What’s new in MS: teratogenicity of disease-modifying drugs, extended interval natalizumab dosing, a potential biomarker, the “MS hug,” and virtual reality therapy.
Advances in multiple sclerosis (MS) continue to dominate other therapeutic areas in neurology. MS presentations accounted for approximately 15% of the more than 3000 scientific presentations at the 71st American Academy of Neurology meeting in Philadelphia, PA, May 4 to 10, 2019.
Pregnancy outcome and disease-modifying therapies
Multiple sclerosis (MS) occurs more frequently in women, often during childbearing years. Although women with MS require no special gynecologic care during pregnancy, MS management requires close observation and possibly drug or dose adjustment. The Food and Drug Administration (FDA) has not approved any disease-modifying agent for use during pregnancy.
Ahmed and colleagues1 reviewed the outcome of 142 pregnancies in 120 women with MS. During 80 of the 142 pregnancies (56.3%), the fetus was exposed to a disease-modifying agent. The most common disease-modifying agents were beta interferons (35.2%), natalizumab (19.7%), fingolimod (16.9%), and dimethyl fumarate (3.5%). Premature birth occurred in 5% of the exposed group vs 3.2% of the nonexposed group (P=NS). The rate of abortions was also similar (10% in the exposed group vs 11.3% in the nonexposed group). Major fetal malformations did not occur in either group. In this observational study, there was no difference in pregnancy outcomes in pregnant women who received disease-modifying agents vs those who did not.
It is unlikely that there will ever be a definitive study comparing the potential teratogenicity of different disease-modifying agents for MS. Consequently, physicians and their patients must rely on retrospective and registry data. This study should reassure women who become pregnant while under treatment, but more data are needed before disease-modifying agents can be recommended as safe during pregnancy.
Natalizumab dosing and PML
Natalizumab (Tysabri) is a recombinant humanized anti-alpha4-integrin antibody indicated for the treatment of relapsing forms of MS. One of the risks of natalizumab is the occurrence of progressive multifocal leukoencephalopathy (PML), which can result in morbidity and mortality. Risk factors for PML include duration of natalizumab therapy, presence of the JC virus, and prior immunosuppressive therapy. The possibility that extended interval dosing (EID) rather than standard interval dosing (SID) might decrease the risk of PML is under investigation. Typically, patients receive natalizumab as a monthly infusion. All patients treated with natalizumab must be registered in the manufacturer’s TOUCH (Tysabri Outreach: Unified Commitment to Health) prescribing program.
Ryerson and colleagues2 reviewed the TOUCH dataset as of June 2018 to determine whether the incidence of PML differed between patients on EID or SID. Patients were divided into three groups: (1) primary analysis (EID/SID over the past 18 months), (2) secondary analysis (prolonged period of EID/SID), and (3) tertiary analysis (dosing primarily of EID/SID).
In all groups, EID patients had longer median natalizumab exposure durations than SID patients, suggesting better tolerability. In addition, the hazard ratio (HR) for PML was 0.10 (P<.001) for the primary analysis group and 0.20 (P<.001) for the secondary analysis group, both favoring EID. Consequently, EID may be an effective strategy to reduce the risk of PML in patients with MS treated with natalizumab.
It is unknown whether EID decreases the risk of PML, but this study suggests that spacing out natalizumab dosing may postpone the occurrence of this devastating complication of treatment. The issue of efficacy also needs to be considered-some patients with MS may require monthly natalizumab dosing to prevent relapses. Much more data regarding dosing frequency and dose adjustments are needed to provide guidelines for practitioners to individualize and optimize natalizumab therapy.
Monitoring disease activity with serum neurofilament light chains
Medical management of relapsing-remitting MS relies on monitoring disease activity via clinical symptoms and MRI findings. Serum biomarkers of MS activity would potentially reduce reliance on MRI and facilitate disease management. Recently, it has been observed that serum neurofilament light chain (NFL) levels, which represent axonal breakdown, correlate with disease activity.
Uher and colleagues3 measured serum levels of NFL with a single molecule array assay in two MS cohorts. In the SET group, there were 163 patients with relapsing-remitting MS (405 samples). In the GeneMSA group, there were 179 patients with relapsing-remitting MS (664 samples). NFL levels were compared with radiological activity on annual MRI scans.
Of the patients with NFL levels higher than the 90th percentile, 81.6% of the SET patients (odds ratio [OR]=3.4) and 48.9% of the GeneMSA patients (OR=2.6) had active radiological disease. Conversely, NFL levels lower than the 30th percentile were associated with the lack of active radiological disease-only 29.3% of the SET group and 10.9% of the GeneMSA group showed any MRI activity. Based on these data, it appears that NFL levels tend to agree with MRI findings and may become a useful biomarker of MS disease activity.
