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By: G. Kan, M.A., M.D.

Clinical Director, Midwestern University Arizona College of Osteopathic Medicine

Classification of infantile seizures: implications for identification and treatment of inborn errors of metabolism medications requiring aims testing discount phenytoin online. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients treatment 1st line order phenytoin 100 mg without a prescription. Randomised medicine keri hilson lyrics phenytoin 100 mg lowest price, placebocontrolled study of vigabatrin as first-line treatment of infantile spasms medications bad for kidneys order phenytoin 100 mg on-line. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Topiramate: efficacy and tolerability in children according to epilepsy syndromes. Cognitive function in preschool children after epilepsy surgery: rationale for early intervention. Incidence of death in patients with intractable epilepsy during nitrazepam treatment. This epilepsy classification remains in place despite ongoing discussion and is appended to this chapter. This classification, like all other classification systems, is not without its shortcomings, and new approaches have been proposed. This classification provided the major division between "partial" (focal) and generalized epilepsies. About 15 years later, a revision introduced the concept of epilepsy syndromes "defined as an epileptic disorder characterized by a cluster of signs and symptoms customarily occurring together. The primary dichotomy of these classification systems was set between localization-related (focal) epilepsies, "in which seizure semiology or findings at investigation disclose a localized origin of the seizures" (1), and generalized epilepsies, characterized by "seizures in which the first clinical changes indicate initial involvement of both hemispheres. In addition to localizing information, previous epilepsy classifications also contained etiologic information. The 1970 epilepsy classification5 further divided the generalized epilepsies into primary-those occurring in the setting of normal neurologic status, with seizures that begin in childhood or adolescence and lack any clear cause-and secondary-those involving abnormal neurologic or psychological findings and diffuse or multifocal brain lesions. It is important to differentiate between epilepsy, epilepsy syndrome, and seizure types as different entities. Individuals who have had only febrile seizures or only neonatal seizures as herein defined are excluded from this category" (7). The definition of epilepsy requires the occurrence of at least one epileptic seizure. Elements in the definition of epilepsy include history of at least one seizure, enduring alteration in the brain that increases the likelihood of future seizures, and associated neurobiologic, cognitive, psychological, and social disturbances" (8). The concept of epilepsy syndromes was introduced relatively recently (6), and epilepsy syndromes were only introduced in 1985 into the classification (3). An epilepsy syndrome is defined as "a complex of signs and symptoms that define a unique epileptic condition. This must involve more than just a seizure type: thus frontal lobe seizures per se, for instance, do not constitute a syndrome" (9). The 1970 classification5 applied the etiologic dichotomy only to generalized epilepsies because all focal epilepsies were assumed to be associated with some type of brain lesion. This neglected the idiopathic syndrome of benign epilepsy of childhood with centrotemporal spikes, and therefore the 1985 (3) and 1989 (1) revisions applied idiopathic and symptomatic to the focal epilepsies as well. The term cryptogenic was added in the 1989 (1) classification to describe epilepsy syndromes that are presumed to be symptomatic but are of unknown cause in specific patients. Discussion of the 1989 Proposal Despite its widespread use, the 1989 proposal has been criticized because of its stiff separation between "partial" and "generalized" epilepsies neglecting multiregional epilepsies and other conditions on the borderline between generalized and focal epilepsies. Furthermore the terms "idiopathic," "cryptogenic," and "symptomatic" have frequently been misunderstood and were thought to be imprecise. Additionally, this system did not accommodate the rapidly growing knowledge in the field and did not differentiate between "wellaccepted" and "controversial" syndromes (9,10).

