Heart rate variability in patients with untreated epilepsy.

BACKGROUND: Several studies have reported reduced heart rate variability (HRV) in patients with chronic epilepsy under treatment with antiepileptic drugs. This impairment in cardiac autonomic control might be of relevance in relation to the risk of sudden unexpected death in patients with chronic refractory epilepsy. Little information is, however, available on HRV in untreated patients with newly diagnosed epilepsy. METHODS: We used spectral analysis to assess HRV based on 24h ambulatory EKG recordings in 22 consecutive untreated patients with epilepsy (15 with localization-related, 4 with generalized idiopathic and 3 with undetermined epilepsy). The HRV in these patients was compared with 22 age and sex matched healthy controls. RESULTS: When analysing the full 24h recordings, there were no significant difference between the patients and the controls in any of the analyzed measures of HRV: standard deviation of RR-intervals (P=0.191), total power (P=0.170), very low frequency power (P=0.329), low frequency power (LF) (P=0.161), high frequency power (HF) (P=0.186) and the LF/HF ratio (P=0.472). The results were very similar for daytime and nighttime recordings. CONCLUSION: Our results suggest that there is no major effect of epilepsy as such on HRV in patients with untreated epilepsy. It should be emphasized that this study assessed newly diagnosed patients and that the results may not be applicable to patients with chronic epilepsy.

Circadian variation in heart-rate variability in localization-related epilepsy.

PURPOSE: Case-control studies of sudden unexpected death in epilepsy (SUDEP) have reported that SUDEP is more likely to occur during sleep and thus presumably during night hours. The circadian variation of heart-rate variability (HRV) might be of relevance to this risk. We examined night versus daytime HRV in patients with newly diagnosed and refractory localization-related epilepsy, assessing the effects of drug treatment and epilepsy surgery on the night/daytime HRV ratio. METHODS: We used spectral analysis to assess HRV and calculated the night-time (00.00-05.00)/daytime (07.30-21.30) ratio of HRV in 14 patients with newly diagnosed localization-related epilepsy before and during carbamazepine (CBZ) treatment and in 21 patients with temporal lobe epilepsy before and after epilepsy surgery. Both groups were compared with age- and sex-matched controls. RESULTS: No significant differences were found from controls in the night/daytime ratios of HRV whether compared before or after initiation of treatment with CBZ in newly diagnosed epilepsy patients. When patients were used as their own controls, night/daytime ratios of standard deviation of RR intervals (p = 0.04) and total power (p = 0.04) were significantly lower during treatment than before. Compared with those of controls, the night/daytime ratios were lower in epilepsy surgery patients before surgery [low-frequency power (p = 0.04); high-frequency power (p = 0.04)]. Night/daytime ratios did not change significantly after surgery. CONCLUSIONS: The HRV of the patients was more affected during night-time when the risk of SUDEP seems to be highest in such patients.

Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy.

Previous studies indicate that epilepsy patients may have impaired autonomic cardiovascular control in the interictal state although it is unclear whether the observed reduction in cardiovascular responses is due to the epilepsy and the interictal epileptogenic discharges, or to the treatment with antiepileptic drugs. Spectral analysis of heart rate variability makes it possible to partly separate the sympathetic components, low frequency (LF), from the vagal components, high frequency (HF) of autonomic cardiac control. We used spectral analysis of heart rate variability to assess the effect of carbamazepine (CBZ) on autonomic cardiac control in patients with newly diagnosed epilepsy. Fifteen adult outpatients with newly diagnosed seizures/epilepsy underwent 24 h ambulatory EKG recordings before and after commencement of CBZ treatment. Total power as well as low frequency (LF), very low frequency (VLF) and high frequency (HF) power in heart rate variability was calculated. When analysing the full 24 h recordings, patients had significantly lower standard deviation of RR-intervals (P=0.0015), total power (P=0.0010), LF (P=0.0002), VLF (P=0.0025) and HF (P=0.0139) during treatment with CBZ than before. The results were very similar for daytime and night time recordings. Our observations demonstrate that CBZ may suppress both parasympathetic and sympathetic functions in newly diagnosed patients with epilepsy. The possible implications of our results for sudden unexpected death in epilepsy are discussed.

Risk of extremity fractures in adult outpatients with epilepsy.

