Keep Calm and . . . What?
By Moses Rodriguez, Orhun Kantarci, and Istvan PirkoSo all the test results are back, and you’re seeing the patient (and perhaps his/her partner) to report that the patient is in the early stages of multiple sclerosis (MS) or is recovering from a clinically isolated syndrome (CIS) indicative of MS. “What’s the next step?” they may ask. Maybe you’ll tell them to go home and continue training for that cross-country bike trip or planning the wedding or designing a website for their new start-up company.
In 1939, after the outbreak of World War II and in anticipation of air attacks targeting civilians, the British Ministry of Information designed a number of morale-boosting posters to be displayed across the country. The best known of these is “Keep Calm and Carry On,” which has become a new by-word in kitschy folk art as people are buying plaques and posters with this motto and humorous variations (i.e., “Keep Calm and Eat Chocolate,” “Keep Calm and Call Batman”). Keep Calm and Carry On may possibly be the best advice you can offer to someone newly diagnosed with MS.
Not all MS patients will develop severe disability nor will they develop what is known as “progressive MS”. Therefore, we do not believe inducing a sense of doom is a good idea and we do believe that caution should be exercised in recommending treatment for all patients with MS or CIS at the time of diagnosis. This is especially likely true for those patients who recover very well from their initial presenting symptom in a short time without further recurrences within the next three to five years. In the absence of symptoms or successive MRIs with increased areas of plaque, it is reasonable to withhold treatment while scheduling regular follow-up visits for the patient. Patients with MS often do well without any treatment. In addition to the likelihood that the MS may prove benign — though this requires years of follow-up to establish — disease-modifying drugs are only partially effective in the short term, and there is as yet minimal data to suggest that they prevent disability in the long term.
Currently available drugs target the early inflammatory phase of the disease, that is, the phase characterized by relapses and remissions. Most patients begin with a relapsing-remitting course; therefore, it is reasonable to focus on this aspect of the disease process. Unfortunately, none of the established or newer drugs are likely to be curative even if begun at the earliest stage of disease. There is presently very little evidence that partially stopping relapses or modifying the inflammatory response prevent patients from entering the progressive phase of the disease. Further, the lesson from the stronger medications that actually work quite well in eliminating most if not all of the inflammatory activity, such as natalizumab, should make any clinician reluctant to subject a patient to potentially lethal side effects without reasonable evidence of relatively increased inflammatory activity. Nevertheless medicines help the right patient at the right time. MS is a great example of the practice of individualized medicine.
Speaking of individualized medicine, there is a lot that can be done beyond the immunomodulatory treatments for an MS patient with clinically active disease and life-disrupting symptoms. Until a cure for all forms of MS is found, practicing physicians must help patients find symptom-management strategies to improve the quality of daily life. Successful management requires a multidisciplinary integrated approach by all health care providers involved in the patient’s care.
The pathophysiology of MS consists of bouts of inflammatory activity as well as a neurodegenerative process afflicting the central nervous system. Symptoms of MS parallel these processes. Most MS treatment approaches focus on preventing or shortening relapses by modulation (e.g. interferons), suppression (e.g. steroids), or partial elimination (e.g. plasma exchange) of immunological insult. If the acute symptom relates directly to the relapse, then these approaches can be effective. However, many MS symptoms correlate to the neurodegenerative component of the disease or are secondary to disease-associated lifestyle changes, neither of which responds to immuno-mediated strategies. Indeed, some immunomodulation strategies may worsen MS symptoms even while preventing further relapses.
Because many MS symptoms are closely inter-related, it is difficult to treat one symptom without affecting another. Patients may acquire a long list of medications, each addressing a specific symptom, from multiple providers. We recommend assembling a “multidisciplinary team” of consultants with specific interest in MS from neurology, rehabilitation, urology, psychology, psychiatry, speech therapy, sleep medicine, dietetics, patient education, and social services. Neurologists generally lead the care of patients with MS, especially regarding initial diagnosis, changes in diagnosis, choosing disease-modifying medications and prognosis discussions, but rehabilitation specialists often provide more effective symptom management.
We also recommend scheduled reassessments of patient needs as the disease evolves. While preventing relapses may be the primary goal in the early stage, reassurance may be more important in relapse-free periods. These periods allow the patient to focus on life-style adjustments for sleep and weight control. Later, the primary focus can shift to chronic progressive, neurodegenerative worsening. Because many recommendations for symptomatic relief can be stage-specific, we must inform patients from the first interaction that their needs may change. For chronic symptoms, it makes sense to focus on one or two problems at a time to prevent patient burn-out associated with consultations with multiple providers on every visit to the medical center. Early recognition and treatment with one or two drugs dealing with the core complications of MS (immobility, fatigue, sleep problems, weight control, and heat sensitivity) will minimize their impact on future symptoms.
While our goal as clinicians is to keep MS patients comfortable and well able to function, our work at the bench must still aim for prevention and cure. However, after the past decades in which all but a few investigators bought into the hypothesis that MS is only an autoimmune disease and designed experimental treatments accordingly, the lesson is, again, keep calm and don’t look for a one-size-fits-all solution. We need to treat patients by addressing their specific basic pathophysiology. Treating patients based on the immunopathology that characterizes their own lesions will ultimately result in a focused “individualized medicine” approach. For the patient who draws the short straw for MS, there is no short-term and easy answer today. Keep calm, carry on, and adapt to change for the long haul.
Moses Rodriguez, Orhun Kantarci, and Istvan Pirko are the authors of Multiple Sclerosis. Moses Rodriguez, MD, is a Professor of Immunology and Neurology at Mayo Clinic Rochester. He is a past recipient of the American Academy of Neurology’s Frontiers in Neuroscience Award. He is known for his extensive work in immunology and viral models of MS. Monoclonal antibody rHIgM22, helping repair the nervous sytem, discovered and developed in his laboratory, is now in phase I clinical trials sponsored by Acorda Therapeutics, Inc. Orhun Kantarci, MD, born in Turkey, educated in Istanbul University and the Mayo Clinic, is an Assistant Professor of Neurology at Mayo Clinic Rochester and prolific clinician. He is known for his epidemiology and genetics work, currently compiling a virtual bio-repository of MS samples. He spear-headed the clinical trial with rHIgM22. Istvan Pirko, MD, born in Hungary and educated at the University of Budapest, the University of Cincinnati, and the Mayo Clinic College of Medicine, now serves as an Associate Professor of Neurology at Mayo Clinic Rochester and is an expert in diagnostic imaging of demyelinating diseases. He has been at the forefront of imaging demyelinating diseases in mouse models besides humans. The three have collaborated on Multiple Sclerosis (Oxford University Press, May 2013).