Treatment of MOG antibody associated disorders: results of an international survey.

INTRODUCTION: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. OBJECTIVE: To survey the current global clinical practice of clinicians treating MOGAD. METHOD: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019). RESULTS: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. CONCLUSION: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

Nurse led telephone assessment of expanded disability status scale assessment in MS patients at high levels of disability.

BACKGROUND: In clinical trials drop out bias reduces the validity of results. This is a particular problem in long-term multiple sclerosis (MS) studies, particularly when patients become progressively disabled and have increasing difficulty attending assessment clinics. OBJECTIVE: To assess the validity of nurse led telephone assessment of Expanded Disability Status Scale (TEDSS) in MS patients with EDSS scores >6.0. METHODS: We performed a multi-centre, single blind trial to assess nurse derived TEDSS against physician face-to-face EDSS scores derived from neurological examination (FEDSS) in patients with clinically definite MS and EDSS >6.0. RESULTS: Ninety patients (n=15 primary progressive MS, n=74 secondary progressive MS, n=1 relapsing remitting MS) had a mean baseline FEDSS of 7.5. TEDSS correlated with FEDSS (r=0.76, p<0.0001) and kappa scores for perfect agreement, within 0.5 of an EDSS points, and within 1 EDSS point were 0.25, 0.86, and 1.0 respectively. Intra-class correlation between the scoring systems was 0.88, representing a high level of agreement. CONCLUSION: Nurse-led telephone assessment of EDSS gives good agreement with physician derived face-to-face EDSS in MS patients with higher disability scores. This may be a valuable tool to improve clinical follow-up in routine clinical practice and improve patient retention in long-term outcome studies.

The epidemiology of multiple sclerosis in the Isle of Man: 2006-2011.

BACKGROUND: We sought to determine the prevalence of MS on the Isle of Man in 2006 and 2011, and the incidence and mortality rates over this interval. METHODS: Cases were identified by hospital medical record review, General Practitioners and the local MS Society. The significance of the change in prevalence over time and the significance of differences in frequencies by sex and place of birth were assessed by Poisson regression. RESULTS: The 2006 prevalence was 153.64 per 100,000 persons and the 2011 prevalence was 179.89. The prevalence was higher among females and persons born in the Isle of Man at both time points. The 2006-2011 incidence rate was 6.86 per 100,000 person-years, much higher among females and persons born in the Isle of Man. The prevalence sex ratios in 2006 and 2011, 2.77 and 2.59, respectively, and the incidence sex ratio, 2.19, are similar to others found in the region. The mortality rate over the study period was 2.84 per 100,000 person-years, this solely among persons born overseas. CONCLUSIONS: This is the first study of MS epidemiology in the Isle of Man, finding this area to be of high prevalence and to have one of the highest incidence rates in the UK region.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort.

OBJECTIVE: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). METHODS: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3). RESULTS: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression. CONCLUSIONS: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

EFNS guidelines on diagnosis and management of neuromyelitis optica.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge. SEARCH STRATEGY: Evidence for this guideline was collected by searches for original articles, case reports and meta-analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied. RESULTS: Different diagnostic criteria for NMO diagnosis [Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008] and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work-up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion. CONCLUSIONS: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I-III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.

Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it?

BACKGROUND: Therapy-related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for multiple sclerosis (MS). The timing of this complication, risk, mortality and relationship to exposure remain uncertain. METHODS: We searched literature for publications relating to Mitoxantrone in MS, reviewed publication references and handsearched abstract lists to identify case-series reporting follow-up and complications of treatment with Mitoxantrone. We combined this with our local database of 250 cases treated since 1997. We also identified all reported individual cases of TRAL and extracted data reporting exposure (dose or mg/m(2)), timing and outcome of TRAL. RESULTS: Case-series including 5472 patients were identified; mean dose of Mitoxantrone was 74.2 mg/m(2) (range:12-120 mg/m(2)). TRAL was diagnosed in 0.30% (1 in 333). In 34 TRAL cases, sufficient data was available to inform analysis of exposure. Onset was a median of 18.5 months following Mitoxantrone treatment (range:4-60). Acute Myelocytic Leukaemia and Acute Promyelocytic Leukaemia represented 46.4% each of the leukaemia subtypes. Six of 25 TRAL patients, where outcome was reported, died (24%). Over 80% of cases occurred in patients exposed to >60 mg/m(2), with a relative risk of 1.44 (CI95%:1.18-1.70) when comparing total dose >60 mg/m(2) against <60 mg/m(2) strongly suggesting a relationship between risk of TRAL and total dose.

