Multiple Sclerosis Matters are Not All Black and White

A year and a half ago, my older brother was rushed to the emergency room with numbness and tingling in his left extremities.  He left the hospital after a battery of tests – including an MRI of the brain and spinal cord and a spinal tap – and no diagnosis. He was referred to a neurologist and after two more MRIs and repeated assurance that it wasn’t multiple sclerosis (MS), he was diagnosed with MS. From initial onset to diagnosis took a little over a year.

 MS is a progressive, neurological disease whereby a degradation of CNS myelin leads to motor, sensory, cognitive, and psychological symptoms. MS is one of the most common neurological diseases with a worldwide prevalence of about 2.1 million; approximately one-fourth of those diagnoses are accounted for in the U.S. (2).

So why is there so much lag-time between initial sensory symptoms of the first lesion (Clinically Isolated Syndrome, or CIS) and confirmed MS diagnosis? The answer may lie in the simple fact that researchers are looking in the wrong CNS tissue. There are two feasible hypotheses about the progression of the disease. The first, and the most widely accepted hypothesis, is that MS arises in the myelinated CNS white matter and eventually spreads to the gray matter; patient symptomology supports this model - with most individuals initially experiencing sensory impairments followed by cognitive, motor, and psychological symptoms (1). Conversely, some researchers have asserted that gray matter is affected first, followed by white matter degradation (1). Because of the wide acceptance of MS as a disease originating in myelin, diagnoses have been made largely based on differential densities of healthy and impaired CNS white matter via MRI (2). Recently, researchers have used mass spectrometry to perform CSF proteomic analysis in healthy patients, patients with CIS, and patients with relapsing-remitting MS (RRMS) (3). Data indicates that the patients with CIS, who later developed RRMS, had significantly increased levels of proteins associated with gray matter synaptic regulation, but the white matter protein differences were comparable to those observed in the controls (3).  While CNS white matter is clearly implicated in MS, it may be worthwhile to further explore the role of gray matter in early, suspected MS.  Ideally, a more holistic diagnostic approach would decrease the time required to make a definitive MS diagnosis, and consequently allow patients to start treatment before significant disease progression.

References:

1. Chiaet J. Focus shifts to gray matter in search for the cause of multiple sclerosis. Scientific American. Sept. 2013. Retrieved from http://www.scientificamerican.com/article.cfm?id=focus-shifts-to-gray-matter-search-for-cause-multiple-sclerosis.

2. National Multiple Sclerosis Society. 2013.  Retrieved from http://www.nationalmssociety.org/index.aspx

3. Schutzer SE, Angel TE, Liu T, Schepmoes AA, Xie F, et al. Gray matter is targeted in first-attack multiple sclerosis. PLoS ONE. Sept. 2013. 8: e66117.doi:10.1371/journal.pone.0066117