Showing papers in "Current Treatment Options in Neurology in 2008"

The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses

Abstract: The ketogenic diet is well established as therapy for intractable epilepsy. It should be considered first-line therapy in glucose transporter type 1 and pyruvate dehydrogenase deficiency. It should be considered early in the treatment of Dravet syndrome and myoclonic-astatic epilepsy (Doose syndrome). Initial studies indicate that the ketogenic diet appears effective in other metabolic conditions, including phosphofructokinase deficiency and glycogen osis type V (McArdle disease). It appears to function in these disorders by providing an alternative fuel source. A growing body of literature suggests the ketogenic diet may be beneficial in certain neurodegenerative diseases, including Alzheimer disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In these disorders, the ketogenic diet appears to be neuroprotective, promoting enhanced mitochondrial function and rescuing adenosine triphosphate production. Dietary therapy is a promising intervention for cancer, given that it may target the relative inefficiency of tumors in using ketone bodies as an alternative fuel source. The ketogenic diet also may have a role in improving outcomes in trauma and hypoxic injuries.

Treatment of Susac's Syndrome

Abstract: Susac’s syndrome (SS) consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO), and hearing loss. It usually affects women aged 20 to 40, but men are also affected, and the age range extends from 9 to 72 years. It tends to be unrecognized, even in major academic centers. The complete triad may not be present at the onset, which makes diagnosis more difficult. However, since this disorder is treatable, early diagnosis is important.

Treatment of paroxysmal sympathetic hyperactivity

Abstract: Episodes of paroxysmal sympathetic hyperactivity, sometimes referred to as autonomic storms, are not uncommon in patients with severe traumatic brain injury. Their distinctive characteristics include fever, tachycardia, hypertension, tachypnea, hyperhidrosis, and dystonic posturing. The episodes may be induced by stimulation or may occur spontaneously. Their pathophysiology has not been fully elucidated, but the manifestations clearly indicate activation or disinhibition of sympathoexcitatory areas. These spells are often confused with seizures, leading to unnecessary treatment with antiepileptic drugs. General principles in the management of paroxysmal sympathetic hyperactivity include adequate hydration, exclusion of mimicking conditions (infection, pulmonary embolism, hydrocephalus, epilepsy), effective analgesia, and avoidance of triggers, when identified. The most useful pharmacologic agents are morphine sulfate and nonselective β-blockers (eg, propranolol). Intrathecal baclofen may be effective in refractory cases. Bromocriptine and clonidine are helpful in some patients, but their efficacy is less consistent. Early recognition and adequate treatment of paroxysmal sympathetic hyperactivity is important to avoid prolongation of the patient’s stay in the intensive care unit and to enable recovering patients to participate without restrictions in rehabilitation therapy.

Allergy: A Risk Factor for Suicide?

Abstract: The rates of depression, anxiety, and sleep disturbance (suicide risk factors) are greater in patients with allergic rhinitis than in the general population. The rate of allergy is also greater in patients with depression. Preliminary data suggest that patients with a history of allergy may have an increased rate of suicide. Clinicians should actively inquire to diagnose allergy in patients with depression and depression in patients with allergy. Spring peaks of suicide are highly replicated, but their origin is poorly understood. Preliminary epidemiologic data suggest that seasonal spring peaks in aeroallergens are associated with seasonal spring peaks in suicide. Our research in Brown Norway rats demonstrates that sensitization and exposure to aeroallergens induces anxiety-like and aggressive behaviors as well as allergy-related helper T-cell type 2 (Th2) cytokine gene expression in the prefrontal cortex. Thus, it is possible that sensitization and exposure to aeroallergens, which peak in spring, may be conducive to seasonal exacerbation of suicide risk factors such as anxiety, depression, hostility/aggression, and sleep disturbance. Connecting allergy with suicide and suicide risk factors adds to previous neurologic literature connecting allergy with migraines and seizure disorders. Our recent report of Th2 (allergy-mediating) cytokine expression in the orbitofrontal cortex of suicide victims should lead to future studies to test the hypothesis that mediators of allergic inflammation in the nasal cavities may result in Th2 cytokine expression in the brain, influencing affect and behavioral modulation. Certain medications used to treat allergy can exacerbate suicide risk factors, potentially worsening suicide risk and even triggering suicide. Systemic (but not topical) corticosteroids have been associated with manic and depressive episodes and mixed mood states. Recently, the US Food and Drug Administration started investigating the possibility that montelukast may trigger suicide. Although this association requires further exploration and confirmation, clinicians should err on the side of caution, inquiring about past suicide attempts; hopelessness; reasons for living; and suicidal ideation, intent, or plan; and referring the patient to a mental health professional for evaluation if appropriate.

