Epilepsy and Pregnancy: For healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group.

Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy-related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene - Golden Moments of opportunities for improving outcomes -Which Key Groups have a role in making change -When - 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries.

Late-onset Pompe disease primarily affects quality of life in physical health domains.

OBJECTIVE: To investigate quality of life in an international population of patients with late-onset Pompe disease. METHODS: Data on quality of life (SF-36), age, sex, disease duration, wheelchair use, and use of artificial ventilation were collected for 210 adults with Pompe disease from Australia, Germany, the Netherlands, the United Kingdom, and the United States. SF-36 scores were compared between countries and related to patient characteristics. In addition, for the Dutch subgroup (n = 51), comparisons with the general population and 1-year follow-up assessments were performed. RESULTS: No significant differences between countries were found for the four physical health scales. Mean scores on the vitality, role functioning-emotional, and mental health scale differed between countries, but these differences were not consistent. Wheelchair use was associated with lower physical and social functioning scores (B = -23.6 and -15.1, p < 0.001), and the use of artificial ventilation with lower physical functioning scores (B = -8.4, p = 0.004). Patients reported significantly poorer quality of life than the general population on the physical functioning, role functioning-physical, general health, vitality, and social functioning scales. No significant differences in SF-36 scores were found between the baseline and 1-year follow-up measurement. CONCLUSIONS: Patients with late-onset Pompe disease are, on average, markedly affected on the physical health domains of quality of life, but score only slightly lower than the general population on the mental health domains.

Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study.

The lateral segment of the globus pallidus (GPl) is thought to be overactive in levodopa-induced dyskinesia in PD. Stimulation of cannabinoid receptors in the GPl reduces gamma-aminobutyric acid (GABA) reuptake and enhances GABA transmission and may thus alleviate dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), the authors demonstrate that the cannabinoid receptor agonist nabilone significantly reduces levodopa-induced dyskinesia in PD.

The selective vulnerability of nerve cells in Huntington's disease.

It is now more than 7 years since the genetic mutation causing Huntington's disease (HD) was first identified. Unstable CAG expansion in the IT15 gene, responsible for disease, is translated into an abnormally long polyglutamine (polyQ) tract near the N-terminus of the huntingtin protein. The presence of expanded polyQ in the mutant protein leads to its abnormal proteolytic cleavage with liberation of toxic N-terminal fragments that tend to aggregate, probably first in the cytoplasm. Subsequent nuclear translocation of the cleaved mutant huntingtin is associated with formation of intranuclear protein aggregates and neurotoxicity, probably involving apoptotic cascades. These processes, which can be experimentally modelled in cultured neuronal and non-neuronal cells, seem to underlie neurodegeneration in HD, and also other polyQ disorders, such as dentatorubro-pallidoluysian degeneration, spinal and bulbar muscular atrophy and the spinocerebellar ataxias. They do not, however, explain why within the corpus striatum and cerebral cortex certain nerve cells are susceptible to disease and others are not. In the human HD brain, vulnerable pyramidal neurones within the deeper layers of the cerebral cortex frequently contain large intranuclear inclusions composed of N-terminal fragments of huntingtin. Such inclusions are, however, rare within neurones of the striatum, even in the medium spiny neurones preferentially lost from this region. While inclusions per se do not seem to be neurotoxic, they may provide a surrogate marker of molecular pathology. Recent studies indicate that the nuclear accumulation of mutant huntingtin interferes with transcriptional events. Of particular importance may be the effect on the genes encoding neurotransmitter receptor proteins, especially those involved with glutamatergic neurotransmission. Such changes may trigger or facilitate a low-grade, chronic excitotoxicity of the glutamatergic cortical projection neurones on their target cells in the striatum, already partly compromised by the toxic effects of the HD mutation. This combination of insults, for anatomical reasons experienced predominantly by striatal projection neurones, would eventually cause their selective demise.

Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein.

