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However treatment for dogs coughing and gagging purchase trimethoprim 960 mg on-line, among 504 patients who became seizure free initially for at least 1 year xcell antimicrobial wound dressing discount trimethoprim 480mg visa, seizures relapsed in 105 (21%) treatment for dogs kidney failure purchase 960 mg trimethoprim with visa, although seizure control was later regained in the majority (63 patients) (39) virus with fever discount 960mg trimethoprim with mastercard. In an observational study of 144 children with epilepsy onset in the 1960s and followed over an average of 37 years, delayed remission was observed in 50% of children and seizure relapse occurred after initial remission in 33% (53). Unfortunately the relationship with drug treatment was not detailed in the report. In a prospective cohort of 613 children, more than half with delayed intractability (defined as more than 3 years after initial diagnosis) had previously been in remission for at least 1 year, and of the 83 children with intractable epilepsy initially, 13% were in remission when last contacted (54). These observations imply that drug responsiveness in some patients can be regarded as a dynamic process rather than a permanent state. Indeed, it is likely that treatment outcome is highly dependent upon the underlying epilepsy syndromes. A notable example is mesial temporal lobe epilepsy associated with hippocampal sclerosis, for which accumulating evidence suggests a progressive course in some patients (56) but not in others (57). Of 284 patients from the cohort, 26% recalled a previous period of at least 1 year of seizure freedom since the onset of their epilepsy (25). This suggests that for some patients with temporal lobe epilepsy, medical intractability may not declare itself in the early stages of the disorder. Indeed, an initial apparently benign course seems to be one of the characteristics of this condition (58), but how often such a pattern is observed can only be accurately determined in a prospective study in which all patients with temporal lobe epilepsy are followed from the point of presentation with seizures. In the Glasgow cohort, newly diagnosed patients with underlying hippocampal sclerosis differed little in outcome from those with other localization-related epilepsies (38). Clearly, since epilepsy is not a single disease, syndrome and etiology-specific prospective prognostic studies are needed if individual patients are to be managed more appropriately. Operational Definition A pragmatic, unambiguous operational definition of medical intractability constituting the essential elements discussed above is needed in order to apply treatment rationally. The definition requires that the medication is failed despite being used at its clinically effective dose, that is, treatment failure is due to lack of efficacy instead of other reasons, such as an idiosyncratic reaction, and that the seizure-free period should be at least 1 year or 3 times the pre-treatment inter-seizure interval, whichever is longer. Fulfillment of the operational definition of medical intractability should prompt a comprehensive review of the diagnosis and management, preferably by an epilepsy center where epilepsy surgery may be offered as a therapeutic option. Pediatric Issues the timing of epilepsy surgery in children is further complicated by the need to consider the potential consequences of the insults from repeated seizures and from surgical intervention on the developing brain (60). This issue is particularly notable and sensitive when evaluating infants with catastrophic localization-related epilepsies, who may have many Chapter 71: Issues of Medical Intractability for Surgical Candidacy 815 seizures per day. Although controlled studies are lacking, resumption of developmental progression after early surgery has been observed. For instance, Wyllie and colleagues (61) performed various forms of epilepsy surgery in 12 children with a variety of pathologies at a mean age of 15. Therefore, the decision about the timing of surgery in children is strongly affected by the severity and natural history of the specific syndrome, taking into account the potential detrimental effects of continued seizures on neural plasticity, as well as on developmental and psychosocial outcomes. In some cases of catastrophic epilepsy, surgery should be considered even earlier than 2 years of onset following thorough, individualized evaluation (62,63). To this end, there is no substitution for population-based, long-term studies following patients from the point of presentation and diagnosis (64). Whether this would be a more effective management strategy if used earlier and in what situations remain to be determined (40). Outcome studies should also address the fundamental question of what constitutes drug failure. Alternatively, should it be judged according to the individual circumstances of each drug trial Whether drug withdrawal due to intolerability should be regarded as failure in defining drug resistance has not been thoroughly explored. However, these studies and more recent data suggest that the eventual outcome is slightly more favorable if treatment failure is due to poor tolerability rather than to lack of efficacy. It is also likely that in many patients a combination of different mechanisms contribute to therapeutic failure, which may vary widely among individuals. Research during the last two decades has focused on two different major hypotheses. Although a body of experimental data supporting both hypotheses has accumulated, much work needs to be done to determine their clinical relevance, if any. The particular relevance of understanding the mechanisms of drug resistance to defining medical intractability is that biomarkers of drug response may be identified, which may have the potential to inform clinical decision making in terms of treatment approach and defining drug resistance in a more objective fashion.