Sleep in children with autism spectrum disorders

Abstract: Children with autism spectrum disorders frequently have significant sleep problems, most commonly insomnia. Fortunately, a variety of treatments are available, including behavioral interventions and pharmacotherapy. When establishing a treatment plan, it is imperative to understand the underlying etiology of the sleep problem, which in many cases is multifactorial. Some sleep problems, such as suspected obstructive sleep apnea, should be referred to a sleep specialist. Identifying and treating sleep disorders may not only result in improved sleep but also may favorably affect daytime behavior and family functioning. In general, when treating insomnia, behavioral interventions should be instituted initially, followed by pharmacotherapy if needed.

Transcranial direct current stimulation for major depression: a general system for quantifying transcranial electrotherapy dosage.

Abstract: There has been a recent resurgence of interest in therapeutic modalities using transcranial weak electrical stimulation through scalp electrodes, such as trans-cranial direct current stimulation (tDCS), as a means of experimentally modifying and studying brain function and possibly treating psychiatric conditions. A range of electrotherapy paradigms have been investigated, but no consistent method has been indicated for reporting reproducible stimulation "dosage." Anecdotal reports, case studies, and limited clinical trials with small numbers suggest that tDCS may be effective in treating some patients with depression, but methods for selecting the optimal stimulation parameters ("dosage") are not clear, and there is no conclusive indication that tDCS is an effective treatment for depression. Larger, controlled studies are necessary to determine its safety and efficacy in a clinical setting. If tDCS can be established as an effective treatment for depression, it would represent a particularly attractive electrotherapy option, as it is a relatively benign and affordable treatment modality. An accurate system for describing reproducible treatment parameters is essential so that further studies can yield evidence-based guidelines for the clinical use of transcranial current stimulation. Development of appropriate parameters requires a biophysical understanding of how electrotherapy affects brain function and should include different paradigms for different clinical applications. As with any dosage guidelines, such a system does not supersede physician judgment on safety.

Update on the prophylaxis of migraine

Abstract: Migraine prophylaxis is a stepwise procedure with lifestyle advice followed by consideration of medications. Patients should be advised to try to maintain a regular lifestyle, with regular sleep, meals, exercise, and management of stress, perhaps through relaxation techniques or other ways that are sensible for them. If this regimen does not adequately control their migraines, preventatives are indicated. Patients can choose between evidence-based nutraceuticals such as riboflavin, feverfew, butterbur, or coenzyme Q10, or more traditional pharmaco-therapeutics. Medicine choices are somewhat limited by what is available in each country, but from the full range, the medicines of first choice are beta-adrenoceptor blockers, flunarizine, topiramate, and valproic acid. Beta-adrenoceptor blockers are particularly useful in patients also suffering from hypertension or tachycardia. Following recent studies, topiramate has become a first choice for episodic as well as chronic migraine. It is the only prophylactic drug that may lead to weight loss, but it is sometimes associated with adverse cognitive effects. Valproic acid and flunarizine also have very good prophylactic properties. However, valproic acid is often associated with adverse effects, and flunarizine is unavailable in many countries, including the United States. If sequential monotherapies are ineffective, combinations of first-line drugs should be tried before advancing to drugs of second choice, which are associated with more adverse effects or have less well-established prophylactic properties. Amitriptyline should be used carefully because of its anticholinergic effects, although it is useful in comorbid tension-type headache, depression, and sleep disorders. Methysergide is very effective, but it has been supplanted or even made unavailable in many countries because of its well-described association with retroperitoneal fibrosis. Pizotifen has a slightly better safety profile but is unavailable in the United States. Aspirin is particularly useful in patients needing platelet inhibitors for other medical conditions, but the risk of gastrointestinal bleeding must be considered. The prophylactic properties of magnesium, riboflavin, and coenzyme Q10 are low at best, but their lack of severe adverse effects makes them good treatment options. Magnesium may be particularly useful during pregnancy. Lisinopril and candesartan were shown to be effective in single trials and are preferable in patients with hypertension. Acupuncture may be another alternative; although controlled trials have failed to differentiate its effect from placebo, it is at least innocuous. Botulinum toxin A is not effective in the prophylaxis of episodic migraine.

Acute treatment of cerebral venous and dural sinus thrombosis.

