Multiple sclerosis

Multiple sclerosis is an inflammatory demylinating disease directed at the brain and spinal cord characterized by lesions that are due to the perivascular infiltration of monocytes and lymphocytes into the brain parenchyma, brain stem, optic nerve, and spinal cord. There is evidence that its etiology might be viral in origin but the data are inconclusive. The resulting demyelination leads to impaired nerve signaling and subsequent impairment in vision, sensation, movement, and cognition. Multiple sclerosis lesions tend to be focal, and therefore the symptoms are often discretely tied to a particular body region, and multiple symptoms may occur in a single patient. Multiple sclerosis primarily affects adults, with a typical age of onset between 20 and 50 years. An estimated 300 000 individuals in the USA are afflicted with multiple sclerosis. While a relationship between multiple sclerosis risk and latitude exists in North America, Australia, and New Zealand, this is not consistent. Israel, a country with a high immigration rate, has a higher incidence of multiple sclerosis than its latitude would predict. The highest rates of multiple sclerosis are found in the Orkney and Shetland Isles in the UK, and multiple sclerosis is rare in native Africans and Japanese, suggesting a genetic component, supported by association with certain HLA alleles.

Multiple sclerosis patients present with a broad array of symptoms including reduced or abnormal sensations, weakness, vision changes, clumsiness, and loss of bladder control. The diversity of initial symptoms is a reflection of the focal nature of the disease and makes accurate diagnosis a challenge. A number of signs can be assessed to help in making the diagnosis including abnormal eye movements or pupillary response, altered reflex responses, impaired coordination or sensation, and evidence of spasticity or weakness in the arms or legs. Definitive diagnosis is made by a number of tests including blood tests to rule out other possible diagnoses (e.g., Lyme disease), an examination of cerebrospinal fluid to assess the presence of elevated immunoglobulin G (IgG), and oligoclonal banding, a visual evoked potential test to determine if there is a slowing in signal conduction, and a magnetic resonance imaging (MRI) scan to assess the presence of periventricular lesions. Multiple sclerosis patients can go through remission periods that last for as long as 5 years in which the disease is relatively stable.

Glucocorticoid therapy and immunomodulatory drugs are used for the treatment of multiple sclerosis. The former include cyclophosphamide, cladribine, methotrexate, azathiopurine, cyclosporine, and interferon, the latter include Type I (IFN-a and IFN-b) and Type II (IFN-g). Glatiramer acetate, a mixture of synthetic polypeptides composed of the acetate salts of the L-amino acids glutamic acid, alanine, glycine, and lysine that are found in high abundance in myelin basic protein (MBP), reduces the frequency of relapse in patients with relapsing-remitting multiple sclerosis. It is thought to either binding directly to major histocampatibility complex (MHC) class II complexes or induce MBP-specific suppressor cells.

Natalizumab is a humanized monoclonal antibody to a4 integrin that was approved for the treatment of relapsing forms of multiple sclerosis. It has robust effects on relapse rate and lesion activity in multiple sclerosis and may affect disease progression. Following three cases of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab in combination with immunosuppressant therapy, the compound was put on a clinical hold which has now been removed following an additional assessment of the risk-benefit ratio for the use of this biological.

The overall prognosis for patients with autoimmune or neuroinflammatory disease appears good. While there is currently no drug available that will elicit a full remission or reversal of symptoms, there are a variety of choices for both palliative control of symptoms and modification of disease progression. There are significant adverse effects associated with corticosteroid, immunosuppression, and immunomodulation; however, the immunomodulators are relatively well tolerated. 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. 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. Ophthalmic agents

The eye is a key part of the CNS connecting to the brain via the second cranial or optic nerve. Many other receptors and signal transduction process in the eye recapitulate those present in the CNS proper although the cellular architecture of the eye and its function are unique (see 6.12 Ophthalmic Agents). The anterior pole of the eye, composed of the cornea, iris, and lens, serves to focus light onto the photoreceptors of the retina. The retina is a layered structure composed of retinal ganglion cells, amacrine cells, horizontal cells, and photoreceptors that transduces, processes, and integrates visual stimuli. The ganglion cells are the output neurons of the retina, sending axons to the lateral geniculate nucleus by way of the optic nerve. This highly evolved complex system allows for accurate processing of visual stimuli with an exceptional dynamic range. However, it is susceptible to multiple disorders including glaucomas and macular degeneration that ultimately can produce visual defect and blindness.

The glaucomas are a group of disease associated with elevated intraocular pressure. If left untreated, the increase in pressure produces irreversible vision loss by damaging the optic nerve. Glaucoma is the second most common cause of vision loss, and the leading cause of blindness in the USA, affecting over 3 million individuals. Glaucoma typically produces no overt symptoms until vision is irreparably lost. Fortunately, early detection is enabled by a number of facile and routine diagnostic tests such as air-puff tonometry. First-line treatment is usually with topical application of agents that reduce the secretion of aqueous humor such as ^-adrenoceptor blockers (e.g., timolol), and carbonic anhydrase inhibitors (e.g., dorzolamide), or agents that increase the outflow of aqueous humor such as prostaglandin analogs (e.g., latanoprost) and parasympathomimetic drugs (e.g., pilocarpine).

Macular degeneration is a disorder in which the macula, the cone-rich central part of the retina responsible for fine detail and color vision, degenerates. The degeneration can be either a dry form which appears as an atrophy of the retinal pigmented epithelium, or a wet form in which degeneration is caused by the leaking of choroidal neovascularizations. The disorder develops gradually and with age, and is therefore often termed 'age-related macular degeneration.' It is the leading cause of vision loss affecting more than 1.6 million individuals in the USA. Symptoms include a loss of visual acuity, blurred or distorted vision, or a loss of vision in the center of the visual field. Diagnosis is typically made by visual examination, tests of central visual acuity, and fluorescein angiography to assess neovascularization.

Until recently, treatment options were only available for wet macular degeneration and were limited to surgical approaches such as photocoagulation. Several emerging therapies show promise including, intravitreal injections of the vascular endothelial growth factor (VEGF) antagonist, pegaptanib for wet macular degeneration, or the use of high dose combination antioxidant zinc therapy to slow the progression of dry macular degeneration.

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