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Eventually antibiotics zinc generic trimethoprim 480mg amex, all children recover over 6 months to 8 years but may be left with mild speech dysfluency or minor slowing of tongue or jaw movements antibiotics for breeding dogs purchase trimethoprim 960mg free shipping. Positron emission tomography demonstrated a bilateral increase of glucose metabolism in the opercular regions in one patient with this type of nonconvulsive status (55) antimicrobial bath rug purchase trimethoprim 960 mg otc. In addition to partial motor seizures 600 mg antibiotic buy trimethoprim 960 mg lowest price, frequent atonic, atypical absence and myoclonic seizures, often with nonconvulsive status epilepticus, as well as cognitive and behavioral disturbances are seen. Although these children ultimately have remission of their epilepsy, many are left with varying degrees of mental handicap. The medical history is usually uneventful, although 6% to 10% experience neonatal difficulties (including 3% with neonatal seizures), 4% to 5% have preceding mild head injuries, and up to 16% have antecedent febrile seizures (32). Spikes have a characteristic horizontal dipole, with maximal negativity in centrotemporal (inferior rolandic) and positivity in frontal regions (64,65). The focus is unilateral in 60% of cases, bilateral in 40%, and may be synchronous or asynchronous (32). Follow-up recordings showed shifts in foci both toward and away from the centrotemporal area. With remission, spikes disappear first from the waking record and later from the sleep recording (32). Ictal spike-and-wave discharges may show dipole reversal, with electropositivity in the centrotemporal region and negativity in the frontal area; postictal slowing is not seen. The percentage of children with rolandic sharp waves who develop clinically apparent seizures is unclear. Rolandic spikes have also been reported in children with brain tumors, cortical dysplasia, Fragile X syndrome, and Rett syndrome. Neurocognitive deficits appear to correlate with the amount and location of interictal spike discharge. Those with bilateral discharge scored the lowest overall; those with only right-sided discharge performed best. However, those with left centrotemporal discharge demonstrated bihemispheric representation of language, raising the possibility that focal epileptic activity may alter cerebral mechanisms that underlie cognitive functioning. Weglage studied 40 righthanded children with rolandic spikes (20 with and 20 without seizures) (88). Neuropsychological deficits were not related to presence or absence of seizures, seizure frequency, lateraliza- tion of the rolandic focus, or time since diagnosis, but higher spike frequency correlated with greater deficits. In a study of academic performance in 20 children with rolandic epilepsy, Piccinelli found greater cognitive difficulties in those with seizure onset before age 8 years and those with greater activation of epileptiform discharge during sleep (89). Prospective studies (80,90,91) have shown that, like the seizures and epileptiform discharges, the cognitive difficulties also appear to resolve with time. Because they appear to correlate with the amount and side of interictal spike discharge, these discharges may cause "transient cognitive impairment. The latter finding may indicate maturational delay with defective myelination, but the hippocampal changes were unexplained. A no-medication strategy is reasonable for the majority of children who have infrequent, nocturnal, partial seizures. If recurrent generalized or diurnal seizures occur, or if the seizures are sufficiently disturbing to the child or the family, treatment is generally started. However, treatment does not necessarily relieve parental anxiety or monitoring (96). Short intervals between the initial seizures and younger age at onset predict higher seizure frequency. In a child who presents with status as their first manifestation of rolandic epilepsy, abortive therapy with benzodiazepines is a reasonable therapeutic option.