Abstract: Management of thrombosis of the dural sinus and cerebral veins (CVT) includes treatment of the underlying condition, antithrombotic treatment, symptomatic treatment, and the prevention or treatment of complications. Intravenous heparin or subcutaneous low-molecular-weight heparin should be used in acute CVT to prevent thrombus propagation and pulmonary embolism and to increase the chances of recanalization. Anticoagulation is safe and can be used in patients with acute CVT who have intracranial hemorrhagic lesions. Endovascular thrombolysis (with or without mechanical thrombus disruption) is an experimental treatment to be used in experienced centers for severe cases or patients who fail to improve on anticoagulation. Local thrombolysis is not useful in patients with large infarcts and impending herniation. In patients with severe headache and papilledema, intracranial hypertension can be reduced and symptoms relieved through a therapeutic lumbar puncture. Hemicraniectomy may be lifesaving in patients with parenchymal lesions leading to herniation. In patients with acute seizures and supratentorial lesions, antiepileptic drugs should be prescribed. Prophylactic use of these drugs can also be considered for patients with one of these risk factors but should be avoided in patients with neither of them. To reduce the risk of recurrent deep venous thrombosis of the limbs, vitamin K antagonists are given for a variable period depending on the patient's inherent risk of thrombosis, aiming at an International Normalized Ratio of 2 to 3.5. If CVT is related to a transient risk factor (eg, pregnancy, infection), we recommend anticoagulants for 3 months. In patients with idiopathic CVT or CVT associated with "mild" thrombophilia, the period of anticoagulation must be extended to 6 to 12 months. In patients with "severe" thrombophilia (eg, two or more prothrombotic abnormalities or antiphospholipid syndrome), anticoagulants should be given for life. Patients with persistent symptoms of increased intracranial hypertension, visual loss, or both can be treated with repeated lumbar punctures or a lumboperitoneal shunt. For the prevention of remote seizures, antiepileptic drugs are recommended for patients with seizures in the acute phase and for those who experience a seizure after the acute phase. These drugs can also be considered for patients without seizures who have supratentorial hemorrhagic lesions or motor deficits.

Central nervous system histoplasmosis

Abstract: Involvement of the central nervous system (CNS) is recognized clinically in 5% to 10% of patients with progressive disseminated histoplasmosis. The risk of developing CNS histoplasmosis is increased in individuals with impaired cellular immunity, but not all patients with this condition are immunocompromised. Clinical syndromes include chronic meningitis, focal parenchymal lesions of the brain or spinal cord, stroke due to infected emboli, and diffuse encephalitis. CNS histoplasmosis should be considered in any patient with one of these syndromes who has resided in an area endemic for histoplasmosis. A high index of suspicion is necessary when extraneural signs and symptoms are absent. Culture of the causative fungus, Histoplasma capsulatum, from cerebrospinal fluid, brain tissue, or other sites is the gold standard for diagnosis. In culture-negative cases, detection of H. capsulatum antigen in cerebrospinal fluid, urine, or blood is helpful diagnostically. Aggressive and prolonged antifungal therapy is indicated in all cases of CNS histoplasmosis. There are no data from prospective comparative trials upon which to base specific recommendations for treatment. Expert opinion favors an initial course of liposomal amphotericin B, followed by at least 1 year of itraconazole.

Spontaneous intracranial hypotension: The syndrome and its complications

Abstract: Spontaneous intracranial hypotension (SIH) is a syndrome that was largely unknown until the advent of MRI. The incidence of SIH is estimated at 5 per 100,000, which is half the incidence of subarachnoid hemorrhage. The major feature is a postural headache of acute or subacute onset. This headache is absent or minimal when the patient is lying down and rapidly worsens to great intensity when the patient sits or stands. Other features may include nausea, vomiting, vertigo, tinnitus, and marked exacerbation by Valsalva maneuver. SIH is due to a leak of cerebrospinal fluid from a tear in the dural membrane, which occurs most often at the exit zones where the cervical spinal roots leave the subarachnoid space. Other leak sites may be the vestibular system, the cribriform plate, or the pituitary fossa. If the leak continues, the brain loses buoyancy within the cranial space and sags toward the foramen magnum. This, in turn, may produce subdural hygroma or hematoma, brainstem compression, focal cranial nerve palsies, or cerebellar tonsillar herniation. The initial therapy is generally strict bed rest. If this fails, an epidural blood patch is usually successful in sealing the leak and restoring brain buoyancy. A significant minority of patients require a repeat epidural blood patch. If the blood patch fails, a surgical approach may be needed. Repair of the leak and restoration of brain buoyancy will stop the postural headache and, in most cases, will reverse the complications.

Sturge-weber syndrome: a unified pathophysiologic mechanism.

Abstract: According to a new, unifying view of the pathogenesis of Sturge-Weber syndrome and related syndromes, signs and symptoms all arise from localized primary venous dysplasia, with effects of venous hypertension transmitted to nearby areas via persisting communicating venous passageways and compensatory collateral venous channels. Port-wine stains result from a vascular disorder rather than a neural disorder. Symptoms depend upon the extent and location of the venous dysplasia. This hypothesis is supported by published data and by original observations and Doppler ultrasonographic studies of orbital venous flow in patients with the Sturge-Weber syndrome. This new understanding of underlying pathophysiology also elucidates the mechanism for tissue hypertrophy. Therapies aimed at obliterating port-wine stains to minimize the cosmetic blemish will reduce collateral venous blood-flow passageways. In some instances, this reduction may worsen blood stasis within the brain and potentially exacerbate neurologic symptoms.

