Magnetic resonance and various chemical measurements, such as spectroscopy, are being systematically applied to both multiple sclerosis and the experimental model (experimental allergic encephalitis). The dynamic aspects of multiple sclerosis pathology can be visualized on serial magnetic resonance imaging scans, and enhancement techniques help distinguish another type of activity by showing a leaky blood-brain barrier in acute lesions. Quantitative measures applied to the image also appear to provide an index of the burden of disease both in individual patients and in groups. A combination of the dynamic information available from serial studies and the quantitative information concerning burden of disease promises to provide both sensitivity and objectivity to standard outcome measures in multiple sclerosis. In addition, natural history studies of the evolution of magnetic resonance imaging and spectroscopy will revolutionize our understanding of the evolution of the actual tissue changes in multiple sclerosis pathology that can be characterized during life.
The treatment of Parkinson's disease is reviewed. The rationale for using selegiline (deprenyl) as the first treatment in recently diagnosed patients is presented. Selegiline delays the need for levodopa; however, it is unclear whether this results from a symptomatic or a neuroprotective effect of selegiline. Levodopa combined with a decarboxylase inhibitor is the principal treatment for patients with moderate or marked symptoms. There is little evidence that levodopa has a deleterious effect on the court of Parkinson's disease. The relationship of levodopa to dyskinesias and response fluctuations is discussed. Pharmacokinetic and pharmacodynamic studies suggest that continuous dopaminergic stimulation may be superior to intermittent pulse therapy. The best approximation to continuous stimulation is the use of long-acting levodopa-carbidopa preparations supplemented by dopamine agonists.
Antiplatelet therapy is clearly indicated for long-term secondary prevention after transient ischemic attack and ischemic stroke. In stroke-free patients with atrial fibrillation, oral anticoagulants reduce the risk of stroke, and antiplatelet agents may be a lower risk alternative. For the early treatment of the acute phase of ischemic stroke, the role of antiplatelet and anticoagulant therapy is unclear, but is being evaluated in large clinical trials.
Although antipsychotic drugs originally helped to discover dopamine receptors, the five dopamine receptors presently identified and cloned are facilitating the search for and discovery of more selective antipsychotic and antiparkinson drugs. The D1-like dopamine receptors, D1 and D5, are sensitive to the same drugs as the D1 receptor in native tissues, but D5 is about 10 times more sensitive to dopamine than D1. The D2-like receptors, D2, D3, and D4, have approximately similar sensitivities to dopamine, but bromocriptine and raclopride are both about two orders of magnitude weaker at D4, whereas clozapine is one order more potent at D4, as compared with D2 and D3. The human dopamine D4 receptor has many variants. The sensitivities to clozapine of human variants D4.2, D4.4, and D4.7 are approximately similar, with dissociation constants between 5 and 24 nM, matching the spinal fluid concentration of clozapine under therapeutic conditions. Thus antipsychotic action may be effected through blockade of either dopamine D2 or D4 receptors.
The rapid pace of discovery in the molecular biology of glutamate receptors includes advances concerning the N-methyl-D-aspartate receptor. New information emerging in this area is already affecting the study of epilepsy in animal models and provides novel opportunities to extrapolate directly to human disease through isolation and chromosomal localization of human glutamate receptor genes. These discoveries are being exploited for improved understanding and treatment of human epilepsy.
Recent progress in human neurogenetics has led to the discovery of new modes of inheritance and disease expression, including 1) stably inherited duplications in Charcot-Marie-Tooth disease type 1a, 2) dynamic mutations in fragile X syndrome and myotonic dystrophy, and 3) identical mutations with different phenotypes in fatal familial insomnia and Creutzfeldt-Jakob disease. The mechanisms by which known mutations of the amyloid precursor protein lead to early-onset Alzheimer's disease remain unexplained, despite hundreds of recent studies of beta-amyloid.
Mammalian retroviruses of all three subfamilies infect the nervous system. The leukemia viruses (oncovirinae) and lentiviruses (lentivirinae, eg, human immunodeficiency virus) cause serious disease, while the foamy viruses (spumavirinae) have not yet been shown to cause any disease. This review illustrates these diseases by referring particularly to three viruses: the human and murine leukemia viruses (human T-cell leukemia-lymphoma virus type I and murine leukemia virus), and the human immunodeficiency viruses, HIV-1 and 2. Other lentiviruses cause important encephalitides in other animals, notably cats (feline immunodeficiency virus), sheep (maedi/visna virus), and goats (caprine arthritis/encephalitis virus).
Experimental allergic encephalomyelitis, a cell-mediated autoimmune disease, continues to provide interesting data on the mechanisms subserving organ-specific autoimmunity. The elements of the trimolecular complex have been further defined and the conserved molecular basis of the interaction between the T-cell receptor and the major histocompatibility complex class II-peptide antigen complex is better understood. This model also provides new insights into the cellular interactions within the brain during the course of the autoimmune inflammatory response.
Most of the human herpesviruses have a unique relationship with the central nervous system. In this review we summarize recent developments in the establishment of viral latency, and discuss the nervous system illnesses instigated by direct viral cytopathic effect, by immune activation, and by neoplastic events. Special consideration is given to herpesvirus infections in the context of acquired immunodeficiency syndrome, and in association with neonatal infections. New diagnostic techniques and treatments are also summarized.
The treatment of Parkinson's disease is reviewed. The rationale for using selegiline (deprenyl) as the first treatment in recently diagnosed patients is presented. Selegiline delays the need for levodopa; however, it is unclear whether this results from a symptomatic or a neuroprotective effect of selegiline. Levodopa combined with a decarboxylase inhibitor is the principal treatment for patients with moderate or marked symptoms. There is little evidence that levodopa has a deleterious effect on the court of Parkinson's disease. The relationship of levodopa to dyskinesias and response fluctuations is discussed. Pharmacokinetic and pharmacodynamic studies suggest that continuous dopaminergic stimulation may be superior to intermittent pulse therapy. The best approximation to continuous stimulation is the use of long-acting levodopa-carbidopa preparations supplemented by dopamine agonists.
