Multiple sclerosis (MS) is postulated to be a cell mediated autoimmune disease directed against central nervous system myelin components. Our understanding of the disease has been enhanced by a number of factors: 1) advances in our understanding of the immune system; 2) clinical trials which are beginning to identify treatments which can affect MS; 3) a better understanding of the clinical features of MS; and 4) advances in MRI imaging of the brain. Based on the current state of knowledge, this paper proposes a 21 point unifying hypothesis on the etiology and treatment of the disease. This hypothesis makes a series of assumptions, many of which are unproven, and is presented as a framework from which to investigate and treat the disease, not as a established biology. It is hypothesized that the underlying pathogenesis of MS is related to an inappropriate class of immune response against myelin antigens favoring proinflammatory Th1 versus anti-inflammatory Th2 or Th3 type responses. Environmental and genetic factors predispose toward MS by affecting the class of response and effectiveness of treatment is also related to how it impacts on this common final pathway. Because of epitope spreading, there is not one autoantigen involved in MS and the progressive form of MS differs immunologically from the relapsing remitting form. Viruses trigger and perpetuate MS, although MS is not related to a persistent viral infection. Because MS is a multifactorial disease, there are clinical and perhaps immunological subtypes of MS and a single type of treatment is unlikely to control the disease in all patients. Thus, there will be responders and non-responders to each effective therapy and ultimately combination therapy will be required to cure the disease.

Topiramate is a structurally novel anti-epileptic drug with at least 3 postulated mechanisms of action including: 1) potentiation of GABA responses, 2) impairment of AMPA/kainate glutamate receptors and 3) suppression of high frequency action potential firing. It has a favourable pharmacokinetic profile with rapid absorption, good bio-availability, linear pharmacokinetics, relatively long half-life and limited pharmacokinetic drug interactions. However, topiramate can reduce the estrogen component of oral contraceptive medications. Women may require birth control preparations containing 50 (Xg of estrogen. Topiramate clearance is reduced in severe renal failure and increased by enzyme-inducing antiepileptic drugs. The dose of topiramate may have to be reduced in renal failure or when withdrawing enzyme inducers.

Oncogenic mutations resulting in activated Ras Guanosine Triphosphate (GTP) are prevalent in 30% of all human cancers, but not primary nervous system tumors. Several growth factors/receptors are implicated in the pathogenesis of malignant astrocytomas including epidermal growth factor (EGFR) and platelet derived growth factor (PDGF-R) receptors, plus the highly potent and specific angiogenic vascular endothelial growth factor (VEGF). A significant proportion of these tumors also express a truncated EGFR, which is constitutively activated. Our work demonstrates that the mitogenic signals from both the normal PDGF-R and EGFR and the truncated EGFR activate Ras. Inhibition of Ras by genetic or pharmacological strategies leads to decreased astrocytoma tumorgenic growth in vitro and decreased expression of VEGF. This suggests that these agents may be potentially important as novel anti-proliferative and anti-angiogenic therapies for human malignant astrocytomas.

In contrast to astrocytomas, where increased levels of activated Ras GTP results from transmitted signals from activated growth factor receptors, the loss of neurofibromin is postulated to lead to functional up-regulation of the Ras pathway in neurofibromatosis-1(NF-1). We have demonstrated that NF-1 neurofibromas and neurogenic sarcomas, compared to non-NF-1 Schwannomas, have markedly elevated levels of activated Ras GTP. Increased Ras GTP was associated with increased tumor vascularity in the NF-1 neurogenic sarcomas, perhaps related to increased VEGF secretion. The role of Ras inhibitors as potential therapy in this tumor is also under study.

Monotherapy has been promoted as the ideal in epilepsy treatment because of reduced side effects, absence of drug interactions, better compliance, lower cost and, in many cases, improved seizure control compared to polytherapy. The question of monotherapy vs. polytherapy has assumed increasing importance with the availability of multiple new antiepileptic drugs (AEDs), initially tested as add-on agents. The new drugs clobazam, lamotrigine, vigabatrin, gabapentin and topiramate, have also been shown to be effective as monotherapy. These data bring up the possibility of using them as first-line agents. However, a high percentage of patients with resistant epilepsy are treated with polytherapy, which probably benefits only a minority of them. The availability of multiple drugs with different mechanisms of action favours the possibility of "rational polytherapy", taking advantage of possible synergism, a yet unproven concept. This article reviews the theoretical advantages of monotherapy and monotherapy with traditional and newer AEDs.