Congenital Cytomegalovirus Infection: Update on Management Strategies

Abstract: Congenital cytomegalovirus (CMV) infections are underrecognized as a cause of serious morbidity in newborn infants. The era of therapeutic nihilism regarding these infections has come to an end, however, as useful therapies are now available that may modify the outcome. The infected fetus can be treated in utero, or the newborn infant can be treated when CMV is recognized in the neonatal period. Expanded screening of newborns for congenital CMV infection will make it even more important for clinicians to be aware of current therapeutic options. The most effective option for the treatment of life-threatening or sight-threatening CMV disease at any age is the nucleoside analog ganciclovir. For the newborn with congenital CMV infection, the value of ganciclovir appears to relate to its ability to preserve hearing; other improvements in overall neurodevelopmental status are inferred but remain to be proven. In the pregnant woman with primary CMV infection, the use of CMV-specific immune globulin, though still investigational, is garnering attention and may prove to be a valuable therapy.

Progressive multifocal leukoencephalopathy.

Abstract: Treatment of progressive multifocal leukoencephalopathy (PML) in a patient with exogenous immunosuppression starts with discontinuation of immunosuppressive medication. The restored host immunity will clear JC virus, the cause of PML, from the brain via cell-mediated immune mechanisms. Patients with solid-organ transplants will lose the transplanted organ, however, and patients who have auto-immune disorders may experience exacerbation of their underlying disease. These factors need to be weighed against the potentially fatal nature of PML. If the patient’s immunosupression is AIDS-related, highly active antiretroviral therapy (HAART) should be initiated if it has not previously been used. If the patient is already receiving HAART, the therapy should be changed to optimize treatment, with the goals of a nondetectable HIV viral load and normalization or near normalization of the CD4 count. For non-AIDS PML patients, daily intravenous cytosine arabinoside for 5 days can be offered if the patient is not pancytopenic and can tolerate a chemotherapeutic agent. For AIDS patients with PML or failing non-AIDS patients with neurologic deterioration, cidofovir can be considered. These therapies can be offered if neurologic stabilization satisfies the quality-of-life goals for the patient. For patients intolerant of other therapies or unsuited to them, oral mirtazapine or risperidone can be considered. The safety of these agents has been established in the treatment of psychiatric disease, but their efficacy has not yet been proven. Small interfering RNA (siRNA) therapy holds the promise of specific antiviral therapy, but delivery methods, safety, and efficacy are yet to be established.

Sydenham's Chorea.

Abstract: Sydenham’s chorea (SC) is a manifestation of acute rheumatic fever (ARF). Although the incidence of SC has declined significantly, particularly in developed areas, it remains the most common cause of acute chorea in children worldwide. Recent data show that SC accounts for almost all cases of chorea in children in the United States. As there is no specific laboratory marker of this condition, the diagnosis relies on a careful clinical history and laboratory assessment to rule out alternative causes. Morbidity is primarily related to cardiac lesions in ARF. It is recommended that all patients with suspected SC submit to a cardiologic evaluation. Neurologic features encompass motor signs, among which chorea is the most prominent, and nonmotor symptoms such as obsessive-compulsive behavior and attention-deficit/hyperactivity disorder. The first-line treatment of SC is valproic acid. Patients who do not respond to this drug or who present with severe chorea (particularly chorea paralytica, in which the muscle tone is so decreased that patients are bedridden) should be treated with risperidone. Other dopamine receptor-blocking drugs, such as haloperidol, may also be useful. There is growing evidence that immunosuppressive treatment, such as intravenous methylprednisolone followed by a tapering course of oral prednisone, is effective. This option has been used in patients who failed to respond to (or did not tolerate) the previously mentioned therapies. Plasmapheresis and intravenous immunoglobulin are regarded as experimental treatments. Obsessive-compulsive behavior associated with SC is not usually as severe as in other conditions such as Tourette’s syndrome. Finally, because at least 20% of patients with SC experience recurrent attacks of ARF, they carry a high risk of developing severe cardiac lesions. These patients require prophylaxis against streptococcus infection, using penicillin or sulfa drugs.

Long-term seizure and psychosocial outcomes of epilepsy surgery.

