Bone health in adults with epilepsy.

Patients with epilepsy have a 2-6 times greater risk of bone fractures compared with the general population. There are several potential explanations. Some fractures are caused by seizure-related injuries, or they may be associated with the osteopenic effect of reduced physical activity in patients with epilepsy. Antiepileptic drugs (AEDs), especially those that affect the liver enzymes, e.g., phenytoin, carbamazepine, phenobarbital, as well as valproate, are also associated with increased fracture rate and low bone mineral density. Many patients with epilepsy and general practitioners seem unaware of this problem. Measurements of bone density should be taken regularly in patients at risk of developing osteoporosis. Non-pharmaceutical initiatives, such as partaking in regular physical activity and eating a well-balanced diet, should be recommended. The risk of developing osteoporosis should be taken into consideration in the selection of an AED for treating a newly diagnosed patient with epilepsy.

Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations.

OBJECTIVES: To investigate two patients with late onset, progressive external ophthalmoplegia (PEO) and sensory peripheral neuropathy. MATERIALS & METHODS: The patients aged 86 and 50 years were investigated clinically including magnetic resonance imaging of the brain, electrophysiological studies and, in one, skeletal muscle biopsy. Molecular studies included sequencing of the whole coding region of the POLG1 gene and mitochondrial DNA (mtDNA) analysis for deletions and depletion. RESULTS: Both patients were compound heterozygous for gene encoding the catalytic subunit of the DNA-polymerase gamma (POLG1) mutations. One had the p.737R and p.W748S mutations while the other carried the p.T251I, p.P587L and p.W748S mutations. While these mutations have been previously described, these combinations are novel. mtDNA studies in skeletal muscle showed evidence of multiple deletions and approximately 64% depletion of the mitochondrial genome. CONCLUSION: Our findings broaden the genotypic spectrum of POLG-associated PEO and show that in addition to multiple deletions, mtDNA depletion occurs and may contribute to the pathogenesis of this disorder.

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy.

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug-specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20-40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age-matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C-peptide values compared with controls. Regarding possible drug-specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone-binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C-peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug-specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long-term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C-peptide and carnitine ratio. Long-term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.

Alterations in semen parameters in men with epilepsy treated with valproate or carbamazepine monotherapy.

Men with epilepsy are known to have reduced fertility. Whether this is drug-induced or a result of the epilepsy itself is still under debate. Few studies have been carried out on semen from men with epilepsy. The aim of the present study was first to investigate possible drug-specific effects of long-term treatment with either valproate or carbamazepine on semen quality and testicular size, and secondly to see whether the results in epilepsy patients differed from healthy fertile males. Men with epilepsy, 20-40 years old, having used either valproate (n = 16) or carbamazepine (n = 20) for >2 years, were included. The semen data of healthy fertile men without epilepsy in the same age group (n = 90) were used as controls. The semen was examined according to WHO (1999). No significant differences in semen quality were seen between men receiving either valproate or carbamazepine. However, semen from the valproate-treated, as opposed to the carbamazepine-treated, differed from controls with regard to tail abnormalities. Absolute testicular size was not significantly different between the two treatment groups. However, after correcting for changes in body mass index (BMI), the testicular size/BMI ratio was lower in the valproate-treated patients. The valproate-treated patients gained significantly more weight than the carbamazepine-treated patients after start of current medication. No differences between the patient groups were found in terms of libido/potency or number of pregnancies fathered. When comparing all epilepsy patients with healthy fertile males, there was a significant reduction in the percentage of rapidly progressive motile sperms in the semen from epileptic patients. The semen from men with epilepsy also showed significant differences from the controls regarding neck and head abnormalities of the spermatozoa.

Valproate, but not lamotrigine, induces ovarian morphological changes in Wistar rats.

Valproate (VPA) medication is associated with development of polycystic ovaries, menstrual disorders and hormonal changes in women with epilepsy. We sought to determine if changes in the ovaries also occurred in an animal model without epilepsy, and whether this effect could be related to a carcinogenic effect expressed by overexpression of p53. A potentially alternative antiepileptic drug, lamotrigine (LTG), was evaluated simultaneously. To this end, female Wistar rats were fed perorally with VPA 400 mg/kg/day (n = 15), VPA 600 mg/kg/day (n = 20), LTG 10 mg/kg/day (n = 15) or control solution (n = 15) for 90-95 days. There was a significant, dose-dependent increase in the number of follicular cysts, reduction in the number of corpora lutea and reduction of ovarian weight in the VPA group. No ovarian pathology was observed in the LTG group. In neither of the groups were morphological changes seen in other organs, nor was there any overexpression of the tumor suppressor gene p53 found. An alternative antiepileptic drug, LTG, showed no ovarian pathology, and there were no light microscopic changes in other organs, or evidence of pathologic p53 overexpression in the LTG-treated animals.

