Multiple Sclerosis and Other CNS Inflammatory Diseases
Article 1: Multiple Sclerosis Risk Factors and Pathogenesis
Bardia Nourbakhsh, MD, MAS; Ellen M. Mowry, MD, MCR, FAAN, FANA. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):596–610.
PURPOSE OF REVIEW
This article summarizes recent advances in the identification of genetic and environmental factors that affect the risk of developing multiple sclerosis (MS) and the pathogenic processes involved in acute relapses and relapse-independent disability progression.
The number of single-nucleotide polymorphisms associated with increased risk of MS has increased to more than 200 variants. The evidence for the association of Epstein-Barr virus infection, vitamin D deficiency, obesity, and smoking with increased risk of MS has further accumulated, and, in cases of obesity and vitamin D deficiency, the evidence for causal association has strengthened. Interactions between genetic and environmental factors have been studied more extensively. Dietary factors and changes in the gut microbiota are emerging as possible modulators of the disease risk. Several processes important to MS pathogenesis have been newly investigated or investigated more comprehensively, including the role of B cells, innate immune cells, meningeal inflammation, cortical and graymatter demyelination, and early axonal and neuronal loss.
MS is a complex disease in which the interaction between genetic and environmental factors causes a cascade of events, including activation of the adaptive and innate immune system, blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal damage with variable degrees of repair. These events manifest as potentially reversible focal neurologic symptoms or progressive nonremitting physical and cognitive disability, or both. Advances in the understanding of the risk factors and pathogenic mechanisms of MS have resulted in improved therapeutic strategies. The results of ongoing or future studies are needed to successfully and fully translate these advances into clinical practice.
- Unlike several other common neurologic diseases (such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis), no mendelian form of multiple sclerosis has thus far been reported.
- No single autoantigen, autoantibody, or infectious agent has thus far been unequivocally associated with multiple sclerosis.
- Autoreactive lymphocytes that gain access to the central nervous system start a pathogenic cascade that culminates in demyelination, neuroaxonal degeneration, synaptic loss, dying-back oligodendrogliopathy, and, eventually, tissue loss and astrogliosis.
- Demyelination in multiple sclerosis is not confined to the white matter, and cortical and deep gray matter demyelination can be detected pathologically and is present even in early stages of the disease.
- Both T lymphocytes and B lymphocytes, as well as innate immune mechanisms, participate in multiple sclerosis pathogenesis.
- Although demyelination in the central nervous system is the hallmark of multiple sclerosis, axonal injury is present from the earliest stages of the disease and is a major contributor to physical and cognitive disability.
- More than 200 genetic variants have been discovered to be associated with modifying the risk of multiple sclerosis.
- Low sunlight exposure, vitamin D deficiency, obesity, and smoking are factors with strong evidence for association with multiple sclerosis risk.
- Many infectious agents have been reported to be associated with multiple sclerosis risk; however, only Epstein-Barr virus infection has been consistently shown to be a risk factor.
- Exposure to several risk factors for developing multiple sclerosis (including Epstein-Barr virus infection and obesity) during adolescence appears to be more detrimental than exposure in adulthood.
- Statistical interactions between risk factors and mendelian randomization studies have provided evidence for the causal association of several environmental factors and the risk of multiple sclerosis.
- Lung irritation from inhalation of cigarette smoke is likely the mediator of association between smoking and multiple sclerosis risk.
Article 2: Diagnosis, Differential Diagnosis, and Misdiagnosis of Multiple Sclerosis
Andrew J. Solomon, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):611–635.
PURPOSE OF REVIEW
The diagnosis ofmultiple sclerosis (MS) is often challenging. This article discusses approaches to the clinical assessment for MS that may improve diagnostic accuracy.
Contemporary diagnostic criteria for MS continue to evolve, while knowledge about diseases that form the differential diagnosis of MS continues to expand. Recent data concerning causes of MS misdiagnosis (the incorrect assignment of a diagnosis of MS) have further informed approaches to syndromes that may mimic MS and the accurate diagnosis of MS.
This article provides a practical update onMS diagnosis through a discussion of recently revised MS diagnostic criteria, a renewed consideration of MS differential diagnosis, and contemporary data concerning MS misdiagnosis.
- Diagnosis of relapsing-remitting multiple sclerosis begins with confirmation of objective evidence of a syndrome typical for multiple sclerosis.
- Knowledge of the recent revisions to the 2017 McDonald criteria is essential for the proper use of paraclinical (ie, visual evoked potentials, CSF examination) and radiographic data to substitute for a second clinical attack for the demonstration of dissemination in space and dissemination in time for the diagnosis of multiple sclerosis.
- Objective evidence of a demyelinating syndrome typical for multiple sclerosis demonstrating both dissemination in space and dissemination in time must be accompanied by a search for “no better explanation” to confirm a diagnosis of multiple sclerosis.
- A syndrome typical for multiple sclerosis may also exhibit characteristics atypical for multiple sclerosis, suggesting a specific alternative diagnosis.
- The demographic profile of patients presentingwith syndromes typical formultiple sclerosismay provide an important red flag prompting evaluation for alternative diagnoses.
- Noninflammatory conditions may also be mistaken for a typical presentation of multiple sclerosis. Knowledge of broad red flags suggesting a structural, functional, metabolic, infectious, neoplastic, or other disease may lead to a specific alternative diagnosis.