Abstract: Most results reported in studies focusing on long-term outcomes of epilepsy surgery resemble those reported in studies with shorter follow-up, indicating that many of the surgical results are enduring. In general, about 60% of patients with temporal epilepsy and 25% to 40% of those with extratemporal epilepsy achieve long-term seizure freedom after epilepsy surgery. Over a long term, about 20% of patients discontinue antiepileptic drugs, whereas 41% continue monotherapy and 31% use polytherapy. Evidence concerning the impact of epilepsy surgery on mortality is inconclusive, but some data support a reduction in the risk of death if patients become seizure-free. The information regarding long-term cognitive outcomes is limited but is similar to that derived from short-term studies. Decline in verbal memory occurs frequently after resections of the left temporal lobe; better memory outcomes are reported in seizure-free patients, and memory decline has been documented in patients with intractable epilepsy who do not undergo surgery. However, important confounders such as the effects of antiepileptic drugs, practice effects, and regression to the mean have not been adequately accounted for in these studies. All uncontrolled long-term studies report improved psychosocial outcomes with epilepsy surgery, including employment, education, driving status, satisfaction, and quality of life, but the results of the few existing controlled studies are less persuasive.

Treatment options for Duchenne muscular dystrophy.

Abstract: The main goal in the treatment of Duchenne muscular dystrophy (DMD) is to maintain ambulation for as long as possible and to anticipate and manage the associated complications, such as joint contractures, scoliosis, cardiomyopathy, respiratory insufficiency, and weight gain. Cognitive and behavioral symptoms occur in about one third of patients, and it is important to recognize and manage them promptly, developing an individualized plan at school and at home to maximize the patient's cognitive abilities. In the late phase of the disease, palliative care is of paramount importance. Corticosteroid therapy (prednisone and deflazacort) is the only effective pharmacologic treatment for DMD. Daily prednisone treatment increases muscle strength and function, improves pulmonary function, and significantly slows the progression of weakness. Deflazacort has a similar effect on muscle strength, but it is not available in the United States. Treatment with corticosteroid should be offered to all patients with DMD, but the beneficial effects and potential adverse effects should be fully discussed before treatment begins. The optimal dose of prednisone is 0.75 mg/kg per day, up to a maximum of 40 mg/d. If adverse effects occur, a decrease in dosage is appropriate. Monitoring of muscle function and adverse effects by a neurologist or neuromuscular specialist is strongly recommended. Physical and occupational therapists should be involved early in the treatment of patients with DMD to develop a program that includes heel cord stretching and exercise. In the later phases, these therapists can recommend adaptive equipment and maximize independence. Orthopedic consultation is important in monitoring and managing scoliosis and joint contractures in the nonambulatory phase of the disease. Pulmonary evaluation for ventilatory care is important; pulmonary consultation is essential when vital capacity declines. The use of assistive cough devices, nasal bilevel positive airway pressure, and tracheostomy must be discussed with patients and their families. For all patients with DMD, particularly those receiving prednisone, consultation with a dietitian is very helpful to control weight and maintain a healthy diet.

Sleep dysfunction in heart failure.

Abstract: Chronic congestive heart failure is a highly prevalent and progressive disorder associated with excess morbidity and mortality; it has huge economic impact. Left heart failure may be systolic or may occur as isolated diastolic dysfunction. The diastolic form predominates in older people. Sleep disorders are frequent in both types. Most systematic studies have been performed in patients with systolic heart failure. Prospective studies show the presence of obstructive and central sleep apnea, periodic limb movements, and significant alterations in sleep architecture, characterized by poor efficiency, excess stage 1 and arousals, and lack of deep sleep. Both obstructive sleep apnea and central sleep apnea occur in patients with heart failure and have been shown to be associated with excess mortality. Obstructive sleep apnea is best treated with continuous positive airway pressure (CPAP) devices. Central sleep apnea is also best treated with CPAP, but only about 50% of the patients are considered responders. Survival improves when heart failure patients are effectively treated with CPAP for both central and obstructive sleep apnea. A new positive airway pressure device, a pressure support servo-ventilator, is the next best choice for heart failure patients whose central sleep apnea does not respond to CPAP. Nocturnal oxygen should be used for patients whose central sleep apnea does not respond to positive pressure devices. Both periodic limb movements and insomnia could have adverse hemodynamic consequences for the failing heart. There are no guidelines or long-term studies regarding treatment of these conditions in heart failure. For restless legs syndrome with or without periodic limb movements, pramipexole and ropinirole have been approved. Treatment of insomnia comorbid with heart failure depends on the cause. In the absence of any known cause, a trial of ramelteon is the first choice.

Spinal muscular atrophy: Advances in research and consensus on care of patients

Abstract: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of spinal cord motor neurons and muscular atrophy. Advances in recent research have led to understanding of the molecular genetics of SMA. Therapeutic strategies have been developed according to the unique genomic structure of the SMN genes. Three groups of compounds have been identified as therapeutic candidates. One group was identified before the molecular genetics of SMA was understood, chosen on the basis of their effectiveness in similar neurologic disorders. The second group was identified based on their ability to modify SMN2 gene expression. Several of these agents are currently in clinical trials. A third group, identified by large-scale drug screening, is still under preclinical investigation. In addition, other advances in medical technology have led to the publication of a consensus statement regarding the care of SMA patients.

