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Clinical decisions are often made in the presence of some uncertainty. Health care should be based on a combination of scientific evidence, clinical experience, economics, patient value judgments, and preferences. Seizures are not uncommon following brain injury, surgical trauma, hemorrhage, altered brain metabolism, hypoxia, or ischemic events. The impact of seizures in the immediate aftermath of injury may be a prolonged intensive care stay or compounding of the primary injury. The aim of brain injury management is to limit the consequences of the secondary damage. The original intention of seizure prophylaxis was to limit the incidence of early-onset seizures. However, clinical trials have been equivocal on this point, and there is concern about the adverse effects of antiepileptic drug therapy. This review of the literature raises concerns regarding the arbitrary division of seizures into early onset (7 d) and late onset (8 d and beyond). In many cases it would appear that seizures present within 24 hours of the injury or after 7 days, which would be outside of the scope of current seizure prophylaxis guidance. There also does not appear to be a pathophysiological reason to divide brain injury-related seizures into these timeframes. Therefore, a solution to the conundrum is to reevaluate current practice. Prophylaxis could be offered to those receiving intensive care for the primary brain injury, where the impact of seizure would be detrimental to the management of the brain injury, or other clinical judgments where prophylaxis is prudent. Neurosurgical seizure management can then focus attention on which agent has the best adverse effect profile and the duration of therapy. The evidence seems to support levetiracetam as the most appropriate agent. Although previous reviews have identified an increase cost associated with the use of levetiracetam, current cost comparisons with phenytoin demonstrate a marginal price differential. The aim of this review is to assimilate the applicable literature regarding seizure prophylaxis. The final guidance is a forum upon which further clinical research could evaluate a new seizure prophylaxis paradigm.

Background: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease., Methods: We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations., Results: Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants., Conclusions: Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.

Background: In clinical practice, mitochondrial disease is seldom considered until a variable combination of seizures, alteration in tone, muscle weakness, and developmental problems is evident. However, it is not uncommon for one symptom to occur in isolation and dominate the clinical phenotype. We report six patients from two families where dystonia was the principal clinical manifestation. A mitochondrial etiology was considered in each case because of the association of dystonia with other less prominent clinical features such as epilepsy., Methods: Histochemical and biochemical analyses were undertaken in skeletal muscle biopsies from individuals in both families. Sequencing of skeletal muscle mtDNA was also performed and suspected mutations were quantified by hot last cycle PCR-RFLP or primer extension assay. Functional consequences of one of the mutations were investigated by measurement of steady state levels of mitochondrial tRNA., Results: Two distinct mitochondrial pathologies were identified: a novel, homoplasmic mitochondrial tRNA(Cys) (MTTC) mutation and the primary, m.11778G>A Leber hereditary optic neuropathy (LHON) mutation. The mild nature of both mutations has permitted very high levels of mutated mtDNA to accumulate. Patients with the mutation in the MTTC gene have no wild type mtDNA detectable and although the LHON mutation is heteroplasmic in the patients we report, it is commonly observed to be homoplasmic., Conclusions: The mitochondrial etiology identified in these patients emphasizes the pathologic potential of homoplasmic mutations and has important implications for the investigation and genetic counseling of families where dystonia is the principal clinical feature. We advocate that mitochondrial disease should be given serious consideration in patients with familial, progressive dystonia, particularly when additional neurologic features such as epilepsy are present.

Objective: To investigate three families and one sporadic case with a recessively inherited ataxic syndrome., Methods: Clinical and genetic studies were performed in six individuals. Southern blotting and real time PCR were used to detect deletions of mtDNA and mutations in the POLG gene were identified using a combination of DHPLC and direct DNA sequencing., Results: The patients have a distinctive, progressive disorder that starts with episodic symptoms such as migraine-like headache or epilepsy. Ataxia, which is a combination of central and peripheral disease, develops later as does ophthalmoplegia. The commonest form of epilepsy was focal and involved the occipital lobes. Myoclonus was common and patients have a high risk of status epilepticus. MRI typically shows signal changes in the central cerebellum, olivary nuclei, occipital cortex, and thalami. COX negative muscle fibers were found in four of six; in one patient these were rare and in another absent. Multiple mtDNA deletions were identified in all patients, although in two these were not apparent on Southern blotting and real time PCR was required to demonstrate the defect. Two families were homozygous for a previously described POLG mutation, G1399A (A467T). One family and the sporadic case had the same two new mutations, a G to C at position 1491 (Q497H) and a G to C at 2243 (W748S)., Conclusions: Mutations in POLG cause a recessively inherited syndrome with episodic features and progressive ataxia. Characteristic changes on MRI are seen and although skeletal muscle may appear morphologically normal, multiple mtDNA deletions can be detected using real-time PCR.