- The McDonald criteria have not been evaluated in patients presenting with atypical syndromes or typical syndromes with red flags, and additional clinical, paraclinical, or radiographic evaluation and monitoring is necessary to confirm a diagnosis of multiple sclerosis.
- In patients presenting to establish carewith a preexisting diagnosis of multiple sclerosis, reassessment of the accuracy of multiple sclerosis diagnosis is prudent.
- The diagnosis of primary progressivemultiple sclerosis and itsmimics differs fromthat of relapsing-remitting multiple sclerosis and requires a thorough understanding of the assessment of clinical progression.
- Misdiagnosis of multiple sclerosis is often caused bymisapplication of theMcDonald criteria in patients with atypical syndromes, overreliance on or misunderstanding of MRI dissemination in space, or consideration of historical episodes of symptoms without objective evidence of a central nervous system lesion for demonstration of dissemination in time.
Article 3: Phases and Phenotypes of Multiple Sclerosis
Orhun H. Kantarci, MD. Continuum (Minneap Minn). June 2019; 25 (3Multiple Sclerosis and Other CNS Inflammatory Diseases):636–654.
PURPOSE OF REVIEW
This article describes the dynamic evolution ofmultiple sclerosis (MS) through its phases and the impact of this understanding on treatment decisions.
MS consists of three phases: (1) the high-risk phase, (2) the relapsing-remitting phase, and (3) the progressive phase. Increasingly, subclinical disease activity is becoming an integral part of our definition of disease course in MS. In many patients, the relapsing-remitting phase starts as subclinical activity, likely long before they present with a clinically isolated syndrome. Differentiating progressive MS subgroups is also becoming less relevant. This is illustrated by comparing progressive MS that evolves from an asymptomatic state in individuals with radiologically isolated syndrome (primary progressive MS) and symptomatic individuals with relapsing-remitting MS (secondary progressive MS). In each case, the background disease activity and pathology can be indistinguishable. These phases evolve on a continuum and largely follow the aging process with little influence by the preceding clinical activity level. Recently, it also became evident that one or a few poorly recovered relapses at the beginning of clinical manifestations of MS predict much earlier progressive MS onset.
These findings suggest that interventions to prevent progressive MS, when they become available for clinical practice, may need to be considered as early as when the asymptomatic radiologically isolated syndrome is detected. This early treatment approach is being evaluated with ongoing trials with available disease-modifying therapies. In contrast, continuing the use of disease-modifying therapy beyond a certain age may have little benefit. However, being in the progressive phase of MS is not, in itself, an argument against disease-modifying therapy use in active disease in younger patients.
- Current disease course classification in multiple sclerosis consists of three phases: the multiple sclerosis high-risk phase, the relapsing-remitting phase, and the progressive phase.
- Progression is the insidious and irreversible worsening of neurologic function due to multiple sclerosis over years.
- Active disease in multiple sclerosis is defined as new symptomatic relapses or asymptomatic MRI activity (contrast-enhancing T1-hyperintense lesions, new T2-hyperintense lesions, or enlarging T2-hyperintense lesions).
- Worsening disability can be due to the stepwise accumulation of neurologic deficit from partially recovered relapses, the insidious accumulation of neurologic deficit from a progressive disease course, a combination of both, or other multiple sclerosis or non–multiple sclerosis-related factors.
- The relapsing-remitting multiple sclerosis diagnosis that most clinicians are familiar with requires the presence of multiple clinically distinct events affecting different parts of the central nervous system separated in time (arbitrarily defined as at least 1 month apart). This operational diagnostic rule, core to understanding the diagnosis of multiple sclerosis, is referred to as dissemination in time and space.
- When a patient presents with symptoms not typical of multiple sclerosis (MS) and an MRI is obtained that fulfills the diagnostic imaging criteria, a diagnosis of radiologically isolated syndrome is given. When these patients develop their first MS symptom, they fulfill the criteria for single-attack MS (30% in 5-year follow-up). This evolution is significantly faster in pediatric radiologically isolated syndrome (60% in 1-year follow-up).
- Onset of the progressive phase of multiple sclerosis seemingly is age dependent but agnostic for disease duration and preprogressive phase.
- Several clinically useful predictors of evolution to progressive multiple sclerosis (other than age) are having spinal cord lesions, being male, consuming tobacco, being obese, and having a low serum 25-hydroxyvitamin D3 level. Even in the absence of specific medications targeting progression alone in multiple sclerosis, some of these factors are modifiable and, together with an active lifestyle and physical therapy, can potentially help build nervous system reserve and resistance to injury.
- Disease-modifying therapies are efficacious early in multiple sclerosis, but the utility of continuing them in patients older than age 60 should be considered on an individual basis.
- Seemingly a pathologic hallmark of progressive multiple sclerosis, smoldering plaques peak in frequency at around the fifth decade, a timewhen the dominant plaque type also switches fromactive to inactive plaques, mirroring the independent epidemiologic observation of established mean age of progressive multiple sclerosis onset of 45 years.
Article 4: Management of Multiple Sclerosis Relapses
Pavle Repovic, MD, PhD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):655–669.
PURPOSE OF REVIEW
This article provides an overview of the clinical and pathologic features of multiple sclerosis (MS) relapses and reviews evidence-based approaches to their treatment.