Treatment of complex sleep apnea syndrome

Abstract: Patients with complex sleep apnea syndrome (CompSAS) present with features of obstructive sleep apnea syndrome but demonstrate not only instability of upper airway tone (leading to classic obstructive apneas and hypopneas) but also unstable, chemosensitive ventilatory control leading to repetitive central apneas or periodic breathing during sleep. The central apneas often become most apparent after application of continuous positive airway pressure (CPAP) to alleviate upper airway obstruction; patients continue to have fragmented sleep and repetitive desaturations as a result of central apneas and hypopneas. In some patients, central apneas appear to abate over time as a result of some form of adaptation to CPAP. How often this occurs is uncertain, however, and many patients with CompSAS require treatment that combines stabilization of the upper airway obstruction with treatment of respiratory center dysfunction. Adaptive servo-ventilation, which provides both a minimum pressure to hold the airway open and a precisely calculated ventilatory assist to minimize cyclic hypoventilation and hyperventilation, has emerged as a leading treatment. Noninvasive ventilation using bilevel positive airway pressure in the spontaneous-timed mode also may regulate ventilation in some patients with CompSAS. There is anecdotal evidence that CompSAS may be successfully treated using combined PAP therapy with oxygen, carbon dioxide, or the addition of dead space, but data are not sufficient to routinely recommend these methods.

Treatment of epilepsy in the elderly.

Abstract: The elderly are the most rapidly growing segment of the population, and the incidence of epilepsy in persons over 65 is higher than in any other age group. In nursing homes, its incidence is even higher than in community-dwelling persons of similar ages. About 10% of nursing home residents are being treated with antiepileptic drugs (AEDs), with an “epilepsy/seizure” indication reported for about 7.7% of this use. Almost all elderly patients are being treated with AEDs introduced before 1978—phenytoin, carbamazepine, valproate, and barbiturates. However, age-related changes in protein binding, decreases in hepatic and renal clearance, alterations in gastrointestinal absorption, and interactions with drugs used for other conditions make the choice of the best AED difficult. AEDs that do not interact with other drugs, are not metabolized by the liver, and are readily absorbed may offer benefits for the elderly. To complicate matters, the elderly are not a homogeneous population. Today there are many AEDs to choose from, and some of the newer AEDs have more favorable characteristics than the older ones. Choice of an AED should be made on an individual basis, considering the cost of the drug, the cost of consequences of drug-drug interactions, and expenses associated with acute and chronic adverse effects. In other words, clinical skills rather than formulaic approaches are needed to match detailed knowledge of each patient’s characteristics with the properties of the various AEDs.

Use of oral contraceptives and postmenopausal hormone replacement: evidence on risk of stroke.

Abstract: Estrogen and progesterone affect endothelial function, coagulation factors, platelet function, lipids, and inflammation and have neuroprotective effects in experimental animals. Oral contraceptives containing low-dose estrogen increase the risk of ischemic stroke, but the absolute risk is low. Risk factors further increasing the risk of stroke in users of oral contraceptives include smoking, hypertension, diabetes, hyperlipidemia, migraine with aura, and thrombophilia. Progestin-only contraceptives do not increase the risk of stroke and are preferable in women with cerebrovascular disease or risk factors. Hormone replacement therapy (HRT) with estrogen alone or combined with progesterone increases the risk of ischemic stroke by 40% with no effect on hemorrhagic stroke. Stroke risk increases with the dose of estrogen. The time between menopause and the initiation of HRT does not influence ischemic stroke risk. The only indication for HRT is the treatment of vasomotor symptoms; if needed for this purpose, the lowest dose of estrogen should be used for the shortest possible duration.

Pediatric and newborn stroke

Abstract: In children, arterial ischemic stroke is more common than hemorrhage. The clinical presentation differs according to age, stroke type, and location. Seizures are more common with ischemia in children, especially in newborns. The presentation of pediatric ischemic stroke is more complex than in adults, so the clinical phenotype of ischemic stroke is modified. Risk factors for ischemic and hemorrhagic stroke include congenital heart disease, blood disorders, vasculopathies, infections (both current and preceding the stroke), and vascular malformations, but often no discernible etiology is determined. Current treatment is based on consensus rather than large, case-controlled studies. There is no strategy for primary prevention of pediatric or newborn stroke except in sickle cell disease. Most clinicians use aspirin for secondary prevention. Transfusion therapy is proven effective for secondary prevention of stroke associated with sickle cell disease. Prospective cohort studies are needed to understand the natural history of pediatric stroke and to determine which individuals are at greatest risk for incident and recurrent stroke. Effective treatment and prevention strategies can only be developed once the causes of stroke in children are understood and populations at greatest risk are identified.

