results, but with different imaging profiles because each targets a slightly different aspect of the underlying disease pathology.
3. Relapse limiting. Current practice is to treat acute relapses with intravenous methylprednisolone. However, no criteria have been adopted that permit uniform designation of the onset and completion of a relapse. The difficulty in this area arises from the fact that relapses can take numerous forms, from monosymptomatic optic neuritis to acute transverse myelitis, and so forth. Nonetheless, if treatments are to be tested for the ability to shorten individual relapses, then criteria for determining precise clinical onset and end of relapse episodes will be required.
4. Progression altering. To date, clinical measures of progression of disability have correlated poorly with imaging measures in MS clinical trials. The exception appears to be the estimation of brain atrophy. Studies evaluating the effects of agents on disease progression will have to incorporate measures of brain and spinal cord parenchymal volume as well as more sensitive and reproducible measures of neurological function than those currently in use.
5. Neuroprotective and restorative. Chapter 5 discusses the potential of and rationale for the use of various neuroprotective and potentially restorative therapies for MS. Many of the current putative neuroprotective or restorative agents in clinical or pre-clinical research are protein growth factors that must somehow be delivered to the central nervous system (CNS), either directly or across the normally restrictive blood-brain barrier. However, it should be noted that insulin-like growth factor-1 (IGF-1) appears to cross the blood-brain barrier in certain experimental autoimmune encephalomyelitis (EAE) models, so the inflammatory nature of the acute MS lesion might permit the use of such agents in the acute setting. Designs for trials of neuroprotective or glioprotective agents in MS will depend on the nature of the question being asked, as well as the specificities and properties of the agent being tested.
Advances in understanding the molecular neurobiology of myelinated axons, as described in Chapter 2, have revealed much about the contribution of impaired impulse conduction to symptom production in MS. Nonetheless, there is much more to learn about the mechanisms underlying demyelination and axonal injury in MS. What are the precise molecular steps that lead from the initial immunologic assault to the death of oligodendrocytes and the degeneration of axons? Are there steps at which these cascades can be halted? It has recently been suggested that cytokines might play a role in injuring myelinated nerve fibers in MS. More information is needed about which cytokines are involved and which molecular