Despite the increasing number and potency of MS treatments, relapses remain one of the more unpredictable and disconcerting disease aspects for many patients with MS, making their accurate recognition and treatment an essential component of good clinical care. The expanding range of relapse treatments now includes oral corticosteroids, comparable in efficacy to IV methylprednisolone at a fraction of the cost.While this development improves access to prompt treatment, it also underscores the importance of recognizing mimics of MS relapses to reduce corticosteroid overuse and its attendant risks.
Like MS itself, MS relapse remains primarily a clinical diagnosis. The treatment options for MS relapse include corticosteroids, adrenocorticotropic hormone (ACTH), plasma exchange, and rehabilitation, used singly or sequentially, with the goal of limiting the duration and impact of associated disability. Even when treated promptly and effectively, clinical or subclinical sequelae of MS relapses frequently remain.
- Typical manifestations of multiple sclerosis relapses include optic neuritis, spinal cord syndromes, and brainstem syndromes.
- The shared pathologic substrate of multiple sclerosis relapses is impaired axonal conduction resulting from the combined effects of demyelination, inflammation, and variable degree of neuronal loss.
- Viral and bacterial infections increase the risk of multiple sclerosis relapse.
- Resolution of the inflammatory phase of a multiple sclerosis relapse is followed by a reparative phase.
- Even when symptoms are unequivocally multiple sclerosis–related, a distinction needs to be made between a bona fide multiple sclerosis relapse and a pseudorelapse.
- Fluctuation of symptoms in patients with multiple sclerosis is attributed to variable efficiency of repair following a relapse.
- Uhthoff phenomenon refers to reoccurrence of a neurologic deficit from an earlier relapse in the setting of increased core body temperature, classically observed with exercise.
- Several clinical trials and two meta-analyses provide evidence that high-dose corticosteroids hasten neurologic recovery after multiple sclerosis relapse.
- Oral steroids are less expensive, somewhat more convenient, and no less effective than IV steroids for the treatment of multiple sclerosis relapses.
- Given the considerable frequency of steroid side effects, a proactive approach to minimize their impact on patients is recommended.
- Compared to corticosteroids, adrenocorticotropic hormone use in multiple sclerosis relapses is not well defined.
- Second-line treatment options for multiple sclerosis relapse include repetition of corticosteroid treatment (sometimes using a different dose, route, or type of steroid), adrenocorticotropic hormone, and plasma exchange.
- In one study, plasma exchange led to significant improvement in 42% of patients who remained severely impaired after relapses treated with high-dose corticosteroids, compared to only 5% with sham treatment.
- The decision whether to treat or monitor a multiple sclerosis relapse should be made jointly between a patient and a clinician, considering the impact of both the relapse and the proposed treatment on a patient.
Article 5: Clinically Isolated Syndrome and Early Relapsing Multiple Sclerosis
Luanne M. Metz, MD, FRCPC. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):670–688.
PURPOSE OF REVIEW
This article reviews management of clinically isolated syndrome and early relapsing-remitting multiple sclerosis (MS). It provides a general approach to patient management and determination of prognosis, reviews first-line disease-modifying therapies, and provides an approach to treatment selection.
Revision of the MS diagnostic criteria allows an earlier MS diagnosis, which reduces diagnostic uncertainty and often allows additional treatment options. Identification of factors that influence disease activity and progression highlights the importance of counseling patients about behavior modifications that, along with disease-modifying therapy, may improve long-term outcomes. Recommended lifestyle modifications include smoking cessation, vitamin D supplementation, a healthy diet, maintaining a healthy weight, remaining active, and management of cardiovascular risk factors. Identifying individuals at high risk for future disability allows them to make informed decisions about the use of highly effective, higher-risk disease-modifying therapies.
Patients with clinically isolated syndrome, even those with only dissemination in space but not dissemination in time, and patients with relapsing-remitting MS and disease activity within the prior 2 years, are at high risk of disease activity within the next 2 years. Lifestyle modification suggestions and disease-modifying therapy should be considered. Treatment decisions should be made in collaboration with patients using the shared decision-making approach.
- A serious diagnosis such as multiple sclerosis may motivate people toward a healthy lifestyle. Diagnosis provides the opportunity to inform patients of health behaviors that are associated with worse multiple sclerosis outcomes.
- Education and supported self-management are the mainstays of chronic disease management.
- Patients at low risk of disease activity over the short term are less likely to benefit from disease-modifying therapy but may still benefit from disease monitoring because risk assessment is not precise.
- In clinically isolated syndrome, the chance of new clinical or MRI activity is 60% to 70% within 6 months and 80% to 90% within 2 years.
- Factors associated with greater risk of long-term disability may identify those most likely to benefit from initiation of highly effective therapy or additional vigilance in monitoring disease-modifying therapy effectiveness.
- The main advantage of the injectable therapies interferon beta and glatiramer acetate is their long-term safety profile. The main disadvantages are modest efficacy and limited tolerance and convenience because they are injectable.
- The first-line oral therapies dimethyl fumarate and teriflunomide are convenient, but they are relatively new and cause immune suppression long term. Safety, including a long-term risk of malignancy, is a concern. Teriflunomide must be used with caution in women of childbearing age because of the risk of fetal malformation.
- A shared decision-making process should be used to select a preferred disease-modifying therapy option.
- Delays in disease-modifying therapy should be avoided. The risk of reaching an Expanded Disability Status Scale score of 4.0 is increased by 7.4% for every year of delay in treatment initiation after multiple sclerosis onset.
Article 6: Highly Aggressive Multiple Sclerosis
James D. Bowen, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):689–714.