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Children with this Chapter 32: Epilepsy in the Setting of Inherited Metabolic and Mitochondrial Disorders 387 disorder have acquired microcephaly and seizures characterized by intractable infantile spasms bacterial growth discount 480mg trimethoprim overnight delivery, generalized atonic and myoclonic seizures virus fall 2014 960mg trimethoprim amex, and focal motor seizures antibiotics low blood pressure cheap trimethoprim 960mg online. The latter presents with progressive motor deterioration virus reproduction order trimethoprim 960mg otc, schizophrenia-like psychiatric symptoms, and recurrent strokes; seizures are uncommon. Homocystinuria and elevated serum concentrations of homocysteine with reduced or normal serum methionine are the main biochemical features. Dietary supplementation with folic acid, betaine, and methionine has proven beneficial. In the acute setting, high-dose methionine has been effective in stopping seizures (45). Convulsions are frequent and are predominantly generalized, although myoclonic seizures with hypsarrhythmia have been reported. Diagnostic laboratory findings are megaloblastic anemia, homocystinuria, decreased methionine, and normal folate and cobalamin concentrations in the absence of methylmalonic aciduria (45). This disease is tested for in the neonate in certain states via expanded newborn screening and can often be treated prior to symptom onset. As this enzyme links biotin to four carboxylases in the mitochondria and one in the cytosol, an inactivity of all carboxylases results. Although rare, this condition is very important to recognize because prompt treatment with biotin may result in dramatic improvement. Laboratory findings demonstrate ketoacidosis and a characteristic pattern on organic acid analysis. Electrographically, a burst-suppression pattern or multifocal spikes are observed. Late-Onset Multiple Carboxylase Deficiency (Biotinidase Deficiency) this disease is also screened for in certain states via expanded newborn screening. When not diagnosed early, seizures are a prominent feature occurring in 50% to 75% of affected children. Symptoms often begin at 3 to 6 months of age, with hypotonia and developmental delay. As the disease progresses, ataxia, optic atrophy, and sensorineural hearing loss develop. Diagnosis is typically made via abnormalities in urine organic acid and plasma acylcarnitine analysis. Biotinidase enzyme activity can be measured in leukocytes and cultured fibroblasts. As this is a treatable condition, screening followed by a therapeutic trial with high-dose oral biotin should be considered in infants with developmental delay and persistent seizures of unknown etiology (2). Depletion of cerebral creatine due to inborn errors in synthesis or transport leads to a progressive encephalopathy and epilepsy. Development can be delayed from the beginning or after a regression beginning between 3 months and 2 years of age. Other clinical features may include dystonia, dyskinesias, microcephaly, and autistic behaviors (48). A mild form presenting with severe speech delay, mild autism, and infrequent seizures has also been identified (49). Diagnosis is typically via quantifying urine, plasma, and/or spinal fluid guanidinoacetate and creatine. Supplementation with creatine monohydrate (350 mg/kg per day to 2 g/kg per day) has led to improvement in affected individuals though not in patients with creatine transporter disorders (46). Menkes Disease (Kinky Hair Disease) An X-linked disorder of copper absorption, Menkes disease was first described by Menkes and colleagues in 1962. A characteristic twisting of the hair shaft, resulting in "kinky hair" of the head and eyebrows, is noted on microscopic examination of the poorly pigmented hairs. Affected boys may be premature and may have neonatal hyperbilirubinemia or hypothermia. Progressive neurologic deterioration with spasticity is present by 3 months of age, and children may have associated bone and urinary tract abnormalities as well. Seizures are a prominent feature in Menkes disease, with intractable generalized or focal convulsions.