PURPOSE: To study the incidence of extremity fractures in a group of adult patients with epilepsy attending an outpatient clinic compared with the incidence of fractures in the general population in the same geographic area. METHODS: We selected 177 consecutive adult patients with epilepsy attending the outpatient clinic at the Department of Neurology at Karolinska Hospital in Stockholm in 1995. This study population was matched with an Injury Registry to identify those epilepsy patients who during 1991 through 1995 attended the emergency department for an extremity fracture. The observed number of fractures in the epilepsy group was compared with the corresponding number of expected cases based on regional fracture rates. Relative-risk estimates for fractures were calculated with respect to the duration of epilepsy, mono- or polytherapy, and history of tonic-clonic seizures. RESULTS: Twenty (11%) of 177 patients sustained 23 fractures that prompted a visit to the emergency department. The incidence of fractures in the epilepsy patients was 23.8/1,000 person-years. The overall Standardized Morbidity Ratio (SMR) was 2.39 (95% CI, 1.52-3.59). A significantly higher risk for fractures was thus found in patients with epilepsy. Risk factors were age 45 years or older, male sex, and occurrence of generalized seizures. It also was found that the relative risk of fractures was higher during the first and second year compared with >or=5 years after diagnosis (RR, 3.71; 95% CI, 1.20-11.48). CONCLUSIONS: Our results highlight the risk of fractures in outpatients with epilepsy. In this patient group, 43% of the fractures were definitely or possibly seizure related. Males 45 years or older are a particular risk group. Special attention is required for this group of patients who are at higher risk for fractures. The risk is apparently higher in the first 2 years after diagnosis, although potential bias in ascertainment of fracture incidents in our study may have underestimated the long-term risk for fractures.

Cells Expressing mRNA for Neurotrophins and their Receptors During Embryonic Rat Development.

In situ hybridization analysis of cells expressing messenger RNAs (mRNAs) for the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their high-affinity receptors (trk, trkB and trkC) in the rat embryo revealed a complex but specific expression pattern for each of these mRNAs. For all mRNAs a developmentally regulated expression was seen in many different tissues. BDNF and NT-3 mRNAs were expressed in the sensory epithelia of the cochlea and vestibule macula of the sacculus and utricle, and both trkB and trkC mRNA were expressed in the spiral and vestibule ganglia innervating these sensory structures. NGF and NT-3 mRNA were found in the iris, innervated by the sympathetic neurons of the superior cervical ganglion and sensory neurons from the trigeminal ganglion, which expressed both trk and trkC mRNAs. Both NGF and NT-3 mRNAs were also expressed in other target fields of the trigeminal ganglion, the epithelium of the whisker follicles (NT-3 mRNA) and in the epithelium of the nose, tongue and jaw. NT-3 mRNA was found in the cerebellar external granule layer and trkC mRNA in the Purkinje layer of the cerebellar primordia. These sites of synthesis are consistent with a target-derived neurotrophic interaction for NGF, BDNF and NT-3. However, in some cases mRNAs for both the neurotrophins and their high-affinity receptors were detected in the same tissue, including the dorsal root, geniculate, superior, jugular, petrose and nodose ganglia, as well as in the hippocampus, frontal cortical plate and pineal recess, implying a local mode of action. Combined, these data suggest a broad function for the neurotrophins and their receptors in supporting neural innervation during embryonic development. The results also identify several novel neuronal systems that are likely to depend on the neurotrophins in vivo.

Regulation of Neurotrophin mRNA Expression in the Rat Brain by Glucocorticoids.

Northern blot analysis was used to examine the effects of glucocorticoids on neurotrophin mRNA expression in the rat cerebral cortex and hippocampus. The results show that 3 days after adrenalectomy the mRNA levels for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) decreased significantly in both these regions. In adrenalectomized animals given dexamethasone replacement the mRNA levels for the three neurotrophins were restored to control levels. The effect of a single dose of dexamethasone (5 mg/kg) administered i.p. to intact animals on the expression of neurotrophins was also examined. NGF and NT-3 mRNAs showed a 2.5-fold and a 1.4-fold increase, respectively, during the first 4 h after the injection. The increase was followed by a decrease, with levels approximately 50% of control 24 and 48 h after the injection. In contrast, the level of BDNF mRNA did not change during the first 10 h after the injection, but decreased to 70% of control 48 h after the injection. These data indicate that glucocorticoids regulate neurotrophin mRNA expression both in the cortex and in the hippocampus, and suggest further that the known effects of glucocorticoids on neuronal survival in the brain could be due to changes in the levels of neurotrophins in the brain.

Cells that Express Brain-Derived Neurotrophic Factor mRNA in the Developing Postnatal Rat Brain.