PURPOSE OF REVIEW
Newly introduced disease-modifying therapies offer greater efficacy than previous therapies but also have serious side effects. This article reviews factors useful in identifying those at risk of developing aggressive relapsing multiple sclerosis (MS) and therapies available for treatment.
Several factors predict aggressive MS, including demographic factors, relapses, symptom characteristics, MRI activity, and other biomarkers. These can be used to select patients for more aggressive therapies, including natalizumab, alemtuzumab, fingolimod, and ocrelizumab. Additional off-label treatments are available for patients with severe disease. The benefits and side effects of these treatments must be considered when making therapeutic decisions.
Selecting patients who are most appropriate for aggressive therapy involves considering risk factors for poor outcomes, early recognition of treatment failure, balancing treatment efficacy and side effects, and sharing the decision with patients to assist them in making optimal treatment choices. Vigilance for signs of treatment failure and early switching to more aggressive therapy are important components in optimal care.
- Demographic factors that suggest a more aggressive multiple sclerosis course include male sex, onset after 40 years of age, nonwhite race, and smoking.
- Clinical characteristics that predict the risk of aggressive multiple sclerosis include frequent relapses; shorter interattack intervals; incomplete recovery from attacks; pyramidal, cerebellar, sphincter, or cognitive symptoms; and multifocal onset.
- Rapidly worsening disability andmultiple sclerosis that is progressive fromonset predict an aggressive course.
- MRI characteristics that predict more aggressive course include the number and volume of T2 lesions; the presence of gadolinium-enhancing lesions; the volume of T1-hypointense lesions; and the presence of atrophy, infratentorial lesions, or spinal cord lesions.
- Oligoclonal bands are associated with several markers for aggressive multiple sclerosis.
- The most serious side effect of natalizumab is progressive multifocal leukoencephalopathy. The risk of progressive multifocal leukoencephalopathy is estimated by the duration of natalizumab therapy, prior immunosuppressive use, and JC virus antibody index.
- Rebound can occur between 3 and 6 months after stopping natalizumab. Other disease-modifying therapies should be started before this time to minimize rebound risk.
- The side effects of alemtuzumab include immediate infusion reactions, autoimmune diseases, infections, and malignancies.
- The side effects of fingolimod include first-dose bradycardia. Fingolimod and siponimod may cause macular edema and opportunistic infections, including Cryptococcus and progressive multifocal leukoencephalopathy. Risk for infection cannot be assessed using absolute lymphocyte counts.
- The side effects of ocrelizumab include infusion reactions, infections (especially herpes infections), and possible malignancy; progressive multifocal leukoencephalopathy and reactivation of hepatitis B are theoretical risks, but thus far no cases have been seen.
- Cladribine is an oral immunosuppressant that was recently approved by the US Food and Drug Administration. Side effects include infections and malignancies.
- Mitoxantrone’s use has been limited by cardiotoxicity and acute myelogenous leukemia.
- Cyclophosphamide is widely available and has some evidence to support its use, but definitive trials have not been performed.
- Rituximab’s mechanism of action and side effects are similar to those of ocrelizumab. Rituximab is not US Food and Drug Administration approved for multiple sclerosis, but many have used it off-label because it is less expensive than ocrelizumab.
- High-dose immunosuppressive therapy with stem cell transplantation is the most aggressive therapy available for multiple sclerosis today. Outcomes are possibly double the rate of “no evidence of disease activity” of other therapies. Thus far, only phase 2 studies have been completed.
Article 7: Monitoring, Switching, and Stopping Multiple Sclerosis Disease-Modifying Therapies
Robert H. Gross, MD; John R. Corboy, MD, FAAN. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):715–735.
PURPOSE OF REVIEW
This article reviews appropriate monitoring of the various multiple sclerosis (MS) disease-modifying therapies, summarizes the reasons patients switch or stop treatment, and provides a framework for making these management decisions.
With the increasing number of highly effective immunotherapies available forMS, the possibility of better control of the disease has increased, but with it, the potential for side effects has rendered treatment decisions more complicated. Starting treatment early with more effective and better-tolerated disease-modifying therapies reduces the likelihood of switching because of breakthrough disease or lack of compliance. Clinical and radiographic surveillance, and often blood and other paraclinical tests, should be performed periodically, depending on the disease-modifying therapy. Helping patients navigate the uncertainty around switching or stopping treatment, either temporarily or permanently, is one of the most important things we do as providers of MS care.
Ongoing monitoring of drug therapy is a crucial component of long-term MS care. Switching treatments may be necessary for a variety of reasons. Permanent discontinuation of treatment may be appropriate for some patients with MS, although more study is needed in this area.
- Studies of factors related to multiple sclerosis disease-modifying therapies highlight that adherence is extremely variable and that switching or discontinuing disease-modifying therapies is very common in both the long and short term.
- Discontinuation of disease-modifying therapy may be temporary because of insurance interruption; a desire to become pregnant, becoming pregnant, or lactating; lack of adherence (for many reasons); or deliberate installation of a washout period between medications when switching disease-modifying therapies to limit overlapping risks with two medications used in sequence.
- Requiring patients to use less effective and less tolerable disease-modifying therapies first simply subjects patients to greater disability and discomfort over time.
- Ultimately, best practice likely reinforces that individual aspects should dictate the optimal approach for any one patient.
- Decisions made at the beginning of the disease course have potential long-term implications for use of other disease-modifying therapies.