The long-standing debate between proponents of monotherapy and those of polytherapy for treatment of epilepsy has been rekindled by the recent development of several new antiepileptic drugs. The likelihood of improved seizure control on polytherapy must be weighed against the risk of increased side effects, complex drug interactions and cost. Providing maximal seizure control while avoiding overtreatment is a challenge which requires an ongoing critical evaluation of each patient's management. This review provides a framework for decision-making by considering issues affecting the choice between monotherapy and polytherapy in five clinical situations: 1) newly diagnosed epilepsy; 2) seizures on monotherapy; 3) seizures controlled on polytherapy; 4) not controlled on polytherapy; 5) change in medical condition.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SODl) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.

The pharmacologic management of major motor status epilepticus is summarized. When general anesthesia is required, the electroencephalogram (EEG) is used for monitoring the adequacy of treatment. The EEG findings may also be important in recognizing status epilepticus and monitoring its response to treatment when this is clinically difficult, as when it occurs in comatose or pharmacologically paralyzed patients or in the context of severe brain damage. Finally, the EEG helps to clarify the nature of motor activities of uncertain basis in patients in the intensive care unit and has indicated that non-convulsive seizures or status are more common than clinically suspected in such patients.

We review forms of diaschisis and their relationship with neurobehavioral and neuropsychological findings. The following forms of diaschisis are discussed: (1) cortico-cerebellar diaschisis; (2) cerebello-cortical diaschisis; (3) transhemispheric diaschisis; (4) cortico-thalamic diaschisis; (5) thalamo-cortical diaschisis; and (6) basal ganglia-cortical diaschisis. For each form, the neurobehavioral and neuropsychological findings are discussed. Diaschisis can be classified from the behavioral point of view as follows: (1) forms in which the metabolic effect at distance is not followed by neurobehavioral impairment; (2) forms in which the remote metabolic impairment could induce neurobehavioral and neuropsychological disorders; and (3) forms in which the role of the lesion itself and its remote metabolic effects on the production of neurobehavioral and neuropsychological abnormalities cannot be disentangled.

In controlled clinical trials, topiramate (TopamaxR) has demonstrated efficacy in refractory patients with complex partial seizures and secondarily generalized tonic-clonic seizures. Approximately 45 percent of 534 patients had a ≥ 50 percent reduction in seizure frequency. Limited open label trials have shown that topiramate has broad spectrum activity and may be effective in patients with primary generalized epilepsies. The efficacy of topiramate compares very favourably with the efficacy of other new antiepileptic drugs recently introduced.

Topiramate (TPM), a new antiepileptic medication, is efficacious as adjunctive therapy in adults with partial onset seizures. Its efficacy as adjunctive therapy in children was evaluated in two randomized double-blind placebo-controlled trials involving childhood epileptic encephalopathy (the Lennox-Gastaut syndrome) and partial onset seizures. In these studies, topiramate adjunctive therapy resulted in a significant reduction in drop attacks (tonic or atonic seizures) in patients with the Lennox Gastaut syndrome and a significant reduction in partial onset seizures in children with refractory partial epilepsy. In both trials, TPM's efficacy improved as the dose escalated from the double-blind phase to the open-label portion. The minimally effective topiramate dose for adjunctive therapy in children with refractory epilepsy appears to be 6 mg/kg/day. Topiramate was well tolerated with mild or moderate side effects, predominantly related to the central nervous system. Practical tips are provided that may increase the chance that topiramate will be effective and well tolerated. The most important advice is a “start low, go slow” approach. An initial TPM dose of 0.5 - 1 mg/kg/day followed by weekly increments of 0.5 - 1 mg/kg is usually well tolerated. Based on these studies, topiramate appears to be an important addition to our pediatric AED armamentarium.

Data from clinical trials with lamotrigine indicate that the risk of serious rash in pediatric patients is higher than in adults. The incidence of rash associated with hospitalization among adults treated with lamotrigine is 0.3% and among pediatric patients 1.0%. The incidence of cases reported as possible Stevens-Johnson syndrome is 0.1% for adult patients and 0.5% for pediatric patients. These rates reflect lamotrigine dosing and concomitant AEDs used in these trials, both of which are risk factors for rash. Since many of the trials were conducted prior to the establishment of the current dosing recommendations, the incidence of serious rash in clinical trials does not necessarily reflect the incidence to be expected with use of current dosing recommendations. The higher incidence of serious rash in pediatric patients may at least partially be accounted for by the differential effects of the risk factors of dosing and concomitant use of valproic acid in these patients.