The old adage, “treat the patient, not the MRI,” has fallen by the wayside when it comes to MS. It has become apparent that many patients, even if asymptomatic, have ongoing disease activity that can be detected by periodic MRI scans. How often to perform MRI and when to change therapy due to detection of disease activity remain active areas of investigation. If NFL levels reflect disease activity as well as MRI, they may provide a less cumbersome and perhaps less expensive method of monitoring disease activity in people with MS. It does not appear that NFL levels have reached that standard yet.
The “MS hug”
The lay term, “MS hug,” may be used by people with MS to describe dysesthetic sensory symptoms. Wingerchuk and colleagues4 at the Mayo Clinic, Arizona, evaluated the charts of 116 patients with MS (71% female, 76% with relapsing disease) who reported the MS hug. The investigators defined the MS hug as a “unilateral or bilateral segmental constricting (squeezing, band-like, or girdle-like) sensation involving the thorax, abdomen, or both that was associated with objective evidence of a neuroanatomically appropriate current or prior spinal cord lesion and not attributable to another cause.”
Although 116 patients reported the MS hug, only 46 (41%) had symptoms and pathophysiology that met the study definition. In these patients, symptoms occurred during cord relapse evolution (41%), more than 3 months post-relapse or during the progressive phase (39%), or during early recovery (20%). Of the remaining 70 patients who complained of an MS hug, 27 (39%) had other types of neuropathic pain.
Six patients (9%) with symptoms suggestive of the MS hug had serious causes not related to MS that required immediate intervention. These included three patients with herpes zoster and one patient each with cholecystitis, myocardial infarction, and pulmonary embolism. Other non-MS causes of the MS hug included musculoskeletal discomfort, gastroesophageal reflux disease, anxiety, and bowel symptoms. Eleven patients (16%) had no clear etiology. The authors caution that the term MS hug may accurately describe spinal cord symptoms in people with MS but may also indicate unrelated medical problems that may be serious and require immediate treatment.
Although many somatic symptoms in people with MS may be related to their underlying disease, some symptoms may reflect different pathology. This study emphasizes the importance of investigating all symptoms in people with MS in order to detect and treat potentially serious comorbidities.
Virtual reality therapy
People with MS may suffer chronic symptoms such as depression, fatigue, and pain, which may respond only partially to conventional treatment. In an ongoing study, Shaw and colleagues5 explored the use of virtual reality in an attempt to alleviate symptoms. Treatment consisted of eight 35-minute sessions with an HTC Vive headset. Patients were randomized to either passive (viewing) or interactive (moving). Patients were monitored by a technician for safety. The Positive and Negative Affect Schedule (PANAS) and Patient Reported Outcomes Measurement Information System (PROMIS) scales were administered prior to and following virtual reality treatment to assess response. Data available thus far for eight patients indicated that all experienced an improved positive affect and reduced negative affect. The authors concluded that virtual reality is a promising tool for symptomatic treatment of patients with MS and other chronic neurologic conditions.
While there have been many advances in the treatment of the inflammatory component of MS, comprehensive patient management demands symptom improvement as well. This study suggests that virtual reality therapy may become a helpful modality.
This brief sample of advances in MS presented at the 2019 American Academy of Neurology meeting includes the effect of disease-modifying agents on fetal outcome, diminished risk of PML via extended natalizumab dosing, the potential of NFL as an MS activity biomarker, the diverse etiologies that underlie the “MS hug,” and the potential for virtual reality therapy to alleviate affective symptoms in people with MS. Many more presentations at the meeting demonstrated progress in the understanding and treatment of MS.
About the author
Andrew Wilner, MD, is a neurologist who blogs at www.andrewwilner.com/blog. His latest book is The Locum Life: A Physician’s Guide to Locum Tenens.
1. Ahmed SF, Almuteri ML, Al-Hashel J, Alroughani R. Pregnancy outcome in multiple sclerosis patients exposed to disease modifying therapies. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P4.2-100.
2. Ryerson LZ, Foley J, Chang I, et al. Reduced risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab extended interval dosing (EID): updated analysis of the TOUCH Prescribing Program database. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract S26.006.
3. Uher T, Schaedelin S, Benova B, et al. Monitoring of subclinical disease activity by serum neurofilament light chain levels in multiple sclerosis. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract S37.005.
4. Wingerchuk D, Sanchez CV, Carter J. The “MS hug”: definition, characteristics, course, and misattribution risk. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P5.2-111.
5. Shaw M, Palmeri M, Krupp L, Charvet L. Acute and lasting benefits of a virtual reality in multiple sclerosis. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P1.7-010.