- One source of ambiguity when considering switching disease-modifying therapy is that no standard definition of treatment “failure” exists, nor is there a universally accepted standard as to the appropriate time to switch disease-modifying therapies in multiple sclerosis.
- With the recognition of “no evidence of disease activity” as a treatment goal and ever-higher rates of no evidence of disease activity emerging from clinical trials of multiple sclerosis disease-modifying therapies, disease activity that previously would have been tolerated is now frequently no longer deemed acceptable.
- Practices vary regarding the use and length of washout periods, and evidence from randomized controlled trials to guide management is limited.
- An overly lengthy washout risks disease reactivation, especiallywith disease-modifying therapies that impair lymphocyte migration or trafficking and the cessation of which can be associated with rebound activity (fingolimod, natalizumab).
- In the natural history of multiple sclerosis, the risk of what are considered new episodes of inflammation, relapses, and gadolinium-enhancing lesions on MRI scans is highest after clinical onset and generally diminishes significantly with age, so that by age 50 the annual risk of any of the three is below 10%.
- As all presently available disease-modifying therapies alter, modulate, or suppress the immune system, with minimal documented effects on potential repair or regeneration of the nervous system, the benefits have been shown to be greatest in those with active inflammatory disease (ie, younger patients).
- Stopping disease-modifying therapies may have potential benefits, including fewer side effects, long-term risks, costs, and reminders that the patient has MS.
- Young age, a recent MS diagnosis, and recent disease activity (relapses or MRI changes) are characteristic of those most likely to benefit from MS immunotherapy.
Article 8: Progressive Multiple Sclerosis
Daniel Ontaneda, MD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):736–752.
PURPOSE OF REVIEW
This article provides an update on progressive forms of multiple sclerosis (MS), with a focus on pathogenic mechanisms, clinical features, imaging features, and recent therapeutic advances.
Progressive forms of MS are identified by a history of progressive accrual of disability independent of relapse, but they share many biological, clinical, and MRI features with relapsing MS. Both relapses and new lesions can occur in the context of progressive MS, and establishing when the transition from relapsing to progressive MS occurs is often difficult. Several pathogenic mechanisms coexist in progressive MS. Targeting inflammation in both primary and secondary progressive MS appears to reduce the accumulation of disability.
Progressive MS remains a diagnostic challenge, and the pathogenesis underlying progression is complex. Significant overlap in the biology and clinical and imaging features of progressive MS exists with relapsing forms of the disease. The use of disease-modifying and symptomatic treatments may improve the quality of life for patients with progressive MS.
- Progressive multiple sclerosis was previously considered an untreatable from of the disease, but current and future disease-modifying agents will change our approach to this form of the disease.
- Several mechanisms are present in both relapsing and progressive multiple sclerosis, and differences between relapsing and progressive multiple sclerosis are more relative than absolute.
- Inflammation plays a significant role in the pathogenesis of progressive multiple sclerosis.
- Because of the insidious onset of symptoms, the diagnosis of progressive multiple sclerosis is typically delayed, both as the initial presentation in primary progressive multiple sclerosis and when reclassifying a patient with relapsing-remitting multiple sclerosis as having secondary progressive multiple sclerosis.
- The 2017 McDonald diagnostic criteria for multiple sclerosis include specific criteria for primary progressive multiple sclerosis, including 1 year of disability progression (retrospectively or prospectively determined) independent of relapses plus at least two of the following: one ormore T2 lesions in characteristic regions on brain MRI, two or more spinal cord MRI lesions, or the presence of CSF oligoclonal bands.
- Progressive and relapsing multiple sclerosis should be considered to occur on a spectrum rather than as different diseases, and the understanding that these two forms share several common features in biology, clinical evolution, and imaging findings is growing.
- Measurement of progressive accrual of disability is inherently difficult and remains a significant obstacle in progressive multiple sclerosis.
- Brain lesions in progressive multiple sclerosis are indistinguishable from those seen in relapsing multiple sclerosis; however, on average, patients with primary progressive multiple sclerosis tend to have fewer brain T2 lesions and fewer lesions with gadolinium enhancement.
- Conventional and advanced spinal cord MRI measures hold promise as potential biomarkers for progressive multiple sclerosis.
- Siponimod was studied in a phase 3 trial in secondary progressive multiple sclerosis and is now approved by the US Food and Drug Administration for the treatment of active secondary progressive multiple sclerosis.
- Ocrelizumab is now an approved medication for primary progressive multiple sclerosis and will be helpful in treating the inflammatory components in patients with the disease, especially in younger patients with inflammatory disease on MRI.
Article 9: Management of Multiple Sclerosis Symptoms and Comorbidities
W. Oliver Tobin, MBBCh, BAO, PhD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):753–772.
PURPOSE OF REVIEW
This article discusses the prevalence, identification, and management of multiple sclerosis (MS)–related symptoms and associated comorbidities, including complications that can present at all stages of the disease course.
The impact of comorbidities on the outcome of MS is increasingly recognized. This presents an opportunity to impact the course and outcome of MS by identifying and treating associated comorbidities that may be more amenable to treatment than the underlying inflammatory and neurodegenerative disease. The identification of MS-related symptoms and comorbidities is facilitated by brief screening tools, ideally completed by the patient and automatically entered into the patient record, with therapeutic suggestions for the provider. The development of free, open-source screening tools that can be integrated with electronic health records provides
opportunities to identify and treat MS-related symptoms and comorbidities at an early stage.
