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The Neurology HUB – written by: Neha V. Safi, MD, and Stephen Krieger, MD, FAAN
Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). In 2017, an estimated 913,925 adults were living with MS in the US, and that number continues to grow.1 The sex-specific incidence of MS has always favored women over men with an estimated female-to-male ratio ranging from 1.4:1 in 1955 to between 2:1 and 3:1 in 2020.2,3 Although the basis for this widening gender gap is not fully understood, changes in many factors may contribute, of which reproductive behavior, therapeutic hormone use, or cigarette smoking are just a few.4 Regardless of the etiology of this difference, it is important for providers to understand the nuances of caring for men with MS because they present with distinct concerns, offer unique management challenges, and fall within an apparent minority.
DISEASE COURSE
The clinical course of MS can vary. Whereas relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) refer, respectively, to a relapsing or progressive course from onset, secondary progressive MS (SPMS) denotes a gradual decline after an initial course of RRMS. Studies show that the female-to-male ratio for RR/SPMS patients is 2.5:1. Male sex, however, is independently associated with a faster progression from RRMS to SPMS. Of note, studies demonstrate that the female-to-male ratio in PPMS is 1.2:1. The etiology of these differences in sex ratio remains unidentified; however, it has been noted that male individuals with PPMS accumulate disability more rapidly than their female counterparts even in the early stages of the disease course.5 Alternatively, the difference in sex ratio between relapsing and progressive forms could be a result of differences in the underlying pathophysiology. In RRMS, the main mechanism fueling the disease is thought to be inflammatory, as opposed to PP/SPMS where neurodegeneration is more apparent. Underlying hormonal changes may account for the sex-specific ratios found within each disease course. Although there is evidence to suggest testosterone may be a protective factor for the development of experimental autoimmune encephalomyelitis (EAE) in animal models, alternative data show that treatment with exogenous testosterone may be toxic for cultured oligodendrocytes. Considering the conflicting evidence, more studies are required to further understand the effects of testosterone and other hormones on autoimmunity and how this might apply to MS.4,6-8
PRESENTING SYMPTOMS AND DISABILITY PROGRESSION
Not only are men more likely to have a progressive form of MS, but they are also more likely to have different presenting symptoms and disability progression throughout the course of their disease (See Case Study: Clinical Presentation). In RRMS, men more frequently present with motor symptoms, whereas women more frequently present with optic neuritis.4 This is important to note because there is evidence suggesting pyramidal presenting symptoms increase the risk for both disability and transition to SPMS.9 More importantly, incomplete recovery from a relapse, regardless of the category of presenting symptom, is a poor prognostic sign in MS and portends a greater degree of disability. The Expanded Disability Status Scale (EDSS) is a standardized method to quantify disability over time in people with MS. EDSS scores range from 0, indicating normal neurologic function, to 10, indicating death caused by MS. The EDSS carries more weight for ambulation deficits, often affected by pyramidal symptoms, with a key distinction at EDSS of 6 for the use of a unilateral assistive device.10 Although a large natural history study of people with MS who did not use disease-modifying treatments (DMTs) found male sex was associated with a shorter time to conversion to SPMS, individuals with PPMS in this study reached an EDSS of 6 several years earlier than those with RRMS, despite parallel development of disability in both men and women with progressive disease.4
MRI is an essential diagnostic tool in MS with clear guidelines for the diagnosis of MS in the 2017 McDonald criteria that include MRI findings, clinical symptoms, and cerebrospinal fluid (CSF) analysis results. There are also potential sex-specific aspects of the MRI findings that can be followed to monitor disease activity over time. Early studies showed fewer gadolinium contrast-enhancing (Gd+) lesions and more T1 hypointense lesions (also known as “black holes”) on MRIs from men suggesting more axonal loss.11 Larger follow-up studies that controlled for age at onset and type of MS, however, found no sex-specific difference in the number of Gd+ lesions or T1 hypointense lesions, although there was significantly more regional atrophy, as measured by normalized gray matter volume, in men compared with women.12 The most recent study, from 2020, showed significant evidence for clusters of gray matter volume loss in the putamen, precuneus, and medial frontal cortex that were more pronounced in men compared with women. Men were also noted to have more significant thalamic atrophy and cortical thinning compared with women. Although it is not currently standard practice to monitor gray matter atrophy over time as a clinical predictor, it does show promise as a sensitive biomarker for clinical disability progression. These results also support the idea that male sex may confer an increased risk for disability progression.13
CHOOSING AMONG DMTS
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