Vitamin D receptor gene polymorphism is associated with reduced disability in multiple sclerosis.

Ultraviolet radiation (UVR) may contribute to multiple sclerosis (MS) outcome by a mechanism involving vitamin D and the vitamin D receptor (VDR). In 512 patients with MS duration of 10 or more years, we studied the association of VDR single nucleotide polymorphisms (A/G(1229), C/G(3444), G/A(3944), CC(20965), CC(30056), F/f(30875), C/T(48200), T/t(65013)) with outcome or disability. ff(30875) frequency was lower in cases with EDSS > or = 6.0 than with scores < 6.0 (odds ratio = 0.38, 95% CI = 0.20-0.70). The association of ff(30875) with outcome was not mediated by cumulative exposure to UVR as assessed by questionnaire; low exposure (odds ratio = 0.42, 95% CI = 0.14-1.34) and high exposure (odds ratio = 0.34, 95% CI = 0.16-0.73).

Myelopathy but normal MRI: where next?

For most patients presenting with a spinal cord syndrome MR scanning has become the key investigation in establishing the diagnosis. However, myelopathy with normal spinal imaging remains a common clinical conundrum. In this review we discuss the diagnoses to consider for the neurologist presented with a patient with "MR normal myelopathy". We will illustrate this scenario with a series of short cases and consider the further investigation of "MRI normal" myelopathy.

Studies of associations between disability in multiple sclerosis, skin type, gender and ultraviolet radiation.

Recent studies suggest ultraviolet radiation (UVR)/vitamin D is protective against the development of multiple sclerosis (MS). We determined if outcome in MS is associated with the surrogate for host pigmentation, skin type, and parameters of UVR exposure. We used a validated questionnaire to determine skin type and UVR exposure during childhood (0-16 years), and early adult life (17-40 years), in 448 Caucasians with MS. Outcome was assessed using the Kurtzke Expanded Disability Status Score (EDSS) and Multiple Sclerosis Severity Scale (MSSS). We studied the association of skin type and exposure with dichotomized values of EDSS (< and >or=6) and MSSS (continuous variable) using logistic and linear regression analyses, respectively. Sex, onset age and MS duration were significantly associated with outcome in all patients. In 169 females with established disease (>or=10 years), sun sensitive skin types 1 and 2 were associated with reduced risk of EDSS >or=6 (odds ratio =0.50; 95% CI = 0.26-0.97), and higher MSSS values (coefficient = -0.86; 95% CI = -1.67 to -0.05). Parameters of UVR exposure were not significantly associated with outcome. These preliminary data show an association between skin type and disability in female MS patients. They are compatible with independent studies suggesting that exposure mediates MS pathogenesis via vitamin D. Further studies are required to properly assess these potentially important findings.

A randomized controlled trial of a health promotion education programme for people with multiple sclerosis.

