9 November 2000 15:00 GMT
by Bea Perks
Brain scans can plot the progression of multiple sclerosis (MS) even in patients with mild symptoms and before the neurodegenerative disease becomes irreversible, suggests a neuroscientist expert in the field.
Traditionally, patients must have two attacks before a diagnosis of MS can be made, says Richard Ransohoff of the department of neurosciences at the Lerner Research Institute, which is part of the Cleveland Clinic in Cleveland, Ohio. But the second attack occurs on average 18 months after the first, he notes, by when there's been considerable neuronal damage.
"It's miserable for patients and demoralizing for the caregivers," said Ransohoff. "We're involved in a huge biology experiment and [beta-interferon] is the best hope that we have."
Ransohoff has now identified surrogate markers of the disease's progression that can be picked up by magnetic resonance imaging (MRI) techniques, he told delegates at the Third Joint Meeting of the International Cytokine Society and the International Society for Interferon and Cytokine Research, which ends today in Amsterdam.
"One attack, and three or more typical lesions on a brain scan [indicate that the patient is] 80% likely to have a second attack within 18 months," he said. "If there are no lesions, it is only 5% likely."
Ransohoff's development of surrogate markers has enabled his patients to satisfy the requirements of US health insurance policies that previously demanded evidence of two attacks before meeting the cost of beta-interferon therapy.
In the UK, half-hearted provision of MS treatment, under the auspices of the government's so-called National Institute for Clinical Excellence (NICE), created what has become known as a "post code lottery" in which patients' right of access to beta-interferon depended on where they lived.
An appeal by representative agencies and drugs companies against NICE's interpretation of government guidelines was upheld this week, and the institute has again been forced to reconsider its position on providing treatment for MS patients.
MS is characterized, says Ransohoff, by a "tempo of inflammatory events". A series of relapses, in which patients experience numbness in the limbs or, in more severe cases, paralysis or loss of vision, interspersed with remissions belies the fact that "MS is continuously active from onset in most patients," he notes.
He stressed to delegates that it is not adequate to diagnose MS on the frequency of attacks alone.
Since the first detailed description of the disease 150 years ago, it has been known that myelin, which forms a protective sheath around nerve cells, is the primary target. But "demyelination" is reversible. Without treatment, however, there is permanent irreversible damage as axons deteriorate.
The relapsing/remitting phase of the disease, which is reversible, is followed by chronic, progressive and irreversible neurodegeneration, about 20 years later. Ransohoff aims to characterize the early events in MS pathogenesis in the hope that therapeutic intervention will prevent progression to permanent damage later on.
There is a strong relationship linking inflammation, tissue injury and progression in MS, he notes. The cerebrospinal fluid (CSF), which bathes neurons, is packed with inflammatory leukocytes. "In everybody all the time, cells leave the blood and enter the CSF, and then go away," he said. "In MS, they stay there."
The leukocytes, or more particularly one group of them, the macrophages, damage the myelin sheath. But they are simply following orders - from another group of leukocytes, the lymphocytes, that are also present in large numbers in the CSF.
Leukocyte trafficking is directed by a powerful family of proteins known as chemokines. Ransohoff has shown that two chemokines in particular, IP-10 (interferon inducible protein 10) and RANTES (regulated on activation normal T-cell expressed and secreted), are concentrated in the CSF of MS patients.
Cells respond to chemokines by virtue of specialised receptors on their surfaces - and these too are highly concentrated on the surfaces of cells in the CSF.
"The MS lesion represents an ordered structure," Ransohoff told BioMedNet, "mediated by the chemokines and their receptors." Importantly, chemokine levels rise in MS patients during a relapse, a feature that emphasizes his dissatisfaction with the monitoring of symptoms as a predictor of the course of the disease.
Research by Ransohoff and others has shown that beta-interferon is able
to reduce dramatically the number of inflammatory cells in the CSF. But
to be effective, he says, treatment must occur "definitively and early
in the inflammatory process".