Sleep disorders in Parkinson’s disease

Abstract: The sleep disturbances observed in Parkinson's disease (PD) and other parkinsonian disorders cover a wide range. The nighttime sleep disturbances include sleep fragmentation caused by recurrent PD symptoms, sleep apnea, restless legs syndrome, periodic limb movements during sleep, and rapid eye movement sleep behavior disorder. Excessive daytime sleepiness may result from these nocturnal sleep disturbances, be caused by the medications used to treat PD, or be intrinsic to PD itself. Treatment of sleep disturbances in PD is complex and often requires multiple therapeutic strategies.

Nonpharmacologic treatment of insomnia.

Abstract: Insomnia is a widespread and debilitating disorder. Regardless of the initial cause, it may assume a chronic course perpetuated by psychological and behavioral factors. Although sedative-hypnotic medications are the most common treatment for insomnia, they pose certain risks such as adverse effects and dependence. Furthermore, medications target symptoms and fail to address the underlying perpetuating mechanisms. There are many nonpharmacologic treatment options for insomnia, including cognitive/behavioral methods, relaxation strategies, and complementary and alternative medicine (CAM) approaches. Most CAM therapies lack sufficient scientific evidence to recommend their use. Over the past 30 years, cognitive-behavioral therapies have emerged as the treatment of choice for chronic insomnia. These therapies target behavioral, cognitive, and conditioning factors underlying insomnia, thereby restoring normal sleep-wake functioning. The effectiveness of these therapies is well established. They compare favorably to pharmacologic approaches, with the added benefits of few or no adverse effects and no risk of abuse or dependence. Perhaps most importantly, behavioral insomnia therapies offer a potential cure for the insomnia, instead of the symptom-focused approach provided by medications. Despite the proven success of cognitive-behavioral therapies, they are not widely available to patients with insomnia because of a paucity of behavioral sleep specialists. Efforts are now being made to disseminate these treatments to meet the demand. Emerging therapies hold promise for further refinement and development of successful treatments.

Generic antiepileptic drugs.

Abstract: Generic antiepileptic drugs (AEDs) generally provide safe, effective, lower-cost alternatives to brand-name drugs. To be approved by the US Food and Drug Administration (FDA), manufacturers must show that generic drugs are comparable to brand-name formulations, meeting bioequivalence, dissolution, and manufacturing quality standards. Bioequivalence for most generic formulations is evaluated by measuring blood pharmacokinetic values in a small, crossover study of adult volunteers taking single doses of brand-name and generic AEDs. Bioequivalence standards require that ratios of average peak drug concentrations (Cmax) and total extent of absorption (area under the curve, AUC) for a test drug be within 80% to 125% of the reference brand-name drug, with a confidence interval of 90%. Bioequivalence of most generic AEDs, however, has not been evaluated in patients with epilepsy or in other special populations such as elderly patients or patients taking multiple AEDs and prodrugs. Moreover, evidence is limited regarding the adequacy of FDA generic standards for AEDs, particularly for “narrow therapeutic ratio” medications such as oxcarbazepine, although two carbamazepine studies are supportive. Most patients can successfully initiate therapy with generic AEDs and can safely switch from brand-name to generic AEDs (and sometimes back again). The FDA, however, has not shown safety in generic-to-generic switches, which could potentially cause drug concentration changes of up to 40%. Less expensive generic formulations will soon be available for most of the “second generation” AEDs—zonisamide, for example, recently had 17 generic formulations approved in the United States—providing substantial savings in health care costs.

Neurocritical care of patients with central nervous system infections

Abstract: Bacterial meningitis and viral encephalitis are life-threatening infections with high mortality rates. Patients who survive these infections often remain permanently disabled. Potential neurologic complications requiring careful attention include impaired consciousness, elevated intracranial pressure (ICP), hydrocephalus, stroke, and seizures. Systemic complications are also common and are frequently the immediate cause of death. The importance of emergent administration of appropriate antimicrobial therapy cannot be overstated, but critical care of these patients should focus not only on treatment of the underlying infection and its immediate complications but also on minimizing secondary brain injury. Given the increasing complexity of the diagnostic and therapeutic modalities available to manage central nervous system (CNS) infections, the involvement of neurocritical care units and neurointensivists may be particularly helpful in improving outcomes. It is our opinion that ICP measurement should be strongly considered in selected patients with CNS infections, particularly those who are comatose. Treatments for intracranial hypertension, specifically in the setting of CNS infection, are described in this paper. For bacterial meningitis, intravenous dexamethasone should be administered, beginning concomitantly with the initial dose of antibiotics, at least until Streptococcus pneumoniae can be excluded as a pathogen. Clinicians should maintain a high index of suspicion for nonconvulsive seizures. Deterioration in neurologic status should also prompt early use of CT or magnetic resonance angiography and venography to exclude cerebrovascular complications.