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F: Interictal 2-[18F]fluoro-2deoxy-D-glucose positron emission tomography at 13 months showing right parieto-occipitotemporal hypometabolism medications removed by dialysis cheap phenytoin online american express. Histopathologic analysis of resected tissue revealed microscopic cortical dysplasia symptoms nerve damage generic phenytoin 100 mg with mastercard, possibly as a result of disturbance of late neuronal migration at the time of the intrauterine intraventricular hemorrhage medicine prices best order phenytoin. The infant remains free of seizures 17 months after operation and has made "catch-up" developmental progress treatment centers for depression buy 100mg phenytoin mastercard. Epilepsy surgery in the setting of periventricular leukomalacia and focal cortical dysplasia. In adolescents and adults, the main goals are usually related to driving, independence, and employment, and their achievement requires complete postoperative freedom from seizures. For infants and children, the goals often center on relief of catastrophic epilepsy, resumption of developmental progression, and improvement in behavior. These goals may sometimes be reached even in the absence of complete freedom from seizures. For infants and young children with many daily seizures and developmental stagnation or regression, a postoperative outcome with rare or infrequent seizures and resumption of developmental progression may be gratifying. Midline shift with bulging of anterior falx to the left and compression of the right lateral ventricle suggest a mass effect as a result of increased volume of the brain parenchyma. Dysplastic changes are diffuse, with thick and disorganized cortex, poor gray-white matter differentiation, and abnormal signal in the white matter. Even in the less-favorable-outcome group with malformation of cortical development, 68% of patients in the Cleveland Clinic series had few or no seizures after surgery (3). Developmental delay is common in pediatric epilepsy surgery candidates, especially infants. Duchowny and associates noted normal preoperative development in only 20% of infant candidates for epilepsy surgery, whereas the remainder had moderate (52%) or severe (28%) delay (1). Postoperatively, the developmentally normal infants remained normal after surgery, whereas the severely delayed infants remained severely delayed. Parents reported cognitive and social gains in children with seizure-free outcome, although these were difficult to appreciate on examination (1). In a series of infants who had epilepsy surgery at the Cleveland Clinic (49), the developmental quotient indicated modest postoperative improvement in mental age. Developmental status before surgery predicted developmental function after surgery, and patients who were operated on at younger age and with epileptic spasms showed the largest increase in developmental quotient after surgery (49). These results suggest that early surgery for refractory epilepsy may offer an opportunity for improved developmental outcome. Early surgical intervention may reduce this risk, but quantitative and prospectively collected data are scant. Asarnow and colleagues studied results of the Vineland assessment in 24 patients with infantile spasms who underwent focal cortical resection or hemispherectomy at a mean age of 21 months (53). Raw scores 2 years after surgery increased significantly compared with preoperative levels, although only four children had a normal rate of development. Presurgical Assessment of the Epilepsies With Clinical Neurophysiology and Functional Imaging. Surgery within the first year of life may therefore maximize developmental outcome by allowing resumption of developmental progression during critical stages of brain maturation (53). A more recent study (54) on cognitive outcome of hemispherectomy in 53 children who underwent presurgical and postsurgical testing reported moderate cognitive and behavioral improvement in most patients. The most significant predictor of cognitive skills after surgery was etiology, with dysplasia patients scoring lowest in intelligence and language but not in visual-motor skills (54). At the advent of epilepsy surgery, Falconer urged that adolescents be considered for operative treatment before the end of secondary school so that they could pass more normally through the maturational stages of early adulthood (13).

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Paradoxical lateralization of parasagittal sharp waves in a patient with epilepsia partialis continua medications given im purchase phenytoin with american express. Two types of febrile seizures: anoxic (syncopal) and epileptic mechanisms differentiated by oculocardiac reflex medicine vs dentistry purchase phenytoin 100 mg with amex. Multifocal independent spike syndrome: relationship to hypsarrhythmia and the slow spike-wave (Lennox-Gastaut) syndrome treatment 5th finger fracture phenytoin 100 mg discount. Commission on Classification and Terminology of the International League against Epilepsy treatment water on the knee buy discount phenytoin online. Electroencephalography: Basic Principles, Clinical Applications and Related Fields. As more diagnostic and treatment modalities became available, the resulting confusion pointed to the need for a widely accepted system. In light of still unresolved issues and controversies, however, the Commission is further revising this seizure classification system (14). Consciousness during a seizure may be difficult to determine and offers little localizing information because seizures with or without loss of consciousness may arise from any region of the brain. A classification system encompassing a broad range of seizure symptomatology would be especially valuable to neurologists evaluating patients for epilepsy surgery because convergence of data from different lines of testing is key to localization of the epileptogenic zone. Recently, it has become clear that a strict one-to-one relationship between electroclinical syndromes and the corresponding epilepsy syndromes does not exist. These observations suggested a strong correlation between the clinical characteristics of seizures and the underlying epileptic process. Continued research identified various electroclinical syndromes whose correct identification was considered essential for the correct diagnosis and management of a patient with epilepsy. This 134 Chapter 10: Classification of Seizures 135 were previously often found only on histopathologic analysis. Whereas focal epilepsy in children, adolescents, and adults tend to present with features commonly associated with focal epilepsies-for example, auras and clonic jerking of one extremity-infants with focal epilepsy frequently only exhibit subtle focal motor signs or symmetric tonic movements commonly thought to be associated with generalized epileptogenicity (18,19). This system, which has been used at selected epilepsy centers for more than 10 years, and has been slightly modified since its first publication in 1998, has several advantages. This system recognizes that seizure symptomatology alone provides limited information about the best choice of antiepileptic drugs, prognosis, and other therapeutic considerations. Seizures characterized by sensory or psychic disturbances without loss of consciousness or other features are called auras; seizures in which the most prominent feature is an alteration or loss of cognitive functions. In simple motor seizures, unnatural and apparently involuntary motor movements are similar to those elicited by electrical stimulation of the primary motor areas. In complex motor seizures, relatively complicated movements simulate natural movements but are inappropriate for the situation ("automatisms"). The term "complex" here does not mean that the patient loses awareness during the seizures, although impaired consciousness is common. Complex motor seizures may be further subdivided into (1) automotor seizures with repetitive oral or gestural automatisms (often seen in temporal lobe epilepsy); (2) hypermotor seizures with violent proximal movements (frequently seen in seizures arising from mesial or orbitofrontal regions); and (3) gelastic seizures with inappropriate laughter, typically seen with hypothalamic hamartoma. Dyscognitive seizures are subdivided into dialeptic seizures (predominant loss of consciousness) and delirious seizures (predominant confusion or emotional alteration, disordered thinking). Knowledge of the focal or generalized nature of the epilepsy is not required for this classification. The neutral but unfamiliar term "dialeptic" was proposed to avoid confusion with the traditional use of "absence" as an electroclinical syndrome. Seizures that do not fit into any of the four categories mentioned above are classified as special seizures.

