Developing evidence-based guidelines for the safety of symptomatic drugs in multiple sclerosis during pregnancy and breastfeeding: A systematic review and Delphi consensus.

BACKGROUND: Multiple sclerosis (MS) is frequently diagnosed in people of reproductive age, many of whom will become pregnant following diagnosis. Although many women report an improvement in symptoms and relapses during pregnancy, symptoms such as fatigue and spasticity are commonly reported and can worsen. Prescribing medications during pregnancy and breastfeeding presents unique challenges and guidance on the use of symptomatic therapies is limited. OBJECTIVES: This paper aims to provide a consensus on the current evidence base to facilitate informed decision-making and optimise pre-conception counselling. METHODS: A list of most commonly prescribed medications for symptom management in MS was created using pregnancy and MS-related READ codes in the Welsh GP Dataset, followed by a review by MS neurologists. RESULTS: A final list of 24 medications was generated for review. Searches were performed on each medication, and evidence graded using standardised criteria. Evidence-based recommendations were developed and distributed to experts in the field and revised according to feedback using modified Delphi criteria. CONCLUSIONS: Our guidelines provide evidence-based recommendations on the safety of symptomatic therapies during pregnancy and breastfeeding for general practitioners and specialist teams working with people with MS who are hoping to embark on pregnancy or are currently pregnant. Individual risk-benefit ratios should be considered during pre-conception counselling to optimise symptom burden and minimise harm to both parent and child.

Anti-CD20 therapies in pregnancy and breast feeding: a review and ABN guidelines.

Neurologists increasingly use anti-CD20 therapies, including for women of childbearing age, despite these medications being unlicensed for use in pregnancy. Current evidence suggests that women can safely conceive while taking anti-CD20 therapy. Women should not be denied treatment during pregnancy when it is clinically indicated, although they should be counselled regarding live vaccinations for their infant. Women receiving regular ocrelizumab for multiple sclerosis should preferably wait 3 months before trying to conceive. There are few data around ofatumumab in pregnancy, and while there is probably a class effect across all anti-CD20 therapies, ofatumumab may need to be continued during pregnancy to maintain efficacy. We recommend that anti-CD20 therapies can be safely given while breast feeding. It is important to make time to discuss treatments with women of childbearing age to help them choose their most suitable treatment. Outcomes should be monitored in pregnancy registries.

UK variance in DMT advice and prescribing in MS and pregnancy: Impact of the UK consensus on pregnancy in multiple sclerosis ABN guidelines.

BACKGROUND: The ABN Multiple Sclerosis (MS) pregnancy guidelines set out to combine best current evidence with expert consensus. They were developed to provide a practical framework to support neurologists when counselling women with MS regarding pregnancy. A key objective was to reduce variation in practice and increase clarity for patients in an area of uncertainty. METHODS: In order to assess the impact of these guidelines on practice, and assess ongoing areas of need, we conducted an online survey about MS and pregnancy. This survey was cascaded via email to UK neurologists between December 2019 and January 2020. Individuals completed this questionnaire anonymously. RESULTS: The majority of respondents reported changing their prescribing practice with interferon-beta preparations (IFN-B) and natalizumab. The ABN guidelines were the most commonly cited reason for change (76%). However, there was considerable variation in advice regarding the use of both DMTs in pregnancy. CONCLUSIONS: There is substantial variation in advice given to women with MS around pregnancy, and this is reflected in prescribing practice by UK Neurologists. Awareness of national guidelines is good, and these have driven change in a majority of MS neurologists. There remains the need to continually update and communicate these guidelines, particularly as recommendations evolve with increasing evidence.

Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications.

There is mounting evidence regarding the role of impairment in neuromodulatory networks for neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the role of neuromodulatory networks in multiple sclerosis (MS) has not been assessed. We applied resting-state functional connectivity and graph theory to investigate the changes in the functional connectivity within neuromodulatory networks including the serotonergic, noradrenergic, cholinergic, and dopaminergic systems in MS. Twenty-nine MS patients and twenty-four age- and gender-matched healthy controls performed clinical and cognitive assessments including the expanded disability status score, symbol digit modalities test, and Hamilton Depression rating scale. We demonstrated a diffuse reorganization of network topography (P < 0.01) in serotonergic, cholinergic, noradrenergic, and dopaminergic networks in patients with MS. Serotonergic, noradrenergic, and cholinergic network functional connectivity derangement was associated with disease duration, EDSS, and depressive symptoms (P < 0.01). Derangements in serotonergic, noradrenergic, cholinergic, and dopaminergic network impairment were associated with cognitive abilities (P < 0.01). Our results indicate that functional connectivity changes within neuromodulatory networks might be a useful tool in predicting disability burden over time, and could serve as a surrogate endpoint to assess efficacy for symptomatic treatments.

A 30-Year Clinical and Magnetic Resonance Imaging Observational Study of Multiple Sclerosis and Clinically Isolated Syndromes.