OBJECTIVE: To evaluate the effectiveness of a health promotion education programme for people with multiple sclerosis (the OPTIMISE programme) in terms of increasing the level of health-promoting activity undertaken, improving self-efficacy and enhancing quality of life. DESIGN: A randomized controlled single blinded trial. Non-parametric analysis was undertaken to test for significant differences between treatment and control groups change scores. SUBJECTS AND SETTING: Sixty-two adults (32 treatment and 30 control subjects) with multiple sclerosis of any type, Expanded Disability Status Scale (EDSS) 1-7. INTERVENTION: An eight-week multidisciplinary outpatient health promotion education programme aimed at increasing knowledge, skills and confidence in undertaking health promotion activities. OUTCOME MEASURES: Health Promoting Lifestyle Profile, Self-Rated Abilities for Health Practices Scale and the Short Form 36 Item Health Survey. RESULTS: Following completion of the programme, treatment subjects had significantly higher levels of health promotion activity undertaken (P < 0.01) and self-efficacy for health promotion activities (P < 0.01). These benefits were sustained for at least three months after the programme ceased. Certain domains of quality of life also improved in treatment subjects more than controls (physical P = 0.03, mental health and general health P = 0.01), although only mental health and general health showed further improvement at three months. Participants provided positive feedback regarding the usefulness of the intervention and demonstrated observable changes to their health promotion behaviours. CONCLUSIONS: The OPTIMISE programme produced significant changes in health-promoting behaviours.

Susceptibility and outcome in MS: associations with polymorphisms in pigmentation-related genes.

Multiple sclerosis (MS) risk is determined by environment and genes. The authors investigated in 419 cases and 422 controls if polymorphism in the vitamin D receptor (VDR), melanocortin-1 receptor (MC1R), and tyrosinase (TYR) genes is linked with MS risk and outcome. VDR ff was associated with reduced (odds ratio [OR] = 0.59) and MC1R His294-encoding alleles with increased (OR = 2.21) risk. MC1R Glu84/Glu84 was linked with disability (OR = 5.65). These preliminary data suggest a role for these genes in MS pathogenesis.

Anti-spasticity agents for multiple sclerosis.

BACKGROUND: Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care. A variety of oral and parenteral medications are available. OBJECTIVES: To assess the absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis (MS) patients. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (January 1966 to June 2003), EMBASE (January 1988 to June 2003), bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies. SELECTION CRITERIA: Double-blind, randomised controlled trials (either placebo-controlled or comparative studies) of at least seven days duration. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and the findings of the trials were summarised. Missing data were collected by correspondence with principal investigators. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed. MAIN RESULTS: Twenty-six placebo-controlled studies (using baclofen, dantrolene, tizanidine, botulinum toxin, vigabatrin, prazepam, threonine and cannabinoids) and thirteen comparative studies met the selection criteria and were included in this review. Only fifteen of these studies used the Ashworth scale, of which only three of the eight placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs. Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive. REVIEWER'S CONCLUSIONS: The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing. The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.

A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment.

BACKGROUND: There is evidence to support both the use of intravenous methylprednisolone (IVMP) in multiple sclerosis (MS) relapse and physiotherapy in the management of MS, but no studies have investigated the combination of steroids and rehabilitation together. OBJECTIVES: To evaluate the benefits of IVMP with planned, comprehensive multidisciplinary team (MDT) care compared to IVMP with standard care. METHODS: In this randomised controlled trial, patients confirmed to have had a definite MS relapse severe enough to warrant IVMP (1 g daily for three days) were randomised to two groups. The control group was managed according to the standard ward routine; the treatment group received planned coordinated multidisciplinary team assessment and treatment. Baseline assessments, including demographics and Expanded Disability Status Scale (EDSS) were carried out on both groups. The primary outcome measures were Guy's Neurological Disability Scale (GNDS), and Amended Motor Club Assessment (AMCA). The secondary measures were the Barthel Index (BI), Human Activity Profile (HAP), and Short Form Item 36 Health Survey (SF-36). All measures have published data on reliability and validity. Measures were administered at one and three months. RESULTS: Forty subjects, including 27 females, completed data collection. There were no significant differences between the two groups at baseline. Results showed statistically significant differences in GNDS (p = 0.03), AMCA (p = 0.03), HAPM (p < 0.01), HAPA (p = 0.02), and BI (p = 0.02) at three months in favour of planned MDT care. CONCLUSION: This study indicates that combining steroids with planned MDT care is superior to administering them in a standard neurology or day ward setting. Further research is necessary in order to confirm this finding.