Intranuclear inclusion bodies are a shared pathological feature of Huntington's disease (HD) and its transgenic mouse model. Using a panel of antibodies spanning the entire huntingtin molecule, we have investigated the pattern of immunoreactivity within the intranuclear inclusions in the frontal cortex and striatum of patients with HD. The intranuclear inclusions reacted with anti-ubiquitin and antibodies against the N-terminal portion of huntingtin (CAG53b, HP1), but not with HD1 and the 1C2 antibodies that detect the expanded polyglutamine tract nor the more C-terminal antibodies. However, the 1C2, HP1, CAG53b, and HD1 antibodies detected granular cytoplasmic deposits in cortical and striatal neurons that also contained intranuclear N-terminal huntingtin immunoreactivity. These data show a differential intracellular location of truncated huntingtin in the HD brain. Both the cytoplasmic and the nuclear aggregates of the protein fragments could be neurotoxic. The frequency of the cortical intranuclear inclusions correlated with the size of CAG expansion and was inversely related to the age at onset and death. No such correlations were detected for the striatum, which most likely reflects a more advanced neuronal loss accrued by the time of death.

Superior sagittal sinus obstruction and tuberculous abscess.

Intracranial tumours such as meningiomas may occasionally produce raised intracranial pressure by occluding a venous sinus. More uncommonly, midline tumours in the occipital regions of the skull can produce elevated intracranial pressure by non-thrombotic compression of the superior sagittal sinus. We present a case of raised intracranial pressure secondary to non-thrombotic obstruction of the superior sagittal sinus by a midline tuberculous abscess.

Efaroxan, an alpha-2 antagonist, in the treatment of progressive supranuclear palsy.

We have tested, in a prospective randomized, double-blind, placebo-controlled, crossover, 12-week study, the effects of 2 mg efaroxan, a potent alpha-2 antagonist, given three times per day to 14 patients with progressive supranuclear palsy. Efaroxan did not induce any significant change on any motor assessment criteria. The present data do not confirm the assumption that the blockade of alpha-2 receptors might be a useful pharmacologic strategy to improve patients with progressive supranuclear palsy.

Clinical presentation and patterns of regional cerebral atrophy related to the length of trinucleotide repeat expansion in patients with adult onset Huntington's disease.

We correlated trinucleotide CAG repeat numbers in the huntingtin gene with the regional brain atrophy and clinical phenotype in 23 adult autopsy cases of Huntington's disease (HD). CAG repeat number (39-56, mean 45.4 +/- 4.6) correlated inversely (P < 0.0001) with age at onset and death, but not with disease duration or initial symptoms. Cross-sectional areas of the striatum, pallidum, thalamus, amygdala, hippocampus, and the cortical grey and white matter within the frontal, temporal and parietal lobes at four levels (genu of the corpus callosum, amygdala, accumbens, hippocampus) were measured morphometrically from the coronal brain slices using image analysis. None of these morphometric variables correlated with number of CAG repeats. Thus, tissue atrophy in advanced HD is unrelated to the underlying genetic defect.

Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson's disease: implications for the pathogenesis of the on-off phenomenon.

OBJECTIVES: To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS: Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS: A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION: The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.

The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson's disease.

Dopamine is equally well deaminated oxidatively by monoamine oxidase (MAO) A and B types. Selegiline (L-deprenyl), a selective inhibitor of MAO-B, ameliorates the "wearing off" akinesia and delays the need for levodopa in mild, previously untreated Parkinson's disease. The therapeutic potential of selective inhibition of MAO-A in Parkinson's disease has not been examined in detail. MAO-A accounts for only about 20% of total MAO activity in the human basal ganglia, and it differs from MAO-B in distribution. In contrast to MAO-B, which is confined to the extraneuronal compartment, MAO-A is found both extraneuronally and within the presynaptic dopaminergic terminals. The inhibition of MAO-A might alter the intraneuronal handling of dopamine reuptaken from synaptic clefts and thereby prolong oral levodopa benefit. We have given moclobemide, a selective, reversible inhibitor of MAO-A, to nondepressed patients with Parkinson's disease receiving standard levodopa/peripheral decarboxylase inhibitor or levodopa with dopaminergic agonist (bromocriptine, pergolide). Selegiline was discontinued at least 8 weeks earlier. A standard oral levodopa challenge was performed at the patient's entry to the study and repeated on the 22nd day of moclobemide treatment (150 mg thrice daily). The overall time spent "on" and "off" before the onset of treatment and during the last week on the drug was estimated from the patients' diaries. Neuropsychological assessments were also made before and after 3 weeks of moclobemide to measure possible effects on cognitive performance and mood. In acute levodopa challenge, the latency of motor response was significantly shortened and its duration was prolonged during moclobemide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Idiopathic Parkinson's disease: epidemiology, diagnosis and management.

