Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome

We describe a novel mitochondrial ND2 mutation (T4681C) in a patient presenting with Leigh Syndrome. Biochemical analyses revealed a low isolated complex I activity in patient's fibroblasts, blood and skeletal muscle. Mutant transmitochondrial cybrid clones retained the specific complex I defect, demonstrating the mitochondrial genetic origin of the disease. The mutation leads to a L71P substitution at an evolutionary conserved amino acid stretch. By two-dimensional blue native electrophoresis (2D-BN-SDS-PAGE), decreased complex I levels were observed together with an accumulation of specific assembly intermediates, suggesting that the mutation disturbs the complex I assembly pathway.     

Magnetic resonance imaging of severe, long-term, opiate-abuse patients without neurologic symptoms may show enlarged cerebrospinal spaces but no signs of brain pathology of vascular origin

BACKGROUND: Recreational drug abuse is one of the most important risk factors for stroke in young adults. Abuse of opiates may lead to severe acute neurologic problems due to ischemia or hemorrhage. In contrast, their minor effects on brain structures are not well established. We evaluated brain magnetic resonance images (MRI) of opiate-dependent subjects who had no major neurologic symptoms or psychiatric disorder. METHODS: Seventeen opiate-dependent patients and 17 controls underwent 1.5 T MRI. Any abnormalities in signal intensity of the brain were recorded. Areas of vermis, corpus callosum, and midline internal skull surface (MISS) were measured from midline sagittal slice. To evaluate size of cortical sulci, sylvian fissures, and ventricles, axial images were compared with standard sets of reference images. In addition, bifrontal and sylvian-fissure ratios were measured. RESULTS: Only one patient had a small subcortical post-traumatic lesion; otherwise, gray and white matter showed normal signal intensities. Opiate-dependent subjects had significantly wider sylvian fissures (p=0.008, Mann-Whitney U) and larger ventricles (p=0.04) than controls. Bifrontal and sylvian-fissure ratios were significantly higher in patient group than in controls (p=0.013 and p=0.005, respectively). CONCLUSIONS: No signs of brain pathology of vascular origin were found. From the clinical point of view, we want to emphasize that in the first acute neurologic attack of opiate-dependent patients, any abnormal signal intensity in MRI is most probably associated with the patient's current situation. Sylvian fissures and ventricles were wider in opiate-dependent subjects than in controls, which may be related to brain atrophy located especially in frontal and temporal lobes.     

Refractory generalised convulsive status epilepticus : a guide to treatment

The patient with status epilepticus has continuous or rapidly repeating seizures. Generalised convulsive status epilepticus (GCSE) is the most common form of the disorder and is a life-threatening condition that requires prompt medical management. Status epilepticus that does not respond to first-line benzodiazepines (lorazepam or diazepam) or to second-line antiepileptic drugs (phenytoin/fosphenytoin, phenobarbital or valproate) is usually considered refractory and requires more aggressive treatment.The optimal treatment of refractory GCSE has not been defined, but patients should be treated in an intensive care unit, as artificial ventilation and haemodynamic support are required. Invasive haemodynamic monitoring is often necessary and EEG monitoring is essential.The drug treatment of refractory GCSE involves general anaesthesia with continuous intravenous anaesthetics given in doses that abolish all clinical and electrographic epileptic activity, often requiring sedation to the point of burst suppression on the EEG. Barbiturate anaesthetics, pentobarbital in the US and thiopental sodium in Europe and Australia, are the most frequently used agents and are highly effective for refractory GCSE both in children and adults. Indeed, they remain the only way to stop seizure activity with certainty in severely refractory cases. Other options are midazolam for adults and children and propofol for adults only.Regardless of the drug selected, intravenous fluids and vasopressors are usually required to treat hypotension. Once seizures have been controlled for 12-24 hours, continuous intravenous therapy should be gradually tapered off if the drug being administered is midazolam or propofol. Gradual tapering is probably not necessary with pentobarbital or thiopental sodium. Continuous EEG monitoring is required during high-dose treatment and while therapy is gradually withdrawn. During withdrawal of anaesthetic therapy, intravenous phenytoin/fosphenytoin or valproate should be continued (these agents having been administered during earlier phases of GCSE) to ensure an adequate baseline of antiepileptic medication so as to prevent the recurrence of status epilepticus. If additional medication is needed, the most appropriate antiepileptic drugs are gabapentin for focal seizures and levetiracetam and topiramate for all seizure types, as these drugs can be started at high doses with a low risk of idiosyncratic reactions.Even with current best practice, mortality in patients who experience refractory GCSE is about 50% and only the minority return to their premorbid functional baseline. Therefore, new treatment options are urgently needed. The ideal new drug for refractory GCSE would be one that has the ability to stop seizures more effectively and safely than current drugs, and that has neuroprotective properties to prevent the brain damage and neurological morbidity caused by GCSE.     

Ophthalmologic and neurologic findings in two children exposed to vigabatrin in utero

Vigabatrin (VGB) is an important treatment option for infantile spasms. Vigabatrin-induced visual field defects are at present the most important safety issue in the use of the drug. The knowledge concerning VGB-associated visual dysfunction in pediatric patients, particularly in those who have been exposed to VGB in utero is limited. We explored ophthalmic and neurologic findings in two children who have been exposed prenatally to VGB.     

Pharmacologic management of convulsive status epilepticus in childhood

The incidence of convulsive status epilepticus in children is approximately 20-50/100,000/year, and is an emergency requiring prompt medical intervention. Prolonged seizures lasting over 5 min are unlikely to stop spontaneously, and time-to-treatment influences treatment response. Prolonged seizures should thus be treated as early status epilepticus. Mortality and morbidity increase significantly with the length of ongoing seizure activity, especially after 60 min. Benzodiazepines remain the first-line drug therapy due to their rapid onset of action. Recent studies imply that buccal midazolam is more effective and easier to administer than rectal diazepam. Phenytoin/fosphenytoin and phenobarbital administered intravenously remain the second-line treatments of choice, whilst barbiturates and midazolam as intravenous anesthetics are used for third-line treatment. Electroencephalogram monitoring is essential to evaluate the electrophysiologic treatment response and depth of anesthesia, especially in refractory status epilepticus. In the future, more individualized protocols and pathways are needed in order to optimize treatment responses. Randomized clinical trials are needed to evaluate new treatment protocols, which should not only stop the seizures more effectively but also be safer and include some neuroprotective elements to halt the cascade of neuronal injury and minimize the risk for neurologic morbidity caused by the convulsive status epilepticus.     

APC and β-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers

Objective: The adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes are the two major components of the Wnt signaling pathway that has been shown to play an important role in the formation of certain cancers. The overactivation of the pathway, which results in abnormal accumulation of β-catenin protein in nuclei, contributes to most colorectal cancers (CRCs), both sporadic and hereditary, as well as sporadic endometrial cancers (ECs). Here, we studied the involvement of APC and β-catenin in hereditary nonpolyposis colorectal cancer (HNPCC)-related ECs, and compared the expression patterns to those in HNPCC-related CRCs. Materials and methods: Nineteen ECs and 31 CRCs derived from HNPCC patients were immunohistochemically stained with anti-APC- and anti-β-catenin –antibodies. Results: Tumor-specific loss of APC was observed in 16 of endometrial cancers (3 of 19) and in 39 of colorectal cancers (12 of 31). Consistently, the loss of APC expression was associated with nuclear β-catenin staining. Altogether, aberrant β-catenin localization was observed in 53 of ECs (10 of 19) as compared to 84 of CRCs (26 of 31) (P=0.02).Conclusion: Our results suggest a frequent overactivation of the Wnt signaling pathway in hereditary endometrial cancer. In accordance with studies on sporadic cancers, abnormal accumulation of β-catenin protein in nuclei occurred much less frequently in HNPCC-related ECs than CRCs, which may reflect organ-specific differences in their pathogenesis.     

Remodeling of neuronal circuitries in human temporal lobe epilepsy: Increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex

Neuronal loss and axonal sprouting are the most typical histopathological findings in the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epileptogenesis. Also, little is known about the plasticity outside of the hippocampus. We investigated the immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n = 25) and autopsy controls (n = 7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurite outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-NCAM immunoreactivity was increased both in the inner and outer molecular layers of the dentate gyrus, compared with controls. The intensity of PSA-NCAM immunoreactivity in the inner molecular layer correlated with the duration of epilepsy, severity of hippocampal neuronal loss, density of mossy fiber sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of infragranular immunopositive neurons was increased twofold compared with controls, whereas in TLE patients with severe neuronal loss, the infragranular PSA-NCAM–positive cells were not present. In the hilus, the somata and tortuous dendrites of some surviving neurons were intensely stained in TLE. PSA-NCAM immunoreactivity was also increased in CA1 and in layer II of the rostral entorhinal cortex, where immunopositive neurons were surrounded by PSA-NCAM-positive fibers and puncta. Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the dentate gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.     

Abnormal response recovery in the right somatosensory cortex of dyslexic adults

Somatosensory evoked fields (SEFs) to repetitive tactile stimuli were recorded from eight dyslexic and eight normal-reading adults. Three successive stimuli, produced by diaphragms driven by compressed air, were delivered to thumb, index finger and thumb in sequence, with stimulus-onset asynchronies (SOAs) of 100 and 200 ms in different runs. Both hands were stimulated alternatingly with an intertrain interval of 1 s, and the responses were recorded with a whole-scalp neuromagnetometer. Whereas the primary somatosensory cortex responses to the first stimuli of the trains did not differ between dyslexics and controls, responses to the second stimuli (and the ratios of second to first responses) were significantly smaller in dyslexic than in control subjects in the right hemisphere (differences 41 and 28% for response amplitudes at the 100 and 200 ms SOAs). The results agree with the proposed pansensory nature of temporal processing deficits in dyslexia, specifically demonstrating abnormal response recovery in the right somatosensory cortex.     

Memory and attention in newly diagnosed epileptic seizure disorder

Interictal disturbances of memory and attention were evaluated in 74 adults with newly-diagnosed untreated epileptic seizures and no other known brain pathology. In approximately 30% of the patients with cryptogenic seizures, the average memory and attention scores indicated subtle dysfunction compared with normal control group. The patients had difficulties in tasks requiring memory, sustained attention and flexible mental processing, whereas they had normal attention span, simple speed of tracking and simple psychomotor speed. The memory difficulties may be related to attentional dysfunction leading to impaired or slowed initial encoding of memory trace, and also to a deficit in storing process and hippocampal dysfunction. These findings could have important implications for establishing criteria for identifying patients who develop chronic epilepsy and who thereby would benefit from early therapeutic intervention.