OBJECTIVE: Clinical outcomes in multiple sclerosis (MS) are highly variable. We aim to determine the long-term clinical outcomes in MS, and to identify early prognostic features of these outcomes. METHODS: One hundred thirty-two people presenting with a clinically isolated syndrome were prospectively recruited between 1984 and 1987, and followed up clinically and radiologically 1, 5, 10, 14, 20, and now 30 years later. All available notes and magnetic resonance imaging scans were reviewed, and MS was defined according to the 2010 McDonald criteria. RESULTS: Clinical outcome data were obtained in 120 participants at 30 years. Eighty were known to have developed MS by 30 years. Expanded Disability Status Scale (EDSS) scores were available in 107 participants, of whom 77 had MS; 32 (42%) remained fully ambulatory (EDSS scores ≤3.5), all of whom had relapsing-remitting MS (RRMS), 3 (4%) had RRMS and EDSS scores >3.5, 26 (34%) had secondary progressive MS (all had EDSS scores >3.5), and MS contributed to death in 16 (20%). Of those with MS, 11 received disease-modifying therapy. The strongest early predictors (within 5 years of presentation) of secondary progressive MS at 30 years were presence of baseline infratentorial lesions and deep white matter lesions at 1 year. INTERPRETATION: Thirty years after onset, in a largely untreated cohort, there was a divergence of MS outcomes; some people accrued substantial disability early on, whereas others ran a more favorable long-term course. These outcomes could, in part, be predicted by radiological findings from within 1 year of first presentation. ANN NEUROL 2020;87:63-74.

[18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis.

PURPOSE: We evaluated myelin changes throughout the central nervous system in Multiple Sclerosis (MS) patients by using hybrid [18F]florbetapir PET-MR imaging. METHODS: We included 18 relapsing-remitting MS patients and 12 healthy controls. Each subject performed a hybrid [18F]florbetapir PET-MR and both a clinical and cognitive assessment. [18F]florbetapir binding was measured as distribution volume ratio (DVR), through the Logan graphical reference method and the supervised cluster analysis to extract a reference region, and standard uptake value (SUV) in the 70-90 min interval after injection. The two quantification approaches were compared. We also evaluated changes in the measures derived from diffusion tensor imaging and arterial spin labeling. RESULTS: [18F]florbetapir DVRs decreased from normal-appearing white matter to the centre of T2 lesion (P < 0.001), correlated with fractional anisotropy and with mean, axial and radial diffusivity within T2 lesions (coeff. = -0.15, P < 0.001, coeff. = -0.12, P < 0.001 and coeff. = -0.16, P < 0.001, respectively). Cerebral blood flow was reduced in white matter damaged areas compared to white matter in healthy controls (-10.9%, P = 0.005). SUV70-90 and DVR are equally able to discriminate between intact and damaged myelin (area under the curve 0.76 and 0.66, respectively; P = 0.26). CONCLUSION: Our findings demonstrate that [18F]florbetapir PET imaging can measure in-vivo myelin damage in patients with MS. Demyelination in MS is not restricted to lesions detected through conventional MRI but also involves the normal appearing white matter. Although longitudinal studies are needed, [18F]florbetapir PET imaging may have a role in clinical settings in the management of MS patients.

UK consensus on pregnancy in multiple sclerosis: 'Association of British Neurologists' guidelines.

Multiple sclerosis (MS) is more common in women than men and is most commonly diagnosed in early adulthood; thus, many patients will not have completed their families at the time of diagnosis. There is increasing awareness of the importance of early treatment in preventing long-term disability in MS. Delaying treatment until women with MS have completed their families can lead to the development of irreversible disability in at least some cases. It is therefore important to discuss family planning and pregnancy proactively. However, to date there is limited evidence to inform such discussions. We set out to develop consensus guidelines for the treatment of MS in pregnancy to encourage and facilitate discussions in this important area. The guidelines draw on available evidence from drug-specific pregnancy registers and published literature and have been scored by a panel of experts from a variety of disciplines using modified Delphi criteria. They cover prepregnancy counselling, management during pregnancy, delivery and anaesthetic options, postpartum advice and specific advice regarding currently licensed disease-modifying drugs. As the complexity and range of available disease-modifying drugs increase, further data gathering via a UK-wide MS pregnancy register is recommended.

Vitamin D supplementation.

Vitamin D testing and supplementation is of great interest to neurologists and their patients. Recommended nutritional intakes of vitamin D in the UK remain focused on bone health, despite increasing evidence for a role outside this area. Here we discuss how neurologists might approach vitamin D testing and supplementation, focusing on two conditions associated with vitamin D deficiency that have an increased risk of downstream complications resulting from these: multiple sclerosis and epilepsy. We set out a rationale for testing serum 25-hydroxyvitamin D concentrations and discuss our personal practice in terms of supplementation, with evidence where available.

A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE).

