Study Investigates Possible New Underlying Cause of Multiple Sclerosis

Researchers are beginning a study that will test the possibility that the symptoms of multiple sclerosis result from narrowing of the primary veins outside the skull, a condition called chronic cerebrospinal venous insufficiency (CCSVI). This narrowing restricts the normal outflow of blood from the brain, causing alterations in the blood flow patterns within the brain that eventually causes injury to brain tissue and degeneration of neurons.

CCSVI is a complex vascular condition and has found to be strongly associated with multiple sclerosis, increasing the risk of developing multiple sclerosis by 43 fold.

"If we can prove our hypothesis that cerebrospinal venous insufficiency is the underlying cause of multiple sclerosis it is going to change the face of how we understand multiple sclerosis," said Robert Zivadinov, principal investigator on the study,

The preliminary findings were based on a pilot study that showed that several abnormalities affecting the predominant pathways that return venous blood from the brain to the heart occurred more frequently in multiple sclerosis patients than in controls. Results of this preliminary study, which involved 16 relapsing-remitting multiple sclerosis patients and eight age-and-sex-matched healthy controls, showed that all the multiple sclerosis patients, but none of the controls, had chronic insufficient blood flow out of the brain.

The images from this study were acquired using a method called Doppler ultrasound. The method identified anomalies in the venous blood flow associated with strictures, malformed valves and peculiar webs within the large veins of the neck and brain.

Advanced magnetic resonance imaging scanning (MRI) of the multiple sclerosis study patients also identified distinct areas of iron deposits in the brain, and showed that those deposits may be associated with the location of multiple sclerosis lesions and sites of impaired drainage. The scans also revealed increased brain atrophy and changes in the flow of cerebrospinal fluid in the multiple sclerosis patients.

The new study will involve 1,600 adults and 100 children. The cohort will be comprised of 1,100 patients who were diagnosed with possible or definite multiple sclerosis, 300 age-and-sex matched normal controls, and 300 patients with other autoimmune and neurodegenerative diseases. Enrollment in the study has begun and will continue for two years. Multiple sclerosis patients from across the U.S. are eligible to participate in the study.

"The prevailing wisdom that central nervous system damage in multiple sclerosis is predominantly the result of abnormal immune responses against the patient's nervous tissue has been challenged by research findings, which have demonstrated a significant neurodegenerative component in multiple sclerosis and the progressive loss of neurons" said Zivadinov. “However, these inflammatory and neurodegenerative processes occur concurrently in multiple sclerosis and vary considerably among patients, making it difficult to identify the cause, or causes of the disease. Consequently, the origin and development of multiple sclerosis remains poorly understood, and its cause remains elusive."

To determine if these preliminary findings can be repeated, the researchers will evaluate both the velocity of blood flow through both the brain's blood vessels and the extracranial veins, using Doppler ultrasound.

The technical name of the study is "combined transcranial and extracranial venous Doppler (CTEVD) evaluation in multiple sclerosis and related diseases".

All study subjects will undergo a general clinical examination and a Doppler scan of the head and neck to acquire images of the direction of venous blood flow in different body postures. Participants also will provide blood samples, and complete an extensive environmental questionnaire to identify potential multiple sclerosis risk factors.

All multiple sclerosis patients will undergo MRI of the brain to measure iron deposits in lesions and surrounding areas of the brain using a method called susceptibility-weighted imaging. Iron findings on these images will be related to neuropsychological symptoms.

A sub-cohort of 250 consecutive patients and controls will undergo MRI of the veins of the neck to confirm diagnosis of CCSVI.

Blood samples will be analyzed for proteins and soluble factors associated with central nervous system injury. Other factors of interest in multiple sclerosis research will be looked at, such as vitamin D metabolites and cigarette smoking, which have been linked to increased risk for developing multiple sclerosis as well as multiple sclerosis disease progression.

For more details on the study, send an email to ctevd@bnac.net.
References:
1. Robert Zivadinov, et al. University at Buffalo.
2. Image by Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist.

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