Identification and management of MS-related symptoms and comorbidities can lead to improved outcomes, improved quality of life, and reduced disease activity. The use of brief patient-reported screening tools at or before the point of care can facilitate identification of symptoms and comorbidities that may be amenable to intervention.
- Fatigue is the most common symptom in patients with multiple sclerosis, present in almost half of patients with clinically isolated syndrome and over 80% of patients over the course of the disease.
- Restless legs syndrome has been reported in 13% to 65% of patientswithmultiple sclerosis and appears to be related to spinal cord disease.
- Limited evidence exists for commonly used but unapproved medications, such as amantadine, modafinil, armodafinil, methylphenidate, and amphetamine compounds for management of fatigue in multiple sclerosis.
- It is recommended that all patients with multiple sclerosis be screened for depression at annual visits.
- Screening for depression and anxiety can be completely automated, with the patient responding electronically to brief screening questionnaires and the responses automatically recorded in the patient’s electronic health record.
- Patients may develop cognitive dysfunction in the absence of a significant burden of white matter disease and in the absence of accumulating T2-hyperintense brain lesions.
- Interpretation of a cognitive assessment at a single point in time may not provide an adequate assessment of an individual’s overall performance.
- Paroxysmal symptoms in multiple sclerosis are typically sensory with variable motor involvement. They usually last between 1 and 90 seconds and are exquisitely sensitive to sodium channel blockade.
- Commonly used aural thermometers are often inaccurate in the setting of hypothermia, and identification of hypothermia requires the use of a low-reading rectal thermometer.
- Initial treatment of spasticity should primarily focus on stretching exercises. Stretches should be held for 30 to 60 seconds, and patients should be counseled to stretch twice daily.
- For patients who are nonambulatory with severe spasticity that is not responsive to or intolerant of other treatment strategies, intrathecal baclofen is a useful strategy, particularly for facilitating toileting and cleaning.
- In contrast to other neurologic disorders affecting the spinal cord, such as spina bifida, upper urinary tract disorders in multiple sclerosis are rare, possibly because of the slowly progressive nature of the disease.
- In patients with multiple sclerosis presenting with urinary symptoms, a urinalysis and postvoid residual ultrasound of the bladder should be performed.
- Indwelling catheters are associated with a greater risk of urinary tract infections, genital erosions, and bladder stone formation than intermittent catheterization.
- Percutaneous and transcutaneous tibial nerve stimulation have been shown to have short-term benefits on urinary symptoms for patients with overactive bladder secondary to multiple sclerosis and may also have a positive effect on fecal incontinence.
- Sexual dysfunction affects up to 90% of patients with multiple sclerosis during the course of the disease.
Article 10: Pregnancy and Family Planning in Multiple Sclerosis
Annette M. Langer-Gould, MD, PhD. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):773–792.
PURPOSE OF REVIEW
This article provides practical guidance on successful management of women with multiple sclerosis (MS) through pregnancy and the postpartum period.
Recent studies indicate that most women diagnosed with MS today can have children, breast-feed, and resume beta interferons or glatiramer acetate per their preferences without incurring an increased risk of relapses during the postpartum period. More than 40% of women with mild MS do not require any treatment before conception or in the postpartum period. Women with highly active MS can now become well-controlled before, throughout, and after pregnancy via highly effective treatments. Unfortunately, pregnancy does not protect against relapses following the cessation of fingolimod or natalizumab, and some women experience severe rebound relapses during pregnancy. Accidental first-trimester exposure to teriflunomide or fingolimod increases the risk of fetal harm.
Most women with MS can have normal pregnancies and breast-feed without incurring harm. Clinicians should avoid prescribing medications with known teratogenic potential (teriflunomide, fingolimod), known risk of severe rebound relapses (fingolimod, natalizumab), or unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of childbearing age who desire pregnancy or are not on reliable birth control. If a treatment needs to be resumed during breast-feeding, clinicians should opt for glatiramer acetate, interferon beta, natalizumab, or rituximab/ocrelizumab, as biologically plausible risks to the infant are exceedingly low.
- Multiple sclerosis does not increase the risk of infertility, adverse pregnancy outcomes, or adverse neonatal outcomes, but some multiple sclerosis treatments may increase these risks.
- Potential risks not captured by US Food and Drug Administration pregnancy categories include neonatal immunosuppression, impaired early-life neurocognitive development, delayed toxicities in the child (eg, cancer), and risks incurred from severe rebound relapses in pregnancy.
- It is important to assess whether the patient’s disease activity is adequately controlled before counseling about pregnancy. First decide whether patients with multiple sclerosis need to be on highly effective or modestly effective disease-modifying therapy to control their disease activity, then consider the possibility of pregnancy when choosing a disease-modifying therapy.
- It is important to ask patients with multiple sclerosis about pregnancy plans and contraception regularly.
- Many patients with multiple sclerosis have adequately controlled disease without any treatment or only modestly effective disease-modifying therapies. If these patients start trying to conceive, discontinuing treatment, if any, is prudent.
- Glatiramer acetate and interferon beta are the preferred modestly effective disease-modifying therapies for women who are not on reliable birth control.
- Consider a B-cell–depleting drug if a highly effective disease-modifying therapy is needed for a woman who is trying to get pregnant or not on reliable birth control. Assess for pregnancy before each infusion and do not infuse the medication if the patient is currently pregnant.