Brain-derived neurotrophic factor (BDNF) is a member of a family of related neurotrophic proteins which includes nerve growth factor (NGF) and hippocampus-derived neurotrophic factor/neurotrophin-3 (NT-3). To obtain information regarding possible roles for BDNF during postnatal brain development, we have examined the temporal and spatial expression of this trophic factor using in situ hybridization. In specific neocortical regions BDNF mRNA-expressing cells were seen at 2 weeks of age and thereafter. One particular neuronal cell type strikingly labelled was the inverted pyramidal cell population in the deep layers of parietotemporal cortex. In pyriform and cingulate cortices, BDNF mRNA was detected at postnatal day 1 and 1 week of age, respectively, with increasing levels during ontogeny. Several forebrain regions, including the thalamic anterior paraventricular nucleus, hypothalamic ventromedial nucleus as well as the preoptic area, contained moderate levels of BDNF mRNA throughout development. BDNF mRNA was detected transiently in several brainstem structures, notably in the substantia nigra and interpeduncular nucleus. Expression of this trophic factor in hippocampus was relatively low in the early neonatal brain, but attained high levels in the CA3 and CA4 regions as well as in the dentate gyrus by 2 weeks of age. At this early age, which is still during the period of neurogenesis in the dentate gyrus, labelling was restricted to the outer layer, which contained cells with a more mature appearance. However, by 3 weeks of age labelling was distributed throughout the granule cell layer. Our results show both transient and persistent expression of BDNF mRNA in various regions of the developing rat brain and suggest that there is a caudal to rostral gradient of BDNF expression during postnatal brain development, which may be correlated to neuronal maturation.

Localization of Sequences Determining Cell Type Specificity and NGF Responsiveness in the Promoter Region of the Rat Choline Acetyltransferase Gene.

A genomic clone containing 7 kb of 5' flanking sequences from the rat choline acetyltransferase (ChAT) gene was isolated and shown to contain a TATA box-like sequence and several consensus binding sites for the transcription factor AP1. Two constructs containing 450 and 1450 base pairs (bp), respectively, of 5' flanking sequences promoted expression of a fused chloramphenicol acetyltransfersase (CAT) gene when transfected into fibroblast FR3T3, Sertoli TM4, phaeochromocytoma PC12 and cholinergic neuronal SN6 cell lines. In contrast, a longer construct containing 3850 bp of 5' flanking sequence allowed CAT activity only in the cholinergic cell line SN6. CAT activity with this construct was suppressed in the three other cell lines, indicating that the distal region of the ChAT promoter contains a cell type-specific silencer-like element that restricts ChAT gene expression to cholinergic cells. Treatment of PC12 cells with nerve growth factor (NGF) increased the promoter activity of the -450 and -1450 constructs approximately four-fold and allowed promoter activity from the -3850 construct, indicating that elements involved in NGF responsiveness of the ChAT promoter are contained in the first 450 bp of upstream sequence. These results support a model in which gene transcription controlled by cell-type specific regulatory elements contribute to the establishment, maintenance and plasticity of the cholinergic transmitter phenotype in the nervous system.

Developmentally Regulated Expression of HDNF/NT-3 mRNA in Rat Spinal Cord Motoneurons and Expression of BDNF mRNA in Embryonic Dorsal Root Ganglion.

Northern blot analysis was used to demonstrate high levels of hippocampus-derived neurotrophic factor/neurotrophin-3 (HDNF/NT-3) mRNA in the embryonic day (E) 13 - 14 and 15 - 16 spinal cord. The level decreased at E18 - 19 and remained the same until postnatal day (P) 1, after which it decreased further to a level below the detection limit in the adult. In situ hybridization revealed that the NT-3 mRNA detected in the developing spinal cord was derived from motoneurons and the decrease seen at E18 - 19 was caused by a reduction in the number of motoneurons expressing NT-3 mRNA. The distribution of NT-3 mRNA-expressing cells in the E15 spinal cord was very similar to the distribution of cells expressing choline acetyltransferase or nerve growth factor receptor (NGFR) mRNA. Moreover, a striking similarity between the developmentally regulated expression of NT-3 and NGFR mRNA was noted in spinal cord motoneurons. A subpopulation of all neurons in the dorsal root ganglia expressed brain-derived neurotrophic factor (BDNF) mRNA from E13, the earliest time examined, to adulthood. These results are consistent with a trophic role of NT-3 for proprioceptive sensory neurons innervating the ventral horn, and imply a local action of BDNF for developing sensory neurons within the dorsal root ganglia.