[Cerebral microembolism detected by transcranial Doppler ultrasonography]. / Cerebrale mikroemboli pvist med transkranial ultralyddopplerundersøkelse.

The clinical diagnosis of brain embolism has traditionally been based on evidence suggesting a potential embolic source. However, it is now possible to detect circulating cerebral microemboli by means of transcranial Doppler ultrasound. We explain the theory behind microembolus detection, and discuss initial clinical experience of this method. During invasive cardiovascular investigations and surgery this method can warn the physician that microemboli are entering the cerebral circulation, and preventive measures can be taken. Cerebral microemboli are quite often detected in stroke prone patients, and their presence probably indicates increased risk of stroke. In the acute phase of ischemic stroke, microembolus detection may help to decide the etiology and the source of the emboli. When microemboli are detected in cases of acute embolic stroke, serial detections can be performed which, in future studies, might be of help when evaluating the effect of the treatment.

Hypothalamocerebellar and cerebellohypothalamic projections--circuits for regulating nonsomatic cerebellar activity?

Cerebellar involvement in visceral and affective responses is known from physiological and behavioral studies, but the pathways involved in these responses have remained enigmatic. Over the last ten years neuroanatomical studies have shown that the cerebellum and hypothalamus are interconnected by direct hypothalamocerebellar and cerebellohypothalamic projections and by a multitude of indirect pathways. The hypothalamocerebellar projection terminates in the cerebellar nuclei and in all layers of the cerebellar cortex as multilayered fibres. This projection is, at least in part, histaminergic. New immunocytochemical experiments indicate that small numbers of hypothalamocerebellar neurones may contain GABA- or glycine-like immunoreactivity. GABA may function as a transmitter in hypothalamocerebellar fibres, probably in conjunction with histamine, but it is not clear whether glycine may also function as a transmitter or only serve metabolic functions. The bidirectional pathways between the cerebellum and hypothalamus may be part of the circuits through which the cerebellum participates in the modulation of a variety of nonsomatic events. In addition, new observations on patients with well localized cerebellar lesions reveal simultaneous somatic and visceral dysfunction. Recent research on direct hypothalamocerebellar pathways and on other connections between hypothalamus and cerebellum is reviewed. It is hypothesized that the cerebellum may act as a general modulator and coordinator of a wide range of central nervous activities, somatic as well as nonsomatic.

The hypothalamocerebellar projection in the cat: branching and nuclear termination.

The hypothalamic projection to the cerebellar nuclei and cortex in the cat was studied by means of retrograde transport of wheat germ agglutinin-horseradish peroxidase complex and various fluorescent tracers. The hypothalamocerebellar nuclear projection originates from various parts of the posterior hypothalamus and reaches mainly the ipsilateral fastigial and interposed nuclei, but all nuclei receive some hypothalamocerebellar fibres. It appears from our double labelling experiments that at least one half of the hypothalamocerebellar nuclear neurones by means of axon collaterals also projects to the cerebellar cortex. Experiments with depositions of fluorescent tracers in both cerebellar hemispheres show that some hypothalamocerebellar fibres branch to reach different parts of the cerebellar cortex. Previous studies have shown that hypothalamocerebellar axons may be branches of hypothalamic efferents to other sites. However, experiments with combined fluorescent tracer depositions in the cerebellum and hippocampus gave no evidence for hypothalamic neurones with axon collaterals to both these regions.

A projection from the periaqueductal grey to the lateral reticular nucleus in the cat.

A projection from the periaqueductal grey (PAG) to the lateral reticular nucleus (NRL) in the cat was demonstrated by means of retrograde transport of the wheat germ agglutinin-horseradish peroxidase complex. The connection has its main origin ipsilaterally in the ventral part of the caudal PAG, but scanty projections from other parts of the PAG were also found. The neurons projecting to the NRL are of varying shapes and sizes, but most cells have a maximum diameter of less than 20 micron. The findings are discussed in relation to the other afferent and efferent connections of the NRL.

A projection from the raphe nuclei to the lateral reticular nucleus in the cat.

By means of retrograde transport of the wheat germ agglutinin-horseradish peroxidase complex afferent fibres to the lateral reticular nucleus from the raphe nuclei were demonstrated in the cat. The projection is bilateral and has its main origin in nucleus raphe pallidus and magnus, but there appear to be contributions also from nucleus raphe obscurus, dorsalis and linearis rostralis.