- Pregnancy does not protect against the risk of return of disease activity or rebound relapses after cessation of fingolimod or natalizumab.
- To prevent return of disease activity or rebound relapses during pregnancy after cessation of fingolimod or natalizumab, consider switching women to a B-cell–depleting therapy before conception.
- Fingolimod and natalizumab rebound relapses are treatable, even if they occur during pregnancy.
- Encourage and support breast-feeding for optimal infant and maternal health.
- Glatiramer acetate and interferon beta pose exceedingly low risk to infants via breast milk exposure and can be resumed when desired.
- Natalizumab and rituximab have very low theoretical risks to infants with breast milk exposure only and may be resumed during lactation if necessary.
Article 11: Pediatric Central Nervous System Demyelinating Diseases
Tanuja Chitnis, MD, FAAN. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):793–814.
PURPOSE OF REVIEW
This article provides an up-to-date summary of the categories, diagnosis, and management of pediatric demyelinating disorders.
Understanding of the diverse spectrum of pediatric demyelinating disorders, including monophasic and multiphasic forms, has improved. Pediatric multiple sclerosis (MS) is the most common demyelinating disorder in children, and recent genetic and environmental risk research has clarified that pediatric MS is on the same continuum of disease as adult MS. Recent advances in the treatment of pediatric MS include clinical trials leading to regulatory agency–approved treatments. The identification of myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies in children has been amajor advance, allowing for appropriate treatment and management of these syndromes.
Antibody testing is now helping to define subtypes of pediatric demyelinating disorders, including myelin oligodendrocyte glycoprotein–seropositive and aquaporin-4–seropositive cases that are distinct from pediatric MS. Treatments for pediatric MS are being evaluated in clinical trials.
- Major advances in pediatric demyelinating disease in the past 5 years include improved diagnostic criteria, antibody-based biomarkers, predictors of a multiphasic course, and treatment advances for these disorders. Recent work on the genetic and environmental risk factors for pediatric multiple sclerosis points to similarities with adult disease.
- An important advance in pediatric demyelinating disorders is the recognition that an acute demyelinating syndrome can represent the first attack of not onlymultiple sclerosis but also neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein (MOG) antibody–associated demyelinating disease, and other multiphasic disorders in children.
- Several studies have identified risk factors for multiple sclerosis in children, including CSF profiles with pleocytosis, Epstein-Barr virus–positive serostatus, obesity, low vitamin D levels, and the presence of T2 lesions on brain MRI. Age older than 11 and postpubertal status at the time of a clinically isolated syndrome also increase the risk for multiple sclerosis.
- Puberty is an important transition period for the clinical onset of pediatric multiple sclerosis, with 80% to 85% of children being peripubertal or postpubertal at the time of first symptoms in a large US cohort.
- In general, children with multiple sclerosis experience 2 to 3 times as many relapses as adult patients with multiple sclerosis, reflecting a continuum in the inverse relationship of age and relapse rate.
- Types of relapses or attacks in pediatric multiple sclerosis include optic neuritis, transverse myelitis, brainstem attacks, and cerebral attacks.
- Between one-third and two-thirds of pediatric patients withmultiple sclerosismay have significant cognitive deficits, including issues with information processing and processing speed, memory deficits, executive dysfunction, and lowered IQs, as well as deficits in social cognition.
- In 2018, fingolimod was approved by the US Food and Drug Administration for use as first-line treatment in childrenwith multiple sclerosis aged 10 to 17; it has received preliminary approval by the European Medicines Agency as second-line treatment based on the results of the PARADIGMS clinical trial.
- Adherence to disease-modifying therapy may be challenging, particularly in adolescents, in the setting of miseducation about the expectations for disease-modifying therapies, unaddressed side effects, busy family schedules, and travel/college.
- Up to 3% to 5% of cases of NMOSD have pediatric onset. The overall incidence of NMOSD in children and adults ranges from 0.05 to 4 per 100,000 per year, and prevalence ranges from 0.52 to 4.4 per 100,000. In Japan, the incidence of pediatric NMOSD was reported as 0.06 per 100,000 children.
- Approximately 65% of pediatric patients with NMOSD are aquaporin-4 antibody seropositive; however, seropositivity may not occur at the time of the initial attack but up to 4 years later. Therefore, serial testing is recommended for highly suspicious cases.
- Since cell-based assays became available, anti– MOG antibodies have been reported in the serum of 18% to 35% of children with an acute demyelinating syndrome.
- MOG antibody testing has now been optimized, offering increased sensitivity and specificity compared to other methods. The MOG antibody is most often detected in the serum and rarely in the CSF. The current consensus is that serum testing has the highest yield.
Article 12: Neuromyelitis Optica Spectrum Disorder and Other Non–Multiple Sclerosis Central Nervous System Inflammatory Diseases
Eoin P. Flanagan, MBBCh. Continuum (Minneap Minn). June 2019; 25 (3 Multiple Sclerosis and Other CNS Inflammatory Diseases):815–844.
PURPOSE OF REVIEW
This article reviews the clinical features, diagnostic approach, treatment, and prognosis of central nervous system inflammatory diseases that mimic multiple sclerosis (MS), including those defined by recently discovered autoantibody biomarkers.
The discovery of autoantibody biomarkers of inflammatory demyelinating diseases of the central nervous system (aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG) and the recognition that, despite some overlap, their clinical phenotypes are distinct from MS have revolutionized this field of neurology. These autoantibody biomarkers assist in diagnosis and have improved our understanding of the underlying disease pathogenesis. This has allowed targeted treatments to be translated into clinical trials, three of which are now under way in aquaporin-4 IgG–seropositive neuromyelitis optica (NMO) spectrum disorder.