Since the introduction of levodopa therapy for idiopathic Parkinson's disease over 20 years ago, there has been an awakening of research interest in this chronic neuro-degenerative disorder. This paper describes current understanding of the role of genetic and environmental factors in the aetiology of idiopathic Parkinson's disease and problems associated with both diagnosis and management. It briefly outlines both pharmacological and non-pharmacological options for treatment. Despite an increasing armoury of available treatments, the optimum management for this condition remains controversial.

Expression of cholinergic phenotype by embryonic ventral horn neurons transplanted into the spinal cord in the rat.

Solid grafts of E12 embryonic spinal ventral horn were transplanted into motoneuron-depleted adult lumbar spinal cord in the rat. A muscle was implanted parallel to the vertebral column with its nerve inserted into the lumbar cord at the site of transplantation so as to provide a target for innervation by the grafted neurons. Previous retrograde labelling studies have shown that modest numbers of grafted motoneuron-like cells participate in the muscle's reinnervation and these are often found outside the graft within the host spinal cord. However, Nissl stained sections show that larger numbers of neurons survive within tissue recognisable as being of graft origin. In this study we have examined the expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) by neurons within the graft. These enzymes are involved in cholinergic neurotransmission and are characteristic of motoneurons. Thirty-four to seventy days following transplantation the grafts contained numerous neurons with acetylcholinesterase (AChE) activity. Different patterns of AChE staining were observed which probably reflected the degree of differentiation and maturation within the graft. AChE positive neurons were found in isolation or in groups resembling developing motor pools. Most of the AChE-positive neurons appeared immature with scant cytoplasm. However, neurons could be found which appeared relatively mature with a regularly shaped nucleus, prominent nucleolus and Nissl bodies. The grafts contained few AChE-positive axons and no dense plexuses of varicose fibres around the neurons such as are found around motoneurons in the mature ventral horn. Comparisons between the size of AChE-positive neurons in the graft and the size of AChE-positive neurons in the developing ventral horn found that the size of grafted neurons to be intermediate between the sizes of spinal motoneurons at E19 and P0. Far fewer grafted neurons were found to be immunoreactive for choline acetyltransferase (ChAT) than histochemically reactive for AChE. This was consistent with our findings in the spinal cord during normal development where we found that fixation and staining procedures which labelled adult motoneurons failed to reliably demonstrate ChAT immunoreactivety in normal motoneurons prenatally, although AChE histochemical reactivity could be demonstrated as early as E16. We conclude that the grafts contain numbers of immature motoneurons which fail to proceed beyond a certain stage of development, perhaps because of a failure to form appropriate efferent and afferent connections.

Observations on the survival of grafted embryonic motoneurons in the spinal cord of developing rats.

The sciatic nerve of newborn rats was injured unilaterally. Small solid grafts of ED-12 embryonic spinal cord prelabeled with 5-bromo-2'-deoxyuridine (BrDUr) were inserted into the host's hemicord on the side of the sciatic nerve injury on PD5-12. Each graft was connected to a neuromuscular implant, which in group 1 consisted of the soleus muscle and its nerve taken from the healthy leg of the same rat pup, whereas in group 2 the soleus neuromuscular implant was taken from an immunocompatible adult rat. Six to 12 weeks later the neurons extending axons into the nerve-muscle implants were retrogradely labeled with fast blue and diamidino yellow. The embryonic origin of these neurons was ascertained by visualizing BrDUr using an immunocytochemical method. The grafts survived well and contained many BrDUr-positive neurons. No retrogradely labeled neurons were found in group 1 animals. In group 2 (animals with adult implants) numerous retrogradely labeled neurons were present in the host's neuropil. Despite the access to the target there were no BrDUr-positive cells of embryonic origin that contained the retrograde labels. Indeed no motoneuron-like cells of embryonic origin were seen in the host neuropil in any of the animals which received a graft at the age of 5-12 days. This contrasts with previous studies where the grafts were introduced into the adult spinal cord and motoneuron-like cells of embryonic origin were present in the host neuropil. Thus, it appears that the environment of the developing spinal cord is unfavorable for survival of embryonic motoneurons.

