Overview of Multiple Sclerosis

Alexander D. Rae-Grant and Robert J. Fox

KEY POINTS FOR CLINICIANS

• Multiple sclerosis (MS) is a continuously active disease with subclinical lesions occurring 5 to 10 times as often as clinical relapses.

• Gray matter demyelination occurs commonly and is an early component of MS pathology.

• New international criteria for diagnosis allow for an MS diagnosis at the time of the first clinical event in some patients.

• Monitoring of MS is becoming more important as we have more options for treatment for patients with different risks and monitoring protocols.

• Symptom management is critical in MS care.

In the past, students and trainees were taught that MS was a demyelinating white matter disease that spared the cortex and nerve axons, and had epochs of biological remission. Our concept of the disorder was one of episodes of activity (relapses) followed by disease quiescence. Relapses always resolved, so early treatment was not necessary. Even after the development of brain MRI, lesions correlated poorly with relapses so were frequently ignored. In terms of mechanism, we considered MS solely a disease of autoimmune T-cell activation. We did not think there were other diseases hiding under the umbrella of MS which might require substantially different treatment. Many thought that studying MS and ways of treating it was a waste of research time and effort.

Over the past 25 years, we have seen a revolution in our thinking about this disorder. This revolution has overturned the standard concepts of MS and has refocused our research and treatment approaches dramatically. Of any area in the neurosciences, the field of clinical neuroimmunology has seen the most dramatic change in terms of biological understanding, monitoring strategies, and therapeutic approaches. For those entering the field, this is a time of great promise but also challenge as we balance increasingly powerful medications and treatment against safety, tolerability, and ultimately cost. Despite these advances there is much work to be done, particularly to understand and address the causation and treatment of the progressive components of this disease.

NEW DIRECTIONS IN UNDERSTANDING MS

Prior to the application of MRI, the concept of MS was of a “punctuated equilibrium,” that is, episodes of clinical worsening (relapses) interspersed with clinical and biological remission. Treatment was directed at relapse management, assuming that in between relapses the disease was quiescent. On this background, studies using sequential MRI in MS showed new MRI lesion formation 5 to 10 times as often as new clinical events. Progressive subclinical changes were observed in longitudinal studies, as shown by progressive brain and spinal cord atrophy, change in volume of T2 and T1 brain lesions, and other measures of brain degeneration. Clinical recovery after a relapse was therefore not due to resolution of the lesion per se, but based on a variety of factors including ion-channel redistribution, nitric oxide level modification, change in inflammatory cell populations, neural plasticity, and remyelination. The impact of these observations on our understanding of MS and our approach to its treatment cannot be overemphasized. The observation that much of MS was subclinical moved the philosophy of “treating for relapses” to a preventive strategy for ongoing disease management. Instead of, “treat the patient, not the MRI scan,” we adopted “treat the disease, and use the MRI scan to understand the disease and its activity.” In addition, the common observation that patients often had progression years after disease stability now made more sense, as new lesion formation would gradually erode the brain and spinal cord’s ability to buffer injury.

12Many other observations helped further our understanding of MS. For example, microscopic analysis of brain tissues in MS autopsy cases showed huge numbers of transected axons in acute MS lesions, averaging an astonishing 11,000 per cubic millimeter. Myelin and myelin-producing cells were reduced, too. Outside of focal lesions, axons were reduced in normal appearing white matter, indicating extensive injury beyond the visible lesion boundaries.

Observations from both autopsy and (more recently) brain biopsies have shown conclusively that the gray matter is targeted at least as much as the white matter in MS. While this observation had in fact been made on pathological specimens in the past, recent observations from biopsies of early MS cases emphasized the cortical component of MS and the concept that some immune activity may arise from the cerebrospinal fluid (CSF)/pial boundary into the brain, rather than as a purely blood-borne process. Conventional MRI sequences do not provide sufficient contrast to appreciate cortical demyelination, and so researchers are testing novel techniques to improve the characterization of cortical disease. The presence of early cortical disease may partially explain early cognitive dysfunction and the presence of seizures in a subset of patients with MS.

We have also seen the development of additional concepts regarding MS pathogenesis, among them a dying back oligodendrogliopathy, a complement-mediated inflammatory response, and other pathological and immunological concepts. We have begun to appreciate the importance not only of T cells, but of other immune effector systems such as B cells, macrophages, microglia, and mast cells in the MS cascade of injuries. Whether these observations will be confirmed as truly separate disorders with different treatment paradigms is unclear, but they open the door to potentially subsegment the group of patients we lump together as MS into more precise prognosis and treatment subsets.

The development of robust testing measures to segregate neuromyelitis optica from other neuroimmunological disease is, perhaps, the first of many such changes that will refine the understanding, monitoring, and treatment approaches to our patient population. At the same time, these concepts are allowing us to recognize that the degeneration of progressive MS is likely ongoing during the early, relapsing stage of MS, active inflammation is occurring in some patients in the progressive stage of MS, and the primary and secondary progressive forms of MS may be more similar than different. We have come to recognize that the gradually progressive manifestation of MS likely has a very different pathophysiology from the relapsing manifestation of MS. The underpinnings of progressive MS remain uncertain, but may involve neurodegenerative pathophysiologies such as mitochondrial dysfunction.

NEW DIRECTIONS IN DIAGNOSING MS

Before the widespread availability and use of MRI, the diagnosis of MS was more difficult than it is today. Over the past 15 years, the criteria for the diagnosis of MS have been revised in an attempt to meet two countervailing needs: first, to effectively reduce the number of patients diagnosed with MS who do not have this condition (specificity), and second, to increase the number of patients identified as having MS who have this disorder (sensitivity). In the past, we required either a second clinical event affected a different location of the central nervous system (CNS) to occur after an initial demyelinating event or a new MRI lesion to form before the diagnosis of MS was made. In addition, complex MRI diagnostic criteria were not easily applied in daily practice. In the current iteration of the International Panel Criteria for MS (also known as the McDonald Criteria), patients with a single clinical event who have both enhancing and nonenhancing demyelinating lesions (implying “dissemination in time”) as well as lesions in two or more CNS regions (implying “dissemination in space”) can meet the criteria for MS. These new criteria have sped up the time to diagnosis, reduced the waiting time to demonstrate dissemination in time, and simplified the diagnostic rules. All of these were common sources of frustration and confusion for patients and clinicians alike. Without a single test for MS, clinicians continue to be challenged by patients who have conditions mimicking MS; MS remains a clinical diagnosis, requiring clinical judgment and ongoing surveillance regarding alternative and additional diagnoses.

Another collateral benefit of more robust MRI measures is that CSF testing, at the best of times a distasteful pursuit for patients, is deemphasized in relapsing patients. We are moving to a more noninvasive, but no less scientifically grounded, approach to the diagnosis and monitoring of MS in most patients. However, the role of CSF testing has become more prominent in primary progressive MS, where confusion with other neurodegenerative disorders remains common. In contrast, the roles of evoked potentials have decreased over time, and the current diagnostic criteria do not include any evoked potentials (including visual evoked potentials).

NEW DIRECTIONS IN MONITORING MS

With the advent of multiple long-term therapies for MS, patient management has shifted toward methods to adequately monitor both the disease course and the treatment response. MRI provides a useful tool to monitor for new disease activity as indicated by new lesion formation and enhancing lesions. Conventional MRI also provides a general sense of brain atrophy, the end result of MS injury. As we shift to monitoring and testing treatments for the neurodegenerative component of MS, we will require more robust imaging measures that characterize smaller changes in brain volumes, lesion burden, and other tissue characteristics of both lesional and nonlesional brain tissue.

To this end, MRI appears to have promising utility. Volumetric lesion and atrophy measures are being used in clinical trials and longitudinal studies, and show progressive brain atrophy. Measures such as magnetization transfer ratio (MTR) and MRI spectroscopy may characterize 13the longitudinal change in tissue injury within both focal lesions and other areas of the brain that appear normal using conventional imaging. Diffusion tensor imaging is sensitive to changes in certain white matter tracts and may differentially characterize demyelination and axonal degeneration. Each of these tools may be beneficial in measuring neuroprotective or neurorestorative strategies as we move into new areas of therapeutic development.

Ocular coherence tomography (OCT) is a powerful tool to monitor the result of optic neuritis. Newer generation OCT machines using spectral domain technology have shown a reduction in retinal nerve fiber layer after optic neuritis, as well as injury to other retinal structures. Phase 2 trials of neuroprotective agents are now using OCT as a marker to measure axonal protection. OCT may provide another way of monitoring inflammation, axonal injury, and later degeneration in a quick, convenient, noninvasive, and relatively inexpensive fashion.

In the clinic, we are now using more quantitative measures to assist with the longitudinal monitoring of our patients. The timed 25-foot walk, nine-hole peg test, 6-minute walk, and the timed up and go test, all provide measurable continuous measures of function which can be charted over time. Some clinics are using computer-based measurement tools to track disease activity and measure physical function, depression, and cognitive capacities.

NEW DIRECTIONS IN TREATMENT OF MS DISEASE ACTIVITY

Prior to 1993, there were no Food and Drug Administration (FDA)-approved medicines for MS. Clinicians caring for patients with MS were often discouraged from “wasting their time” doing clinical trials in MS. In contract, currently there are over a dozen FDA-approved medicines for relapsing forms of MS, as well as FDA-approved medicines to increase walking speed in MS, improve bladder dysfunction, and lessen emotional incontinence. The immune targets of FDA-approved therapies have markedly expanded in the past several years and now include B cells and gamma/delta leukocytes. The first therapy for primary progressive MS was approved in 2017. Many more disease-modifying therapies and symptom therapies are currently in phase 2 and phase 3 trials.

