to vehicle controls. Histological analyses corroborated the clinical EAE data. These results suggest that prolactin may be beneficial when administered in combination with interferon-ß in MS.

The natural history of early versus late disability accumulation in primary progressive MS.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is the least common MS disease course and carries the worst prognosis. In relapsing-remitting multiple sclerosis (RRMS) disability accumulation occurs in two distinct phases, but it is unclear whether this is also true for PPMS. Here we investigate factors associated with early and late disability accumulation in PPMS. METHODS: We used Kaplan-Meier survival analyses and Cox regression to investigate the influence of sex, age at disease onset and onset symptoms on time to, and age at, Expanded Disability Status Scale (EDSS) 4 and 6, as well as the time from EDSS 4 to 6 in patients with PPMS. RESULTS: We identified 500 patients with PPMS. The analyses on time to EDSS 4 included 358 patients, and those on time to EDSS 6 included 392 patients. The median times to EDSS 4 and EDSS 6 were 5 and 9 years. The analyses on age at EDSS 4 included 360 patients, and those on age at EDSS 6 included 402 patients. The median ages at EDSS 4 and EDSS 6 were 51 and 55 years. Older age at onset and bilateral motor onset symptoms were independently associated with a shorter time to both EDSS 4 and EDSS 6. Sex and other onset symptoms were not associated with time to, or age at, landmark disability. Only age at onset was significantly associated with the time from EDSS 4 to EDSS 6. CONCLUSIONS: Age at disease onset is the most important predictor of disability accumulation in PPMS. Bilateral motor onset symptoms were associated with quicker disease progression. In contrast to RRMS, we found no evidence for distinct phases of disability accumulation in PPMS. Disability accumulation in PPMS appears to be affected by the same factors throughout its course.

Depression in multiple sclerosis: a long-term longitudinal study.

BACKGROUND: Depression is a common comorbidity in multiple sclerosis (MS), but little is known about its long-term prognosis. Depression in the general population is usually episodic with relatively short-lasting depressive episodes. In this study we investigate the long-term prognosis of depression in MS. METHODS: Using data from a large longitudinal observational study and from the Calgary MS clinic database, we investigated changes in Center for Epidemiological Studies Depression Scale (CESD) scores in MS patients over four years of follow-up. We used logistic regression to investigate the association of the factors sex, age, disease duration, Expanded Disability Status Scale (EDSS), depression at baseline, and antidepressant use with depression at each year of follow-up. RESULTS: CESD scores remained largely stable, or decreased slightly over four years of follow-up, whereas EDSS scores steadily increased. Depression at baseline was the strongest predictor of depression at follow-up; the other factors were not or not consistently associated with depression at follow-up. As expected, antidepressant use was associated with a greater risk of depression at follow-up. Starting and stopping antidepressant treatment during follow-up was not associated with the risk of depression at follow-up or with significant change in CESD scores. CONCLUSION: In contrast to depression in the general population, depression in MS is largely chronic, which suggests a different pathophysiology.

Validity of four screening scales for major depression in MS.

BACKGROUND: There is a role for brief assessment instruments in detection and management of major depression in MS. However, candidate scales have rarely been validated against a validated diagnostic interview. In this study, we evaluated the performance of several candidate scales: Patient Health Questionnaire (PHQ)-9, PHQ-2, Center for Epidemiologic Studies Depression rating scale (CES-D), and Hospital Anxiety and Depression Scale (HADS-D) in relation to the Structured Clinical Interview for DSM-IV (SCID). METHODS: The sample was an unselected series of 152 patients attending a multiple sclerosis (MS) clinic. Participants completed the scales during a clinic visit or returned them by mail. The SCID was administered by telephone within two weeks. The diagnosis of major depressive episode, according to the SCID, was used as a reference standard. Receiver-operator curves (ROC) were fitted and indices of measurement accuracy were calculated. RESULTS: All of the scales performed well, each having an area under the ROC > 90%. For example, the PHQ-9 had 95% sensitivity and 88.3% specificity when scored with a cut-point of 11. This cut-point achieved a 56% positive predictive value for major depression. CONCLUSIONS: While all of the scales performed well in terms of their sensitivity and specificity, the availability of the PHQ-9 in the public domain and its brevity may enhance the feasibility of its use.