Assessment and treatment of stroke in children.

Abstract: Pediatric stroke remains underrecognized by physicians and families despite efforts to increase awareness. Although the incidence is only 2 to 3 per 100,000 children, stroke is a significant cause of disability in childhood. Ischemic and hemorrhagic strokes occur with approximately equal frequency. How these children should be evaluated and treated has not been well studied, except for randomized, controlled trials performed in children with sickle cell disease. There are consensus guidelines for the evaluation and treatment of ischemic stroke in children but not for hemorrhagic stroke. Extrapolation from the adult stroke literature is problematic in some cases. Children should be evaluated urgently and thoroughly, as multiple stroke risk factors may be present. Treatment includes supportive care geared to reducing metabolic demands in the setting of cerebral ischemia or hemorrhage, as well as targeted therapy depending on the presumed cause of stroke and individual patient risk factors.

Sedation in the neurologic intensive care unit.

Abstract: Providing adequate sedation in the neurologic intensive care unit (ICU) depends on determination of proper goals for sedation, adequate assessment of the level of sedation, and appropriate choice of drug based on the patient's physiology. The management of sedation in the ICU will influence long-term outcome. Delirium, anxiety, and pain must be identified and treated separately. The use of protocols can improve compliance with published evidence-based recommendations. Propofol and dexmedetomidine may be used for rapidly titratable sedation, benzodiazepines for anxiolysis, neuroleptics for treatment of delirium, and opiates for analgesia. Unique aspects of patients with acute brain disease, such as elevated intracranial pressure or status epilepticus, require adaptation of sedative regimens. Processed EEG monitoring and volatile anesthetic agents have not yet proven beneficial or practical for use in the ICU.

Treatment of comorbidities of chronic daily headache

Abstract: The treatment of chronic daily headaches should focus not only on establishing an effective plan for pain therapy but also on addressing factors that may diminish progression from episodic headache toward chronic daily headache. These measures may translate into better treatment efficacy and satisfaction, as well as decrease the headache burden. Because episodic migraine progresses to chronic daily headache in some (not most) individuals, research will increasingly focus on identifying factors associated with progression, such as specific genetic and environmental risk factors, including comorbidities. Ultimately, the assessment of the migraine patient will include an evaluation of risk factors for progression. In addition to the symptom profile, evaluation will increasingly focus on comorbidities, ictal and interictal functional consequences of migraine, health-related quality of life, treatment needs, and treatment preferences. Estimation of the risk of progression will incorporate assessments of comorbidity, exposures, and eventually biomarkers. Those with high risk of progression will be more aggressively treated, not just to relieve current pain and disability but to prevent progression. Therefore, treatment will focus on decreasing current burden and preventing future burden.

Treatment of cerebellar masses.

Abstract: Cerebellar masses are a heterogenous group of conditions that can cause compression of the aqueduct or fourth ventricle, resulting in obstructive hydrocephalus, brainstem compression, and upward/downward herniation as a direct result of mass effect. Untreated lesions can be fatal in a few hours, but prompt and appropriate treatment of the mass effect can produce very good outcomes. These patients should be closely followed in a critical care setting that has rapid access to neurosurgical expertise. Medical measures to decrease brain edema should be taken, including elevation of the head of the bed and avoidance of hypo-osmolar solutions, hypercarbia, or hyperthermia. Osmotic diuretics should be initiated promptly in patients with clinical worsening and radiographic evidence of edema resulting in mass effect. However, medical measures should not delay surgical intervention, which should proceed as rapidly as possible when indicated. Cerebellar hemorrhages more than 3 cm in diameter and cerebellar hemispheric strokes involving more than one third of the hemisphere should be considered for early suboccipital craniotomy with decompression. Regardless of lesion size, neurologic deterioration and radiologic signs of obstructive hydrocephalus should call for emergency decompressive surgery with resection of hematoma or necrotic brain tissue. Ventriculostomy should be considered as a bridge to surgical decompression, given the theoretical concern of upward herniation mediated by supratentorial drainage in the face of an underlying posterior fossa mass lesion. Steroids are not indicated for cerebrovascular disease but should be used to treat vasogenic edema induced by tumor. Anticoagulation is reserved for cerebellar venous and dural sinus thrombosis. Specific treatments targeting the underlying pathology should be used aggressively: thrombolysis and endovascular interventions for eligible stroke patients, antibiotic therapy for abscesses, and radiotherapy, chemotherapy, or both for tumors.