Background: The increasing number of transgenic and targeted mutant mice with embryonic cardiac defects has resulted in the need for noninvasive techniques to examine cardiac structure and function in early mouse embryos. We report the first use of a novel 40-MHz ultrasound imaging system in the study of mouse cardiac development in utero., Methods and Results: Transabdominal scans of mouse embryos staged between 8.5 and 13.5 days of gestation (E8.5 to E13.5) were obtained in anesthetized mice. Atrial and ventricular contractions could be discerned from E9.5, and changes in cardiac morphology were observed from E9.5 to E13.5. Hyperechoic streaming patterns delineated flow through the umbilical, vitelline, and other major blood vessels. Diastolic and systolic ventricular areas were determined by planimetry of the epicardial borders, and fractional area change was measured as an index of contractile function. Significant increases in ventricular size were documented at each stage between E10.5 and E13.5, and the ability to perform serial imaging studies over 3 days of embryonic development is described. Finally, the detection of vascular cell adhesion molecule 1 (VCAM-1) homozygous null mutant embryos demonstrates the first example of noninvasive, in utero analysis of cardiac structure and function in a targeted mouse mutant., Conclusions: We used 40-MHz echocardiography to identify key elements of the early mouse embryonic cardiovascular system and for noninvasive dimensional analysis of developing cardiac ventricles. The ability to perform serial measurements and to detect mutant embryos with cardiac defects highlights the usefulness of the technique for investigating normal and abnormal cardiovascular development.

Although the association between celiac disease and progressive myoclonic ataxia is well recognized, in each of the reported cases the neurologic features began in middle adult life and usually in patients who had clinical or laboratory evidence of malabsorption. We report a case of progressive myoclonic ataxia and epilepsy (Ramsay Hunt syndrome) that began in childhood. In this patient there were no features suggestive of gluten intolerance. The presence of antigliadin antibodies in the serum and CSF suggested celiac disease was the cause of the patient's neurologic syndrome. Duodenal morphologic abnormalities reversed with treatment but no major changes were noted in the patient. Celiac disease should be considered in the differential diagnosis of myoclonic ataxia at any age, even in the absence of clinical evidence of gluten-sensitive enteropathy.

We report a sporadic case of chronic progressive external ophthalmoplegia that developed during childhood and was associated with ragged-red and cytochrome c oxidase (COX)-negative fibers in skeletal muscle. Sequencing of all the mitochondrial transfer RNA (tRNA) genes identified a single potentially pathogenic mutation--a T to C transition at position 4274 in the tRNA(Ile) gene. This mutation was not present in skeletal muscle from 79 controls, and the level of the mutation in COX-negative fibers was significantly greater than the level in COX-positive fibers.

The objective of this matched case-control study was to determine whether women with Même or Replicon polyurethane-covered silicone breast implants are exposed to clinically significant levels of free 2,4-TDA from biodegradation of the polyurethane foam. Urine and serum samples were obtained from 61 patients with Même or Replicon breast implants and 61 controls on two separate occasions separated by 10 +/- 3 days. Free TDA was analyzed by gas chromatography combined with negative chemical ionization mass spectrometry with lower limit of quantitation in both urine and serum of 10 pg/ml. The results were correlated with the length of time since implantation. No patients or controls had detectable free 2,4-TDA in their sera. Thirty patients had quantifiable levels of free 2,4-TDA, and 18 had detectable levels in their urine. Controls had no quantifiable levels, but 7 subjects had detectable levels. The biodegradative half-life of the polyurethane foam was estimated to be 2 years. A risk assessment using the cancer potency estimate calculated by the FDA from rat data and the National Academy of Sciences methodology provided a theoretical lifetime risk of approximately one in one million. It was concluded that the polyurethane foam cover on the Même and Replicon breast implants biodegrades. The risk assessment of approximately one in one million derived from this study strengthens earlier conclusions by the Health Protection Branch (Canada) that there is no significant risk of cancer from exposure to the 2,4-TDA formed from this biodegradation.