The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom.

BACKGROUND: A point mutation in protein tyrosine phosphatase receptor, type c polypeptide (PTPRC) has been associated with familial multiple sclerosis. This CG mutation at position 77 of exon 4 results in altered expression of CD45 isoforms on immune cells. OBJECTIVE: To study the incidence of PTPRC mutations in subjects with multiple sclerosis in the North West region of the United Kingdom. METHODS: Affected and unaffected subjects from five pedigrees with familial multiple sclerosis, 330 non-familial cases of multiple sclerosis, and 197 controls were studied. Genomic DNA was amplified using CD45IE34 and CD45IE44 primers, digested with Mspl, and run on an agarose gel. Polymerase chain reaction products were sequenced to exclude any other mutations. RESULTS: No PTPRC exon 4 genomic mutations were seen in any of the five families. In the non-familial cases the incidence of mutation was 4.1% in 197 controls and 5.1% in 330 multiple sclerosis patients. No significant association was found in this study with this mutation and disease susceptibility, sex, or an extended disability scale score of < 5.5. CONCLUSIONS: This candidate does not appear to influence the development of familial multiple sclerosis in this population. The negative result could arise from a type II error owing to the number of families and non-familial cases screened. Alternatively it might suggest that the contribution of the PTPRC mutation depends upon the genetic background.

Interleukin 1 genotypes in multiple sclerosis and relationship to disease severity.

We studied the association between clinical outcome in MS and allelic variants single nucleotide polymorphisms (SNPs) of interleukin-1alpha (IL-1alpha), IL-1beta and a variable number tandem repeat (VNTR) in IL-1 receptor antagonist (IL-1RN). A total of 377 patients with MS were studied. Significant associations between IL-1 genotypes and clinical outcome were found using logistic regression after correction for gender, onset age and disease duration. The same trends were subsequently demonstrated in a second independent group of 67 primary progressive patients. Our results suggest that genetically determined immunomodulation mediated by IL-1 influences long-term prognosis in multiple sclerosis (MS).

Anti-spasticity agents for multiple sclerosis.

BACKGROUND: Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care. A variety of oral and parenteral medications are available. OBJECTIVES: To assess the absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis (MS) patients. SEARCH STRATEGY: Randomised controlled trials (RCTs) of anti-spasticity agents were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies. SELECTION CRITERIA: Double-blind, randomised controlled trials (either placebo-controlled or comparative studies) of at least seven days duration. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and the findings of the trials were summarised. Missing data were collected by correspondence with principal investigators. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed. MAIN RESULTS: Twenty-three placebo-controlled studies (using baclofen, dantrolene, tizanidine, botulinum toxin, vigabatrin, prazepam and threonine) and thirteen comparative studies met the selection criteria. Only thirteen of these studies used the Ashworth scale, of which only three of the six placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs. Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive. REVIEWER'S CONCLUSIONS: The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing. The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.

HLA-DRB1 and disease outcome in multiple sclerosis.

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.

Anti-spasticity agents for multiple sclerosis.

BACKGROUND: Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care. A variety of oral and parenteral medications are available. OBJECTIVES: To assess the absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis (MS) patients. SEARCH STRATEGY: Randomised controlled trials (RCTs) of anti-spasticity agents were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies. SELECTION CRITERIA: Double-blind, randomised controlled trials (either placebo-controlled or comparative studies) of at least seven days duration. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and the findings of the trials were summarised. Missing data were collected by correspondence with principal investigators. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed. MAIN RESULTS: Twenty-three placebo-controlled studies (using baclofen, dantrolene, tizanidine, botulinum toxin, vigabatrin, prazepam and threonine) and thirteen comparative studies met the selection criteria. Only thirteen of these studies used the Ashworth scale, of which only three of the six placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs. Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive. REVIEWER'S CONCLUSIONS: The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing. The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.