125th Annual Meeting
of the American Neurological Association
Rohit Bakshi, MD
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects approximately 250,000 people in the United States. MS is the most common cause of progressive physical disability in young adults. Recent developments pertaining to the pathophysiology, immunomodulatory treatment, and neuroimaging findings in MS were presented at the 125th Annual Meeting of the American Neurological Association in Boston, Massachusetts, as highlighted in this summary. Abstracts based on these presentations were published in the September issue of the Annals of Neurology.
Is MS a Gray Matter Disease?
MS is traditionally thought of as a white matter disease of inflammatory demyelination. However, recent data indicate that MS is a destructive process that includes axonal transection and brain atrophy. In addition, a growing body of evidence shows that the gray matter is commonly involved in MS patients, with pathology including hypometabolism, hypointensity on T2-weighted images, and direct plaque formation. Bo and associates, from Norway and Cleveland, Ohio, morphometrically studied the extent of plaque formation in the cerebral cortex in autopsied brains of 20 patients with MS using a novel approach (immunostaining for myelin basic protein). Eighteen of the 20 brains (averaging 6 lesions per patient) had demyelinating foci in the cortical gray matter that were mainly restricted to the cortex. Thus, direct gray matter involvement appears to be common in MS and may contribute to hypometabolism and subsequent clinical impairments.
Neuroimaging in MS: Continuing MRI Advances
Magnetic Resonance Spectroscopy: Detecting "Invisible" Pathology
Proton MR spectroscopy (MRS) is a noninvasive method of studying the biochemistry of living tissue. N-acetyl-aspartate (NAA) is a marker of neuronal function, choline marks cell membrane and myelin metabolism, and creatine reflects cellular energy. T2-weighted MRI scans are insensitive to the full extent of pathologic changes in the brains of MS patients. Areas that appear normal on T2-weighted images may contain clinically important microscopic disease. It is unclear if pathologic alterations occur in normal-appearing white matter (NAWM) early in the MS disease process and how to best detect these changes.
Rose and collaborators, from Salt Lake City, Utah, used MRS to evaluate NAWM in 22 patients with early stage (clinically suspected) MS vs normal controls. NAWM in patients had higher frontoparietal choline/creatine ratios but normal NAA/creatine ratios as compared with controls. This study suggests that increased cell membrane and myelin turnover occurs in the early stages of MS despite normal conventional MRI findings. MRS may be useful to detect these early microscopic changes in patients at risk for developing typical MS.
Diffusion-weighted imaging (DWI) shows changes in microscopic water molecule motion, or Brownian motion, in tissue. Water molecules in brain tissue are in constant random motion and may diffuse in any direction unless they are limited by biologic barriers such as cell membranes or pathologic processes. Diffusion may also increase in pathologic states if normal barriers are injured or removed. Apparent diffusion coefficient (ADC) values obtained by DWI are a quantitative measure of diffusion properties. Previous DWI studies in MS have demonstrated raised ADC in both lesions and areas of normal-appearing white matter.
Wilson and associates, from Nottingham, United Kingdom, used a semiautomated method to sample a large region of brain, surrounding cerebrospinal fluid (CSF), and ventricles in 22 MS patients. The magnitude of ADC histogram peaks correlated with physical disability and total brain atrophy. Dr. Wilson said, "The increased diffusion may reflect microscopic tissue loss with less restriction to water movement that ultimately leads to atrophy and physical disability." These investigators have offered a new semiautomated method to detect diffusion changes that may be less susceptible to intrarater and interrater variability than previous methods.
Treatment of MS
Immunotherapies to Prevent Relapses
Immunotherapies to Prevent Relapses
The immunomodulatory agents (IMAs) interferon beta-1a, interferon beta-1b, and glatiramer acetate are FDA approved for the treatment of relapsing-remitting MS (RR-MS) in adults. The Medical Advisory Board of the National Multiple Sclerosis Society developed a consensus statement that included the following comments:
This study shows that a majority of patients with RR-MS who are not receiving IMAs are actually appropriate candidates. The reasons for less than expected use of IMAs include both physician- and patient-specific factors. Increasing the use of IMAs in RR-MS patients will likely require better communication of the favorable benefit/risk profile of these agents to both physicians and patients.