It has become clear that an increased efficacy as measured by reduced relapses, short-term measures of disability on exam, and MRI activity can be achieved with some of the newer agents. However, higher efficacy may come with a price, as exemplified by the association of progressive multifocal leukoencephalopathy with several MS therapies. Nevertheless, we are now becoming more adept at risk-stratifying patients for natalizumab by assessing for John Cunningham virus (JCV) antibodies prior to and during therapy. Similar risk stratification is being used for the first oral agent available (fingolimod) by assessing for antibodies against varicella zoster and assessing cardiac rhythm disorders, medications, and baseline eye exam. Surprisingly, the goal of personalized treatment in MS has not been through personalizing efficacy, but through personalizing safety and mitigating risks.

A recently emerging theme in relapsing MS is the recognition that a subset of patients treated in clinical trials appears to be free of disease activity, as defined by stable clinical exam, lack of relapses, and stable MRI without new lesions or gadolinium enhancement. The proportion of patients free of disease activity (also called NEDA: No Evidence of Disease Activity) may become the new benchmark of success, both in clinical trials and in clinical populations. Of course, this simple definition begs the question of whether patients are truly free of disease activity or just lack changes that we can appreciate with current clinical and imaging monitoring methods. This will be a point of discussion particularly as we increase the number of trials in progressive MS, where robust measures of progression are urgently needed to guide treatment assessment and decision making.

NEW DIRECTIONS IN TREATMENT OF MS SYMPTOMS

While the search for newer disease-modifying therapies has been fruitful, other areas of MS management have also moved forward. We have an approved agent for pseudobulbar affect, a socially stigmatizing disorder seen in MS, amyotrophic lateral sclerosis, head injury, and some dementing disorders. A long-acting form of 4-aminopyridine is approved to increase walking speed in MS. Botulinum toxin has been approved for the management of limb spasticity and bladder dysfunction. Additional agents are available for the treatment of neurogenic bladder symptoms. Implanted baclofen pumps provide a management tool for patients with severe spasticity and have seen useful application in both ambulatory and nonambulatory patients. Now, the challenge has become identifying who to treat with what and when, a challenge to be met with better training and careful patient selection.

GREATER RECOGNITION OF THE IMPORTANCE OF OTHER HEALTH MEASURES IN MS

In the past, neurologists typically confined themselves to the diagnosis and sometimes treatment of MS alone. They did not provide care for (or indeed cared about) other medical issues in their MS population. Over the past 10 years, we have come to recognize how comorbid conditions such as obesity, smoking, and vascular disease require attention in the MS population and how they accelerate progression of MS owing to secondary injury. We are seeing a greater focus on the potential role of vitamin D deficiency in the pathogenesis of MS. We are learning that depression, sleep disorders, and pain are not only common in MS, but also drivers of health-related quality of life and even employment in affected patients. We need to treat the whole 14patient and attend the patient’s social surroundings, rather than just seeing them as relapses and brain lesions.

EMBRACING A TEAM APPROACH TO MS

It has become clear that a neurologist alone cannot meet the needs of this challenging patient population. A team approach, where many healthcare practitioners with different competencies aid the patient through their disease course, works better than a solo act. New research has supported the concept that wellness approaches, cognitive behavioral therapies, exercise, rehabilitation, and a host of other interventions are not only beneficial but also critical in enhancing function and improving the lot of patients and their families. As we move into newer healthcare systems, a more comprehensive approach to all the factors which go into MS care needs to be taken so that we can effectively and efficiently help this group of people through their long-term disease.

ONGOING CHALLENGES AND FUTURE PROMISE

Despite great successes in so many areas of MS—successes in understanding its pathogenesis, diagnosis, treatment, and monitoring—many challenges still remain. Perhaps no challenge is more prominent than that of treating progressive MS. Although symptomatic therapies in progressive MS have emerged, there still is a fundamental lack of understanding regarding progressive MS pathobiology, methods for phase 2 proof-of-concept trials, and optimal clinical outcomes for phase 3 trials. These holes in our understanding have inhibited the development of an effective therapy for progressive MS. We also need better clinical and imaging tools to monitor the evolution of MS disease beyond just foci of inflammation. These tools will better characterize disease progression over time and the potential impact of disease-modifying and symptomatic therapies.

At the present time, we are at crossroads in MS. If we catch patients early enough in their relapsing course, intervene, monitor treatment response, and alter treatment accordingly, then we feel we can substantively alter the course of their disease. Admittedly, definitive long-term evidence of this success is still limited, but preliminary clinical trial and innovative propensity-weighted virtual trials suggest this is the case. However, we want to provide more protection from neurological worsening, and optimally to provide for improvement or restoration of function where it has been permanently injured in the past. The continued significant unmet needs and challenges in MS call for an active MS research enterprise, clinically astute and forward-thinking treatment strategies, as well as targeted advocacy and fundraising. The last two decades of tremendous progress in MS need to be leveraged toward the remaining significant unmet needs of this disease.

Finally, there is more to CNS neuroimmunology than just MS. Acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, autoimmune encephalitis, and neurosarcoidosis all share somewhat similar immune pathophysiologies, but have different manifestations, diagnostic criteria, and treatments. Recognizing these entities is important as these patients are often seen by the same providers who care for MS.

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