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Consequently medicine while breastfeeding generic phenytoin 100mg line, diagnoses may be made by those with only minimal expertise in the field (26 the treatment 2014 online order phenytoin 100 mg,27) symptoms enlarged prostate buy phenytoin 100mg without a prescription. Estimates of misdiagnosis rates suggest that over one fifth of persons with a diagnosis of epilepsy may be misdiagnosed (28 treatment yeast uti quality phenytoin 100mg,29). Re-evaluation of initial diagnosis of epilepsy in epidemiological studies report rates of 23% (30,31) with diagnostic doubt among patients diagnosed by neurologists and nonspecialists reported at 5. Epidemiological studies that rely on medical registers for case ascertainment provide valuable insights into levels of misdiagnoses. In fact, approximately 7% of patients were given an epilepsy diagnosis on the basis of one seizure. Primary care registers, a common source of case ascertainment in epidemiological research, have also been found to include persons incorrectly diagnosed with epilepsy. Following the epileptologic evaluation 30% of established and suspected cases were identified as not fulfilling the diagnostic criteria for epilepsy. Unsurprisingly, there has been a call for a gold standard diagnostic criterion to distinguish epileptic seizures from other diagnoses with similar clinical features (28). In addition to the determination of whether someone has epilepsy, adequate information is needed to identify the specific form of epilepsy and its underlying cause. While this level of detail is frequently absent from traditional epidemiological studies, it must be incorporated in the future if epidemiological studies are to continue to inform scientific and clinical endeavors relevant to epilepsy as it is understood and treated today. Without a meaningful diagnostic evaluation, epidemiological studies can do little more than provide an approximate head count which previous work has shown to be rather error-prone. The lumping together of highly diverse disorders that share the diagnostic label "epilepsy" also limits the ability of epidemiological studies to provide meaningful prognostic information. Other case ascertainment options have been employed by epidemiologists, each having its own unique challenges. Screening questionnaires, for example, are a common tool used in epidemiologic studies. In the second phase, these positive cases are evaluated clinically to confirm the presence of epilepsy. The screening tool reported sensitivity and specificity at 96% and 98%, respectively. This screening tool also reported acceptable levels of sensitivity and specificity at 95% and 80%, respectively. Chapter 1: Epidemiologic Aspects of Epilepsy 5 Screening tools are also advocated by the World Health Organisation, whose "Global Campaign against Epilepsy" supports those undertaking epidemiological research in resource-poor countries. Demonstration projects managed under this program, in addition to assessments of local knowledge, attitude and health service provision, undertake epidemiological door-to-door studies to determine prevalence estimates. Other case ascertainment sources used in epidemiological studies include prescription databases recording anti-epilepsy drug usage. By definition, these epidemiological studies estimate "treated epilepsy" and are more common in developed countries where the treatment gap is minimal. Prescription databases have been found to offer a suitable means by which the prevalence of epilepsy can be determined in community samples (42) as the coverage of the databases is typically far broader than medical registers. A potential source of bias in identifying persons with epilepsy from prescription databases is that cases cannot be clinically validated (43,44). This bias is magnified in situations where diagnosis is not recorded on the database and where "estimates" of drug use among people with epilepsy are applied (45,46). While anti-epilepsy drugs have been previously identified as "tracers" of epilepsy due to their chronic and highly specific usage (46) the growing use of anti-epilepsy medication for indications other than epilepsy, such as pain, migraine, bipolar disorders, agitation, hormonal imbalance, and weight reduction must now be considered. In general, reliance on prescription data alone is an inadequate case ascertainment method for epilepsy. A methodology for case ascertainment that is becoming more frequently used in North American studies is the selfreport survey. The Canadian Health Survey, for example, was completed by over 130,000 persons, all of whom were questioned as to their health status, health care utilization, and determinants of health (47). The California Health Interview Survey 2003 provided similar data on over 41,000 persons (50).