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While ictal capture is the most accurate noninvasive method to define the seizure focus virus 7th grade science purchase trimethoprim 960 mg free shipping, caution must be exercised for parietal and occipital foci where the ictal data may be falsely localizing (29 virus protection for ipad purchase trimethoprim 960mg fast delivery,30) virus morphology trimethoprim 480mg overnight delivery. Consistent unifocal interictal epileptiform discharges are a strong predictor of good surgery outcome for both lesional and nonlesional epilepsies (31) sinus infection 9 months pregnant purchase 960mg trimethoprim. In many cases, a large epileptogenic zone necessitates the placement of intracranial electrodes for accurate localization, though advances in neuroimaging have reduced the need for invasive monitoring. Frontal lobe epilepsies are especially problematic as up to 29% of pediatric cases reportedly demonstrate no anatomic abnormality (39). The techniques are often complimentary with each having distinct advantages and disadvantages. Unfortunately, there are no clear guidelines on which patients benefit from these studies and thus clinical practice varies widely among epilepsy surgery centers. Epileptogenic regions may show relative hypometabolism though the cause of this hypometabolism is poorly understood. The region of hypometabolism often extends beyond the epileptogenic zone and limits its specificity (48,49). Ictal hyperperfusion helps differentiate temporal and extratemporal epilepsy, confirms suspected epileptogenicity of a structural lesion, and guides placement of intracranial electrodes. It shows concordance with intracranial localization in 74% of cases (58) and identifies the ictal-onset zone rather than areas of propagation (59). Pediatric studies have shown sensitivities of 70% to 85% for frontal lobe localization but nocturnal and brief events pose logistical challenges (52,63). Invasive Electrophysiology Intrinsically epileptogenic lesions such as cortical malformations often exhibit near-continuous epileptiform activity on electrocorticography which can be used to guide the cortical resection (67,68). Chronic intracranial recordings utilize a variety of electrodes including subdural grids, strips, and depth electrodes. Depth electrodes require strategic placement and have limited ability to sample widespread convexity and basal cortical surfaces. When epilepsy is nonlesional or poorly localized, subdural monitoring provides accurate localizing information. Even for widespread epileptogenic zones, implantation yields valuable information about its borders. Children with intractable epilepsy often have multifocal or multilesional epileptiform abnormalities necessitating implantation of subdural electrodes. Functional Mapping Functional mapping is employed for resections of the central region, dominant inferior frontal cortex, dominant posterior temporal, parietal or occipital lobe, and can be employed in very young children using modified paradigms (72). Direct cortical stimulation also reveals aberrant regions of critical cortex owing to redistribution in regions of cortical dysplasia (73). Primary motor cortex may be mapped to define the boundaries of frontal lobectomy or paracentral corticectomy. Neocortical temporal and parietal resections may necessitate receptive language mapping depending on language lateralization and the posterior extent of the proposed resection. Neuropsychological Evaluation Formal neuropsychologic assessment serves as a baseline to identify specific deficits associated with the epileptogenic region, but often fails to lateralize dysfunction in pediatric cases. Older children and adults demonstrate discrepancies in verbal and performance intelligence quotients, memory deficits, or language lateralization. For extratemporal surgeries, the major pathologies at the Cleveland Clinic (74) were cortical dysplasia (38%), tumors (28%), remote infarct/ischemic lesions (18%), and vascular malformations (3%), while 17% had no pathological substrate and 26% of tumors had coexistent cortical dysplasia. The most common non-neoplastic focal lesions were glioneuronal and vascular malformations. The most common etiologies in the perirolandic region are neoplastic (50%), vascular (15%), cortical dysplasia (12%), and Rasmussen encephalitis (6%) (75). Taylor type 2 lesions are associated with focal thickening of cortex and blurring of the gray-white junction. Type 2b frequently shows increased signal intensity extending from the cortex to the ventricular surface. Tubers are classically multiple and bilateral but partial seizures are often attributable to a single epileptogenic tuber (83,84). Tumors Brain tumors account for 15% to 30% of patients undergoing epilepsy surgery for neocortical epilepsy (17,88).

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