The ability of developing spinal neurons to reinnervate a muscle through a peripheral nerve conduit is enhanced by cografted embryonic spinal cord.

The ability of neurons in the spinal cord of rats aged 5-12 days to reinnervate a muscle via a peripheral nerve bridge was examined and the possible influence of the cografted ED-12 embryonic spinal cord was tested. The soleus muscle was transferred paravertebrally and connected to the contralateral L4-L5 hemicord by its nerve. In some experiments embryonic spinal cord was grafted at the same level. Six to 12 weeks later fast blue and diamidino yellow were injected into the muscle or applied on the cut nerve bridge. The animals were perfused after 3-4 days and their spinal cords were examined using fluorescent microscopy, but retrogradely labeled neurons were only rarely seen. The embryonic spinal cord grafts survived well but had no influence on the outcome of these experiments. However, when neuromuscular implants from adult immunocompatible rats were used instead of the immature autologous ones, a variety of neurons including motoneurons extended their axons into the implants. The numbers of retrogradely labeled neurons were significantly higher in the spinal cords with embryonic grafts. These retrogradely labeled neurons were in the host's grey matter and only exceptionally in the grafts. Thus, the developing neurons can extend their axons outside the spinal cord into the implants of adult soleus muscle and nerve, but immature nerve-muscle implants fail to attract and/or support axonal outgrowth. The reinnervation potential of the host's spinal neurons was enhanced by cografting of embryonic spinal cord.

Possible consequences of disruption of neuromuscular contacts in early development for motoneurone survival.

Motoneurones are known to die (1) during embryonic development (naturally occurring cell death), (2) early in postnatal development after axonal injury, and (3) as a consequence of disease such as SMA. Interactions with the target emerges as an important factor for survival of developing motoneurones. The evidence for the target dependence od of developing motoneurones will be presented and the mechanisms by which the muscle may regulate motoneurone survival discussed. Results that argue for the following proposal will be given: with maturation of the CNS motor activity in all mammals increases as do the functional demands on the motoneurones. The target muscle's role is to induce changes in the motoneurone to make it competent to respond to increased amounts of glutamate from excitatory inputs and thus allow it to carry out the tasks associated with its increased activity. A failure of the muscle to induce these changes in the motoneurone's phenotype in time may lead to motoneurone death. In addition new approaches that could (1) improve motoneurone survival, and (2) use embryonic grafts to replace the lost cells will be discussed.

Factors influencing survival of transplanted embryonic motoneurones in the spinal cord of adult rats.

The survival of transplanted embryonic motoneurones in the initially intact spinal cord of adult rats was studied and compared to that previously observed in the motoneurone-depleted cord. Embryonic (ED 11-12) spinal grafts prelabeled with 5-bromo-2'-deoxyuridine (BrDUr) were placed in the intact lumbar cord of the hosts. To provide a target for grafted embryonic motoneurones and to guide their axons to it, the contralateral extensor hallucis longus (EHL) muscle with its nerve attached was transferred paravertebrally. The nerve stump was implanted in the cord at the site of transplantation. Eight to 14 weeks later BrDUr-labeled motoneurone-like cells had migrated outside the grafts into the host's neuropil, preferentially into the anterior horn. Following injection of HRP into the implanted EHL muscle 6-17 weeks after transplantation a few retrogradely labeled motoneurones were seen in the host's anterior horn around the grafts. The lumbar cord of the rats with neuromuscular implants but without embryonic grafts had no retrogradely labeled cells. However, most animals, both with and without embryonic grafts, had retrogradely labeled motoneurones in the thoracic cord, which may contribute to the reinnervation of the implanted muscle. Thus, although some embryonic motoneurones can survive, migrate into the proper location, and probably innervate a host muscle when transplanted into the intact spinal cord, their number was significantly fewer than that in the motoneurone-depleted cord. The results show that reduction of the host's motoneurone pool increases chances of their survival.