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Early myoclonic epilepsy treatment plantar fasciitis order phenytoin 100mg visa, West syndrome symptoms bronchitis cheap phenytoin 100mg mastercard, and progressive myoclonus epilepsy are three well-recognized epilepsy syndromes in which there is a high likelihood of an inborn error of metabolism symptoms syphilis purchase phenytoin online pills. In other instances symptoms 5 dpo buy 100 mg phenytoin, metabolic and mitochondrial diseases can masquerade as forms of cryptogenic epilepsy. Once the etiology is established, the epilepsy classification will change to symptomatic, generalized epilepsy caused by a specific disorder. In the organization of this chapter, we group the various disorders first by their age at onset (early infancy or later infancy and childhood onset) followed by the metabolic process or organelle affected. We also review the appropriate screening tests that may be performed, where applicable, followed by more definitive diagnostic procedures. Symptoms typically involve variable and fluctuating levels of psychomotor retardation, convulsions, microcephaly, swallowing difficulties, truncal hypotonia, limb hypertonia, involuntary movements, and oculogyric crises. Glycine Encephalopathy (formerly Nonketotic Hyperglycinemia) In this autosomal recessive inborn error of amino acid metabolism, large amounts of glycine accumulate in the body, especially the brain, because of a defect in the multienzyme complex for glycine cleavage. The enzyme system is confined to the mitochondria and is composed of four protein components (designated P, H, T, and L), three of which have a gene identified. The majority of cases present within the first 48 hours of life with lethargy, respiratory difficulties, apnea, and seizures that are often myoclonic or characterized as infantile spasms. Ohtahara syndrome is thought by some authorities to be more commonly associated with structural abnormalities and not as highly associated with errors of metabolism (2). Later onset forms of this disease have also been described, with patients having varying degrees of epilepsy, retardation, and movement abnormalities. An adolescent/adult onset Chapter 32: Epilepsy in the Setting of Inherited Metabolic and Mitochondrial Disorders 385 form presents with associated spastic paraparesis and optic atrophy (5). Because benzoate treatment may deplete carnitine levels, carnitine supplementation is recommended when benzoate is used (9). Strychnine, a glycine antagonist, and diazepam have been reported to blunt seizures, but have not influenced the long-term outcome (10). Even when treated, death often occurs within the first few months to years of life (11). In this condition, glycine concentrations normalize between 2 and 8 weeks of life, and prognosis is favorable (12). Other symptoms include varying degrees of ataxia, hypotonia, speech delay, and mental retardation. A movement disorder with hyperkinetic movements, choreoathetosis, dystonia, and myoclonus can be seen with earlier onset, more severe disease. Thus, one must ensure that the lab processing the specimen is monitoring for this ion. Vitamin and Mineral Metabolism-Related Diseases Pyridoxine (and Folinic Acid) Responsive Epilepsy In pyridoxine responsive epilepsy, refractory seizures typically develop within the first several days of life. These may be characterized by infantile spasms or have a variety of partial, myoclonic, and atonic features. Atypical presentations include a later onset of seizures, seizures that initially respond to treatment and then become intractable, and seizures with only a partial initial response to pyridoxine. Pyridoxine plays several critical roles, including the conversion of levodopa to dopamine and glutamate inactivation via glutamic acid decarboxylase. Previously it was believed that folinic acid responsive epilepsy was a rare yet separate metabolic epileptic encephalopathy with a diagnosis made by identifying a characteristic peak of a yet unknown compound in spinal fluid neurotransmitter analysis (25). Typically there is a pre- or perinatal onset of symptoms including congenital microcephaly, intractable seizures, spastic quadraparesis, and profound cognitive delays. Plasma serine and glycine levels may only be low in fasting specimens but are not reliable indicators as they may also be normal (14). In evaluating these patients, plasma, urine, and spinal fluid levels of pipecolic acid may also be elevated though this chemical is not a reliable biomarker (28). The characteristic peak of this yet unidentified compound is found when spinal fluid neurotransmitter testing is run. Onset of disease may extend beyond the newborn period, making this disorder a consideration in older infants with refractory seizures as well (29,30).

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