Knowledge of the clinical attributes, MRI findings, CSF parameters, and accompanying autoantibody biomarkers can help neurologists distinguish MS from its inflammatory mimics. These antibody biomarkers provide critical diagnostic and prognostic information and guide treatment decisions. Better recognition of the clinical, radiologic, and laboratory features of other inflammatory MS mimics that lack autoantibody biomarkers has allowed us to diagnose these disorders faster and initiate disease-specific treatments more expeditiously.
- Distinguishing multiple sclerosis from its central nervous system inflammatory disease mimics has important therapeutic and prognostic implications.
- In 2004, the discovery of aquaporin-4 (AQP4)–IgG as a specific biomarker of neuromyelitis optica (NMO) allowed its distinction from multiple sclerosis.
- The discovery of AQP4-IgG as a biomarker of NMO led to a recognition that patients can have more limited forms of the disease (eg, recurrent transverse myelitis without optic neuritis) or symptoms beyond the optic nerve and spinal cord (eg, area postrema syndrome), resulting in the current nosology of NMO spectrum disorders (NMOSDs).
- It is important to recognize that in regions where multiple sclerosis prevalence is lower (eg, Asia and regions closer to the equator), NMOSD represents a larger proportion of central nervous system demyelinating diseases and thus should be particularly considered in the differential in those regions.
- NMOSD has three cardinal manifestations: transverse myelitis, optic neuritis, and area postrema syndrome.
- Systemic autoimmune disorders or their autoantibody biomarkers frequently coexist with NMOSD, including systemic lupus erythematosus, Sjögren syndrome, and antiphospholipid antibody syndrome.
- In NMOSD, optic nerve involvement is often bilateral and typically involves the posterior optic pathway, including the optic chiasm, with enhancement usually extending more than half the length of the nerve.
- Typical brain involvement in NMOSD occurs around circumventricular organs where AQP4 expression is highest, with lesions adjacent to the third and fourth ventricles (dorsalmedulla/area postrema)most typical.
- Longitudinally extensive transverse myelitis, with a T2-hyperintense lesion spanning three or more contiguous vertebral segments on MRI, is characteristic of NMOSD and found in approximately 85% in patients.
- Assay techniques for AQP4-IgG have improved over time, and cell-based assays are now recommended (using fluorescence-activated cell sorting or direct immunofluorescence); they yield a sensitivity of 75% to 80% and specificity of greater than 99%.
- Approximately 20% to 25% of patients with NMOSD are AQP4-IgG seronegative.
- AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes, initiating a cascade of immune-mediated inflammation resulting in secondary demyelination.
- The use of plasma exchange for five to seven exchanges for severe, corticosteroid-refractory central nervous system inflammatory demyelinating attacks is supported by data from a prospective randomized sham-controlled crossover trial.
- Despite the lack of completed randomized controlled trials in NMOSD, preventive treatment is strongly recommended in all patients.
- With the use of cell-based assays transfected with myelin oligodendrocyte glycoprotein (MOG) in its conformational form, the antibody has been shown to be a specific biomarker of a spectrum of central nervous system inflammatory demyelinating disease distinct from multiple sclerosis and AQP4-IgG–seropositive NMOSD.
- The major clinical manifestations of MOG-IgG disease include optic neuritis, acute disseminated encephalomyelitis, NMOSD (seronegative for AQP4-IgG), transverse myelitis, and brainstem demyelinating episodes.
- Some patients with MOG-IgG disease have a monophasic course, while others go on to develop relapsing disease.
- Radiologic findings in MOG-IgG disease include enhancement that involves more than half of the length of the optic nerve in 80% of patients and may involve the optic nerve sheath or extend into the orbital fat.
- Multifocal whitematter T2 hyperintensities with involvement of the deep graymatter are typical in MOG-IgG disease, particularly with acute disseminated encephalomyelitis–like presentations.
- Positive oligoclonal bands are found in less than 15% of patients with MOG-IgG.
- A 2018 consensus article outlined patients in whom MOG-IgG should be tested and recommended against testing MOG-IgG in all patients with multiple sclerosis, given the risk of false positives when testing in low-probability situations. In general, testing for MOG-IgG should be reserved for those with one of the classic phenotypes that lacks characteristic features of multiple sclerosis.
- A major area of study in MOG-IgG disease is determining which patients may have amonophasic disorder and not require treatment.
- For patients with relapsing MOG-IgG disease, the treatment approach is almost identical to that of acute and maintenance therapy for NMOSD, although IV immunoglobulin appears to be useful in children acutely and as a maintenance treatment.
- In 2016, an antibody to glial fibrillary acidic protein (GFAP) was reported that, when detected in CSF, appeared to be specific for an inflammatory meningoencephalomyelitis, termed autoimmune GFAP astrocytopathy.
- In autoimmune GFAP astrocyopathy, brain MRI may reveal a characteristic radial perivascular enhancement perpendicular to the ventricles, although a similar pattern can be seen with intravascular lymphoma, neurosarcoidosis, and central nervous system vasculitis.
- Susac syndrome is an inflammatory endotheliopathy that is characterized by a triad of branched retinal artery occlusions, hearing loss, and dementia/encephalopathy.