BACKGROUND: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. OBJECTIVE: To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. DESIGN: A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. PARTICIPANTS: Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). INTERVENTIONS: Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. MAIN OUTCOME MEASURES: Primary outcome measure - American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures - ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. RESULTS: In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. CONCLUSIONS: The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. TRIAL REGISTRATION: EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).

The spectrum of psychosis in multiple sclerosis: a clinical case series.

Psychosis in the context of multiple sclerosis (MS) has previously been reported as a rare occurrence. However, recent epidemiological studies have found prevalence rates of psychosis in MS that are two to three times higher than those in the general population. Untreated psychosis in patients with MS can adversely impact on adherence to MS medication, levels of disability, and quality of life. This retrospective case series describes the spectrum of psychotic disorders occurring in association with MS using demographic, clinical, and neuroimaging data. In the discussion, we highlight the particular diagnostic and treatment challenges that such disorders can pose for clinicians and through our case vignettes provide examples of potential interventions for this complex patient population.

Brain and cord myelin water imaging: a progressive multiple sclerosis biomarker.

OBJECTIVES: Conventional magnetic resonance imaging (MRI) is used to diagnose and monitor inflammatory disease in relapsing remitting (RR) multiple sclerosis (MS). In the less common primary progressive (PP) form of MS, in which focal inflammation is less evident, biomarkers are still needed to enable evaluation of novel therapies in clinical trials. Our objective was to characterize the association - across the brain and cervical spinal cord - between clinical disability measures in PPMS and two potential biomarkers (one for myelin, and one for atrophy, both resulting from the same imaging technique). METHODS: Multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) MRI of the brain and cervical spinal cord were obtained for 15 PPMS patients and 11 matched controls. Data were analysed to estimate the signal related to myelin water (VFM), as well as volume measurements. MS disability was assessed using the Multiple Sclerosis Functional Composite score, which includes measures of cognitive processing (Paced Auditory Serial Addition Test), manual dexterity (9-Hole Peg Test) and ambulatory function (Timed 25-Foot Walk); and the Expanded Disability Status Scale. RESULTS: Brain and spinal cord volumes were different in PPMS compared to controls, particularly ventricular (+ 46%, p = 0.0006) and cervical spinal cord volume (- 16%, p = 0.0001). Brain and spinal cord myelin (VFM) were also reduced in PPMS (brain: - 11%, p = 0.01; spine: - 19%, p = 0.000004). Cognitive processing correlated with brain ventricular volume (p = 0.009). Manual dexterity correlated with brain ventricular volume (p = 0.007), and both brain and spinal cord VFM (p = 0.01 and 0.06, respectively). Ambulation correlated with spinal cord volume (p = 0.04) and spinal cord VFM (p = 0.04). INTERPRETATION: In this study we demonstrated that mcDESPOT can be used to measure myelin and atrophy in the brain and spinal cord. Results correlate well with clinical disability scores in PPMS representing cognitive, fine motor and ambulatory disability.

New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes.

In clinically isolated syndromes, the new McDonald criteria for multiple sclerosis diagnosis require new gadolinium-enhancing lesions for dissemination in time at a 3-month follow-up magnetic resonance imaging scan. In a cohort of 56 patients, these criteria were specific (95%) but less sensitive (58%) for clinically definite multiple sclerosis at 3 years. If new T2 lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of multiple sclerosis in more patients.

Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis.

Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow-up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

Disability and lesion load in MS: a reassessment with MS functional composite score and 3D fast FLAIR.

The correlation between T2 lesion load (LL) detected on conventional MR sequences and disability assessed by the Expanded Disability Status Scale (EDSS) in multiple sclerosis (MS) is, at best, moderate. The present study was performed to determine whether the correlation between disability and LL is improved by (i) use of the more sensitive three-dimensional fast fluid-attenuated inversion recovery (3D-fast FLAIR) sequence; (ii) application of the newly devised MS functional composite (MSFC) score. Forty-one patients with clinically definite or probable MS were studied. All had been followed prospectively for 14 years since their first symptom. EDSS and MSFC score were assessed. Imaging was performed with 3D-fFLAIR, fast spin-echo (FSE), and T1 weighted SE sequences. 3D-fFLAIR detected a 34% higher LL than FSE, but did not improve the correlation between T2 LL and EDSS (r = 0.51 and r = 0.53); the correlation was stronger with T1 LL (r = 0.57). The MSFC score did not significantly correlate with T2 LL or T1 LL. The robust correlation in this cohort between T2 LL and EDSS may reflect the homogeneous disease duration and the wide spread of disability. This correlation was not improved by the increased detection of T2 lesions with the 3D-fFLAIR sequence. The stronger correlation between T1 LL with EDSS is consistent with the finding that this subgroup of lesions represent areas of more severe tissue damage. The MSFC score did not improve the clinico-radiological paradox that is found in MS, despite including information on cognitive function.

A longitudinal study of abnormalities on MRI and disability from multiple sclerosis.

BACKGROUND: In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability. METHODS: Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke's Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability). RESULTS: Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61). CONCLUSIONS: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment.