New onset status epilepticus in older patients: Clinical characteristics and outcome.

PURPOSE: We here evaluated (1) the differential characteristics of status epilepticus (SE) in older (≥60 years) compared to younger adults (18-59 years). In particular, we were interested in (2) the proportion and characteristics of new onset SE in patients with no history of epilepsy (NOSE) in older compared to younger adults, and (3) predictive parameters for clinical outcome in older subjects with NOSE. METHODS: We performed a monocentric retrospective analysis of all adult patients (≥18years) admitted with SE to our tertiary care centre over a period of 10 years (2006-2015) to evaluate clinical characteristics and short-time outcome at discharge. RESULTS: One-hundred-thirty-five patients with SE were included in the study. Mean age at onset was 64 years (range 21-90), eighty-seven of the patients (64%) were older than 60 years. In 76 patients (56%), SE occurred as NOSE, sixty-seven percent of them were aged ≥60 years. There was no age-dependent predominance for NOSE. NOSE was not a relevant outcome predictor, especially regarding age-related subgroups. Older patients with NOSE had less frequently general tonic clonic SE (GTCSE; p=0.001) and were more often female (p=0.01). Regarding outcome parameters and risk factors in older patients with NOSE, unfavourable outcome was associated with infections during in-hospital treatment (0.04), extended stay in ICU (p=0.001), and generally in hospital (p<0.001). CONCLUSION: In our cohort, older patients represented the predominant subgroup in patients with SE. Older patients suffered more often from non-convulsive semiology and had a less favourable short-time outcome. NOSE was not a predictive outcome parameter in older patients. Data suggest that avoiding infections should have a priority because higher infection rates were associated with unfavourable outcome.

Gait instability in valproate-treated patients: Call to measure ammonia levels.

OBJECTIVE: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. METHODS: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. RESULTS: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 µmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. CONCLUSIONS: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.

Adjunctive retigabine in refractory focal epilepsy: Postmarketing experience at four tertiary epilepsy care centers in Germany.

PURPOSE: Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy. METHODS: Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012. RESULTS: A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years. CONCLUSIONS: Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

[ALS and frontotemporal dementia - case report and review of the literature]. / ALS und frontotemporale Demenz - Fallbericht und Literaturübersicht.

The occurrence of cognitive decline in amyotrophic lateral sclerosis (ALS), especially in the form of frontotemporal dementia (FTD), has been described previously. Recent molecular biology and histopathology data suggest that both ALS and FTD may share common pathological pathways and may present two phenotypes of the same proteinopathy. The underlying pathophysiological mechanism may be defective RNA- and DNA-modulation, mediated by the proteins TDP43 and FUS. These findings are suggestive of a new disease category of TDP43-proteinopathies, which include ALS, FTD and overlap syndromes. While about half of the FTD cases are associated with TDP43-deposits, tau is found in the other half. A significant clinical overlap to other tauopathies exists here as well, for instance with corticobasal degeneration. In this paper, we present a case report and review the clinical spectrum and current pathogenetic concepts of FTD.

[Concussive convulsions: seizure or no seizure?]. / Kommotionelle Konvulsionen: Epileptischer Anfall oder nicht?

Convulsions following traumatic brain injury (TBI) represent a diagnostic and therapeutic challenge. They can be differentiated into late (> 7 days after TBI), early (1 - 7 days after TBI), immediate (within the first 24 h after TBI), and impact seizures (within seconds after TBI). Some authors suggest that most impact seizures are non-epileptic in origin and hence coined the term "concussive convulsions" for benign impact seizures. Early and late post-traumatic seizures frequently indicate structural brain damage and transition to chronic, post-traumatic epilepsy. The data for impact seizures or concussive convulsions is less clear: only a small percentage of impact seizures is associated with structural brain damage and the development of post-traumatic epilepsy, rather the majority of cases are benign and associated with an excellent prognosis. Here, we present a case report as a starting point for pathophysiological and clinical considerations regarding convulsions that start within seconds after TBI.

Lentivirus Tau (P301S) expression in adult amyloid precursor protein (APP)-transgenic mice leads to tangle formation.

AIMS: In this study, we aimed to investigate the interaction between amyloid- and Tau-associated pathologies to gain further insights into the development of Alzheimer's disease. We examined the formation of neurofibrillary tangles (NFT) in adult mouse brain without the prior overexpression of Tau at embryonic or early post-natal stages to dissociate any developmental mechanisms. METHODS: Lentivirus technology was used to examine the effects of overexpressing mutant Tau-P301S in the adult mouse brains of both wild-type and amyloid precursor protein (APP)-transgenic mice. RESULTS: We find that injection of lentivirus Tau-P301S into the hippocampus of adult wild-type mice increases levels of hyperphosphorylated Tau, as early as 3 months post injection. However, no NFT are found even after 13 months of Tau expression. In contrast, the overexpression of Tau-P301S in adult APP-transgenic animals results in the formation of Gallyas-stained NFT. CONCLUSIONS: Our current findings are the first to show that overexpression of Tau-P301S in adult mice overexpressing APP, but not wild-type mice, leads to enhanced Tau-related pathology.

Chronic changes in peripheral growth hormone levels do not affect ghrelin stomach mRNA expression and serum ghrelin levels in three transgenic mouse models.

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor. Ghrelin is involved in feeding behaviour and is a potent stimulator of GH release. Chronically increased GH concentrations are known to negatively regulate the pituitary GHS receptor. This study tested whether chronic changes in peripheral GH levels/action affect ghrelin mRNA expression and circulating concentrations of ghrelin. Stomach ghrelin mRNA expression and serum concentrations of ghrelin were measured in three groups of transgenic mice and the respective control animals: group 1, GH-receptor gene disrupted mice (GHR/KO); group 2, mice expressing bovine GH (bGH); and group 3, mice expressing GH-antagonist (GHA). Ghrelin mRNA expression in the stomach, pituitary and hypothalamus of young adult male rats were measured using reverse-transcription-polymerase chain reaction. Ghrelin mRNA expression levels were approximately 3000-fold higher in rat stomach than in rat pituitary. Ghrelin mRNA expression in rat hypothalamus was below the detection limits of our assay. Stomach ghrelin mRNA expression, as well as serum concentrations of ghrelin, did not change significantly in any of the three mouse groups compared to the respective control group. These data support previous observations that the stomach is the main source of circulating ghrelin, and also indicate that stomach ghrelin mRNA expression and serum concentrations of ghrelin are not affected by chronic changes in peripheral GH/insulin-like growth factor-I levels/action.

Life extension versus improving quality of life.

There are two principal directions in ageing research: (i) the quest for understanding the mechanisms that determine the length of life and the use of such knowledge in order to find a potentially life extending treatment and (ii) the attempt to improve the quality of life in the elderly by reversing or preventing functional decline of different tissues without primarily extending life span. This chapter addresses the importance of assessing the potential impact of interventions on quality of life rather than extending life.

Impact of the GH-cortisol ratio on the age-dependent changes in body composition.

Aging is associated with a decrease in GH levels and this is paralleled by changes in body composition, i.e., increased visceral fat, and decreased lean body mass and bone mineral density. Similar changes in body composition are seen in the state of hypercortisolism. Increasing age has been shown to be associated with elevated evening cortisol levels in men. An increased exposure of several tissues to glucocorticoids with aging, i.e., visceral fat cells, in combination with the reduction of the lipolytic effects of declining GH levels, may contribute to the age-dependent increase of visceral fat accumulation. We hypothesize that the age-dependent changes in body fat are the result of an age-dependent decrease of the GH/cortisol ratio at the level of the adipocyte. This is caused by the decline in GH concentrations and the increase in cortisol levels and/or metabolism at the adipocyte.

Perfusion brain scintigraphy studies in infants and children with malformations of the vein of Galen.

Cerebral perfusion brain scintigraphy obtained in six unselected patients (age newborn to 14 years) from among 50 children with vein of Galen malformations was used in conjunction with magnetic resonance imaging to determine the basis of the neurological and cognitive abnormalities in patients with vein of Galen malformations (VGMs). Five had a hemiparesis - persistent, transient, or alternating. Four were developmentally delayed. Two had so far been cognitively normal and acquired a neurological deficit, following an embolization procedure. The school age patient had a nonverbal learning disability. Three had epilepsy and/or an abnormal electroencephalogram. Magnetic resonance imaging documented only the VGM, hydrocephalus and atrophy; one child with perinatal asphyxia had periventricular leukomalacia. Perfusion brain scintigraphy was normal in two (a normal infant, and a toddler with a hemiparesis and aphasia). Abnormal findings included: left parietal hypoperfusion, fronto-temporal atrophy, patchy flow; left fronto-temporal hypoperfusion, left hemiatrophy, bilateral medial temporal hypoperfusion, right cerebellar hypoperfusion; right temporal hypoperfusion, patchy flow; right hemiatrophy, occipital hypoperfusion. Perfusion brain scintigraphy findings correlated better with focal neurological and cognitive defects than did magnetic resonance imaging.

Behavioural profiles of children and adolescents after pre- or perinatal unilateral brain damage.

Recent case reports of individuals with early-onset damage to the prefrontal cortex have suggested that such early insults could result in severely impaired social behaviour in later childhood and adolescence. The investigators speculated that the acquisition of complex social conventions and moral rules had been impaired. In a large cohort of children, we sought to determine whether early focal brain insults might result in clinically significant behavioural or emotional problems. This study reports on 39 children with pre- or perinatal-onset unilateral brain damage (focal lesion) from cerebral infarction or intraparenchymal haemorrhage, using the Achenbach Child Behavior Checklist to assess the presence or absence of behavioural and emotional difficulties. Two-thirds of the subjects had left hemisphere (LH) lesions and one-third had right hemisphere (RH) lesions. Age range was 4.0-15.4 years at the time of questionnaire completion. Their results were compared with those of 54 control children. Analyses were conducted on focal lesion versus controls, RH versus LH lesion, frontal versus non-frontal lesion, and seizure versus non-seizure groups. When the effect of IQ was partialled out, there were no significant differences on the nine Behavior Problem scales, the Internalizing-Externalizing dichotomy or the Total Problem score for any of the group comparisons. Our subjects showed no evidence of clinically significant behavioural or emotional problems, even when the frontal lobe was involved. Individuals with more extensive and bilateral damage may be at higher risk of significant behavioural and emotional dysfunction than were those in our study population. In future studies of brain-behaviour relationships in developing children, all potential causes for any observed behavioural abnormalities, such as genetic and environmental factors and toxin exposure, must be considered before concluding that specific anatomical lesions are causally related to specific behavioural outcomes.

C. elegans: a novel pharmacogenetic model to study Parkinson's disease.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Although the use of vertebrate and tissue culture systems continue to provide valuable insight into the pathology of the neurodegeneration, the molecular determinants involved in the etiology of the disease remain elusive. Because of the high conservation of genes and metabolic pathways between invertebrates and humans, as well as the availability of genetic strategies to identify novel proteins, protein interactions and drug targets, genetic analysis using invertebrate model systems has enormous potential in deducing the factors involved in neuronal disease. In this article, we discuss the opportunities for the use of the nematode Caenorhabditis elegans (C. elegans) for gaining insight into the molecular mechanisms and pathways involved in PD.

Intracerebroventricular administration of the rat growth hormone (GH) receptor antagonist G118R stimulates GH secretion: evidence for the existence of short loop negative feedback of GH.

Pulsatile growth hormone (GH) secretion is regulated by three hypothalamic factors, growth hormone-releasing hormone (GHRH), somatostatin and the natural ligand for the GH secretagogue receptor (Ghrelin). These factors and their effects are, in turn, affected by short loop feedback of GH itself. To test the hypothesis that hypothalamic GH receptors are involved in the ultradian rhythmicity of pituitary GH secretion, the rat GH receptor antagonist (G118R) was administered to adult male rats by intracerebroventricular (i.c. v.) injection and the effects on spontaneous GH secretion were studied. Normal saline was administered i.c.v. to eight control rats. Mean GH concentrations increased significantly in the rat treated with G118R compared to rats that received normal saline. The pulse amplitude rose by a mean of 33.3 ng/ml and the total area under the curve increased by a mean of 15 061 ng/ml x min. The number of GH peaks did not change significantly following G118R. These data suggest that GH regulates its own secretion by acting directly on hypothalamic GH receptors.

Acquired aphasia in children after surgical resection of left-thalamic tumors.

Five children (three males, two females; four right-, one left-handed; age range 6 to 14 years) who developed aphasia after gross-total excision of left predominantly thalamic tumors are reported. Three patients had Broca aphasia, one had mixed transcortical aphasia, and one patient had conduction aphasia. In the months after surgery, three children improved while receiving radiation and/or chemotherapy, although none recovered completely. Two patients with malignant tumors developed worsening aphasia when the tumor recurred, and later died. Two of three patients tested had visuospatial difficulties in addition to language deficits. Attention and executive functioning were affected in three of three patients tested. Memory, verbal and/or visual functioning, were affected in four of four patients tested. Both patients who were tested showed transient right hemineglect. Two of two patients tested were probably apraxic. The wide range of deficits in these children highlights the importance of the thalamus and other subcortical structures in developing cognition.

High plasma growth hormone (GH) levels inhibit expression of GH secretagogue receptor messenger ribonucleic acid levels in the rat pituitary.

Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing hormone. The GHS-R has been cloned from the pituitary and is expressed not only in the pituitary but also in specific areas of the brain, including the hypothalamus. Recent studies suggest that hypothalamic GHS-R expression is regulated by GH. This study was designed to investigate whether pituitary GHS-R expression is modulated by GH. Female Wistar-Furth rats were injected sc with either saline (control) or GC tumor cells (GC) that secrete rat GH. The tumors were allowed to develop for 1-4 weeks. At weeks 1-4, control (n = 4-8) and GC rats (n = 3-8) were killed. Pituitary GHS-R messenger RNA (mRNA) was measured by a quantitative competitive PCR assay. The endogenous GHS-R mRNA levels were measured by determining the amount of competitive template RNA required to produce equimolar amounts of native and competitive template PCR products. The mean log plasma GH levels were significantly greater in the GC rat group than in the control group at weeks 2, 3, and 4. At these times, the mean log pituitary GHS-R mRNA contents were significantly lower in the GC rat group than in the control group. No relationship could be established between log estradiol levels and GHS-R levels. These data indicate that pituitary GHS-R expression is modulated by GH.

Autistic regression with rolandic spikes.

OBJECTIVE: This study was designed to further define the electroencephalographic abnormalities seen in the Landau-Kleffner syndrome variants and the associated clinical features. BACKGROUND: Landau-Kleffner syndrome is rare, but its putative variants are more common. METHOD: We report two patients with centro-temporal spikes, autistic epileptiform regression, and variably prominent oro-motor symptoms. RESULTS: The epileptic aphasia pattern found among patients with prominent Rolandic spikes may more frequently involve expressive language than is seen in the typical Landau-Kleffner syndrome, where verbal auditory agnosia is the rule. CONCLUSIONS: This clinical difference likely reflects the location of the epileptiform activity (centrotemporal as opposed to anterior or mid-temporal) on buccal-lingual function, vocalization, and language production.

Outcome of multiple subpial transections for autistic epileptiform regression.

Treatment options for atypical forms of Landau-Kleffner syndrome (LKS) are not well delineated. Many patients with typical LKS fail to respond to antiepileptic drug treatment, but some benefit from multiple subpial transections (MSTs). The authors report seven patients with autism or autistic epileptiform regression who responded in varying degrees to MSTs after failed medical management. These patients derived from an original cohort of 36 children (29 males, seven females, ranging from 2 years, 3 months to 11 years, 3 months, mean age = 5 years, 8 months) with a history of language delay or regression, as well as varying degrees of social and behavioral abnormalities, who were evaluated with video-electroencephalogram (EEG) monitoring over a 2-year period. Fifteen patients had clinical seizures (11 of the 19 children with autistic epileptiform regression and four of 12 autistic children). Epilepsy was refractory to medication in seven. Surgical treatment variously involved MSTs of the left neocortex in temporal, parietal, and frontal regions, often including regions within the classic perisylvian language areas. One patient also had a left temporal lobectomy. In all seven patients, seizure control or EEG improved after MSTs. Language, social, and overall behavior improved to a moderate degree, although improvements were temporary in most. Autistic epileptiform regression resembles LKS in that both may respond to MST. MST is used to treat epilepsy in eloquent regions. The responsiveness of autistic epileptiform regression to MST buttresses the argument that autistic epileptiform regression is a form of focal epilepsy.