Treatment of Severe Demyelinating Attacks
Some patients with brain or spinal cord demyelinating diseases continue to experience relapses or disease progression despite standard therapies. These include RR-MS patients who fail self-injected immunotherapies, those with secondary progressive disease, and patients with conditions related to MS for which proven therapies do not exist. Therapeutic plasma exchange (TPE) is effective for some patients with severe refractory CNS demyelinating attacks. However, the factors that predict successful treatment are not known.
Keegan and coinvestigators, from Rochester, Minnesota, reviewed the response to treatment of 48 patients who received TPE for severe attacks of MS (n = 16), acute disseminated encephalomyelitis (n = 8), Devic's disease (n = 8), Marburg variant MS (n = 7), and transverse myelitis (n = 4). Neurologic improvement was mild in 5 (10%), moderate in 6 (13%), and marked in 18 (38%). Nineteen patients (40%) did not benefit. Early response (median, 3 days; 2 exchanges) and younger age were significantly associated with marked improvement, while the type of demyelinating disease, neurologic deficit, time to treatment, and CSF findings were not of predictive value. This study confirms and extends previous reports of the efficacy of TPE in severe attacks of MS or related diseases and may assist in patient selection.
Do Infections Cause MS?
There has been increasing attention paid to the possible role of chlamydia or human herpesvirus infections in causing or contributing to MS, but no definite etiologic links have been established. Four presentations at the meeting added further data to the conundrum.
Sriram and associates, from Nashville, Tennessee and Providence, Rhode Island examined the CSF of 13 patients with monosymptomatic MS (M-MS), 18 patients with clinically definite MS (CD-MS), and 16 control patients with other neurologic disease (OND). They performed a nested polymerase chain reaction (PCR) assay for the major outer membrane protein of Chlamydia pneumoniae. PCR was positive for C pneumoniae in the CSF of 46% of M-MS patients and 94% of patients with CD-MS, but only 1 of 16 OND patients. Antibodies in the CSF to C pneumoniae were lower in M-MS than CD-MS, but higher than the OND group. Dr. Sriram commented that "the results argue for early tropism of the organism." Infection of the CNS with C. pneumoniae seems to be a frequent occurrence in MS patients and occurs early in the course of the disease. These findings suggest a pathogenic role for this organism in MS, but a bystander effect is also possible.
In a related presentation, Kaufmann and associates, from Nashville, Tennessee and Baltimore, Maryland, showed that the technique used for the detection of C pneumoniae affects the sensitivity for detection. Different laboratories may obtain divergent results; thus, standardization of analysis methods is important.
Human Herpesvirus 6
focused on the role of human herpesvirus 6 (HHV-6) in MS. Knox and Carrigan,
from Milwaukee, Wisconsin, autopsied CNS and lymphoid tissue of MS patients,
and found rates of HHV-6 type A infection in patients with MS (ie, 75%
and 67% in CNS and lymphoid tissues) to be higher than rates of this infection
in the brains of normal individuals and immunocompromised patients (less
In another study, Goodman and associates, from Rochester, New York, and East Orange, New Jersey, detected HHV-6 in biopsy specimens of acute lesions of 6 patients with large tumorlike MS plaques. Each case ultimately demonstrated a clinical course to confirm the diagnosis of MS. There was a high frequency of lymphocytes, oligodendrocytes, and microglia containing HHV-6 within and at the borders of the lesions. The cells positive for HHV-6 were mainly reactive astrocytes and microglia. By contrast, normal control brains showed a low positivity for HHV-6 genome.
In a third study, Lobeck and colleagues, from Milwaukee, Wisconsin, obtained blood samples from patients with MS during acute relapses and several weeks later during clinical stability, and assessed them for active HHV-6 infection by a rapid culture assay. Fifteen (50%) of the 30 patients were positive for active HHV-6 viremia during relapse while only 17% (5/30) were positive in the follow-up sample (P < .015). This study shows a close relationship between active HHV-6 infection and clinical relapse in RR-MS. In summary, these 3 studies further support a role for HHV-6 infection in the pathogenesis of the disease, although a direct cause and effect relationship is not clearly established.