Stroke and nervous system trauma

Stroke, an acute syndrome of brain ischemia, a 'brain attack,' traumatic brain injury (TBI), and spinal cord injury (SCI) are acute neurological insults that have devastating consequences on both survival and quality of life (see 6.10 Stroke/Traumatic Brain and Spinal Cord Injuries) The catastrophic injury that can occur in the nervous system with the resulting disability following such insults is not due to the primary ischemic infarct, but results from the secondary cascade of biochemical events, glutamate-mediated excitotoxicity, intracellular calcium overload, and reactive oxygen species (ROS)-induced oxidative damage, which take place within the first minutes, hours, and days after the traumatic event. In stroke, when a arterial occlusion is only temporary, e.g., less than 24 h, a transient ischemic attack, recovery can be rapid.

Unlike TBI and SCI where the trauma is typically immediately obvious, stroke is an exclusionary clinical diagnosis that often occurs when the reduction in blood flow in the ischemic core has resulted in an ischemic penumbra being formed. Immediate treatment, like that in cardiac ischemia, is to restore blood flow with thrombolytic therapy, e.g., t-PA (tissue plasminogen activator) accompanied by aspirin or the P2Y12 receptor antagonists, e.g., ticlopidine or clopidogrel, both of which block platelet aggregation and prevent recurrent stroke.

The incidence of stroke in the USA approaches 700000 per year, the majority occurring in the elderly. Of these, 90% are 'ischemic' involving a thromboembolic blockage of a brain artery impairing cerebral blood flow and oxygenation, causing infarction of the brain region. The remaining 10% of strokes are 'hemorrhagic' involving intracerebral hemorrhage where blood is released into the brain parenchyma producing brain damage by triggering brain edema leading to secondary ischemia and subarachnoid hemorrhage where the blood is released into the subarachnoid space. There are about 30 000 aneurysmal subarachnoid hemorrhages and 1.5 million cases of TBI each year in the USA, and 11 000 new cases of SCI each year with an overall prevalence of 250000. Most cases of TBI and SCI occur in the second and third decades of life. Given the incidence, limited treatment options, and disabilities resulting from stroke, TCI, and SCI, there has been considerable effort over the past 20 years to identify agents that address the secondary biochemical cascade of events, including glutamate antagonists, specifically those for the NMDA receptor, calcium channel blockers, and NCEs that modulate ROS production. Without exception, these agents, that include the glutamate antagonists, selfotel, cerestat, lubeluzole, memantine, and citicholine, the GABA partial agonist, chlomethiazole, the calcium channel blocker, nimodipine, the ROS-scavengers, PEG-superoxide dismutase and the 21-amino steroid tirilazad, and the antioxidant/weak NMDA antagonist, dexabinol, failed to show consistent efficacy in controlled clinical trials. As a result while the unmet clinical need remains high, various caveats regarding the relevance of the animal models used to advance NCEs into clinical trials and the dosing regimens used have resulted in a need to restrategize approaches at the research level. Key have been the 3 h window for NCE treatment that is currently incompatible with an exclusionary diagnosis in stroke and the pre- or coadministration of NCE therapy with the traumatic insult in animal models when the human situation requires treatment post stroke, TBI, or SCI. Like trials in stroke, use of the above-mentioned agents where tested in TBI and SCI also gave negative results. The first generation of drug discovery and development efforts in neuroprotection has identified several deficiencies that must be avoided in future campaigns.

6.01.4.2.6 Epilepsy

Epilepsy describes a large class of seizure disorders in which normal patterns of neuronal activity become disturbed, leading to unusual emotions, behaviors, sensations, convulsions, muscle spasms, and loss of consciousness. Epileptic seizures can be divided into either partial (focal) or generalized seizures. Partial seizures (see 6.11 Epilepsy) occur in one part of the brain and can be either simple or complex. Simple partial seizures tend to involve sudden and unexplained sensations or emotions, while complex partial seizures typically involve a loss of, or alteration of, consciousness that may present as repetitive unproductive behaviors. Focal seizures are usually brief, lasting only a few seconds. Generalized seizures are more broadly expressed in the brain, typically involve both hemispheres, and may cause loss of consciousness, spasms, and falls. There are multiple classes of generalized seizure including absence, tonic, clonic, atonic, and tonic-clonic. Epilepsy currently afflicts over 2.7 million Americans with estimates of over 180000 new cases each year. The disorder usually becomes apparent in childhood or adolescence; however, it can develop at any time in life. In some cases, the risk of seizure has a significant impact on daily life, in particular limiting activities such as driving. Furthermore, severe or treatment-resistant seizures have been associated with reduced life expectancy and cognitive impairment.

Diagnosis of epilepsy relies on obtaining a detailed medical history that includes description of symptoms and duration of seizures. Electroencephalography (EEG) is commonly employed in the diagnosis and can provide a powerful tool to rule out disorders such as narcolepsy. In addition to verifying the diagnosis of epilepsy, the EEG can identify specific epileptic syndromes and provide a more detailed assessment of disease prognosis. Rapid diagnosis is essential since many treatments that seem to work well after the first reported seizure are much less effective once the seizures are established.

Current treatments are derived from a broad class of compounds termed antiepileptics or anticonvulsants. While effective, many of these drugs have poorly defined or multiple mechanisms of action. These drugs can be loosely grouped into four categories: blockers of voltage-dependent sodium channels (e.g., phenytoin, carbamazepine), enhancers of GABAergic transmission (e.g., BZs, tiagabine), t-type calcium channel blockers (ethosuximide), and compounds that posses either multiple or unknown mechanisms of action (e.g., valproate, gabapentin, lamotrigine, topiramate). For the most part these compounds are prescribed on the basis of type of seizure and on previous data demonstrating efficacy. For example, partial seizures may be treated with lamotrigine or carbamazepine as a front-line therapy, with the addition of tiagabine or gabapentin as an adjunct if needed. A similar front-line approach is taken for generalized tonic-clonic seizure; however, second-line treatment would include phenytoin or clonazepam. Ethosuximide is a common choice for treating absence seizure with clonazepam or topiramate used as a second-line therapy.

The prognosis for a patient diagnosed with epilepsy is good. Available drugs are efficacious; however, the efficacy varies depending on the seizure type and the individual patient. While many of the older anticonvulsants have significant side effect liabilities, the newer antiepileptic drugs have demonstrated efficacy with much more acceptable therapeutic windows. In spite of this, there are still an estimated 30% of patients who receive no or modest benefit from available treatments. These patients may, as a last resort, turn to surgical resection or vagus nerve stimulation to prevent seizure. Therefore, new compounds that are effective in these resistant patients will be a useful addition to current therapies.

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