Neurologists try to prescribe the appropriate drugs for patients with relapsing-remitting multiple sclerosis (MS) to prevent ongoing disease activity. "Most of us feel that if a patient has incomplete control of his or her disease by their current therapy, we should consider switching therapy," said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.
"In practice, it ends up being quite difficult," he added. "There's probably not unanimity among clinicians as to what constitutes excessive disease activity and which outcome to put more weight on. Exactly what to monitor and what criteria to use to change therapy probably differ from person to person."
“There are no standard guidelines for determining an inadequate response to therapy for any of the agents,” agreed Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. It is difficult to know whether new lesions, for example, occur because the patient’s drug is not working or because his or her disease is getting worse.
Neutralizing antibodies to interferon or natalizumab are “one of the few indicators we have” that the therapy is not working, added Dr. Lublin. “If someone’s not doing well and they have neutralizing antibodies, then that would suggest it’s time for a switch.”
Undesirable side effects and adverse reactions are other fairly straightforward signs that a patient’s therapy should be changed. “If someone transitions into progressive disease, that’s a reasonably good indicator that he or she is probably not doing well enough on their current therapy,” said Dr. Lublin. Other criteria are less clear, however.
How Many Relapses Are Acceptable?
Many neurologists agree about the need to monitor the number and severity of a patient’s relapses, as well as the extent to which the patient recovers from them. If relapses continue, the clinician should consider changing the patient’s medication. But the number of relapses that should prompt a change is uncertain.
In addition, a lack of relapses may not mean that a patient’s disease is stable. “If you look at other markers of disease activity, primarily MRI, you can see that the patients’ brains are continuing to shrink—they’re developing cerebral atrophy—[and] they have multiple new gadolinium-enhancing lesions and T2 lesions forming,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Denver. A patient may have between 10 and 20 MRI lesions before having a relapse, he added. If subclinical disease activity remains untreated, a patient risks developing progressive MS, which can’t be reversed.
MRI May Not Provide a Clear Image of a Patient’s Status
Neurologists also agree about the value of MRI as a measure of a patient’s condition, but have not arrived at a consensus about how many new MRI lesions should prompt a change in therapy. The scans’ relative importance may not be clear, either. “Sometimes MRI activity can happen in the absence of clinical activity, so there’s not always agreement [about] which should take precedence,” said Dr. Cohen.
In addition, MRIs obtained in clinical practice are highly variable. MRIs may be taken on different machines, at different field strengths, and with different acquisition parameters. The orientation of the patient in the machine also may change from one MRI to another. “It can sometimes be hard because of technical considerations to compare one scan to another,” observed Dr. Cohen. “You can see an obvious difference, but it’s very difficult sometimes to quantify the total amount of lesions and to say whether [the patient is] better or worse than last time.”
Clinical trials usually include a detailed protocol for obtaining MRIs, which typically are registered for consistency. Computers often quantify abnormalities such as lesion burden or brain volume. “Most of us don’t have access to those sorts of things in practice,” notes Dr. Cohen. “There may be subtle differences that may be significant, but not so obvious, that we sometimes miss.”
In addition, if a neurologist performs MRI scans once per year, he or she may not notice disease activity if the scans are taken during quiet phases when lesions have shrunk, said Dr. Vollmer. “If you do an MRI on a monthly basis, you can see a remarkable amount of disease activity,” he added, “but we can’t do that in a clinical setting.”
Revisiting the Neurologic Exam
The accumulation of neurologic impairment or disability, as measured by the neurologic exam, also could suggest that a patient’s current therapy is not working. But the neurologic exam “is highly subjective and not readily quantifiable,” said Dr. Cohen. For example, “it’s very hard to tell whether someone’s eye movements are worse today than when you saw them six months ago,” he added.