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The foetal outcomes of 2,635 pregnancies recorded in the Australian Pregnancy Register were studied. In at least the initial 4months of 515 pregnancies, there had been no intrauterine exposure to antiepileptic drugs, though the women involved in 264 of these pregnancies took antiepileptic drugs in later pregnancies. Compared with these 515 drug-unexposed pregnancies, foetal malformations risks were increased more than five-fold in association with valproate monotherapy, and more than doubled in association with carbamazepine monotherapy (p<0.05). There were no statistically significant increases in malformation rates associated with other more commonly used antiepileptic drugs, while the malformation risk in relation to levetiracetam exposure was lower than that in the drug-unexposed pregnancies. The published literature has rather consistently shown raised malformation rates associated with carbamazepine monotherapy, though only once was it statistically significant. There now appears to be enough evidence to make it likely that carbamazepine possesses some teratogenic capacity. This makes it unwise to employ the malformation rate associated with carbamazepine monotherapy as a comparator when assessing the foetal hazards from exposure to newer antiepileptic drugs. Levetiracetam may prove a better comparator if adequate untreated control material is unobtainable., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The demographic characteristics, details of pregnancies, epilepsies, and treatment of 855 pregnant women with epilepsy enrolled in the Australian Antiepileptic Drugs in Pregnancy Register during 1999-2005 were compared with the corresponding data for the 801 women enrolled from 2006-2012. We estimate that the Register captures approximately 1 in 12 of all pregnancies in Australian women with epilepsy. A number of statistically significant changes were found, with nearly all explained by factors such as re-enrolment of women who had enrolled earlier pregnancies, changes in general population behaviour, altered attitudes to prescribing valproate and using it in lower doses, and the advent of newer antiepileptic drugs which have displaced the use of older agents. It appears that the Register has continued to capture a reasonably representative sample of pregnant Australian women with epilepsy as time has passed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We report progress in the accumulation of data by the Australian Pregnancy Register over 64 months, confirming the rise in enrollment and the predominantly epileptic indication for taking antiepileptic drugs. Eighty percent of the enrollment was prospective. The focus of the current report is the observation that as a possible result of education and dissemination of information about the risks of exposure to high-dose valproate, there has been a decline in the drug's doses prescribed in Australia, as well as a decline in the proportion of patients prescribed this drug in pregnancy. The risk of teratogenicity associated with valproate in doses in excess of 1100 mg/day was confirmed, and the incidence of lamotrigine-related malformations was comparable to that associated with exposure to phenytoin and carbamazepine. Reporting of data for this paper took into account the 12 months follow-up period for each pregnancy outcome, thus in effect making the evaluation period 21 months for each pregnancy and its outcome.

Sir John Russell Reynolds was an eminent and highly influential physician in the Victorian era who held the Presidencies of the Royal College of Physicians of London, and of the British Medical Association. He was the protégée of the great experimental physiologist, Marshall Hall, who discovered the reflex arc, and succeeded to Hall's clinical practice in London. Reynolds' thought and clinical activities linked the emerging British neurology of the first half of the 19th century with its blossoming, particularly in London, from 1860 onwards. In his writings Reynolds was the first English author to apply the approach to classification of neurological disorders that is still often used, though now in modified form. He was also the first to enunciate the notion of positive and negative symptoms arising from neurological disease and to suggest their pathogenesis, and was arguably the originator of the influential concept that an idiopathic disease, epilepsy, existed, one to be distinguished from 'epileptiform' seizures due to brain pathology.

Charles Bland Radcliffe (1822-1889) was one of the physicians who made major contributions to the literature on epilepsy in the mid-19th century, when the modern understanding of the disorder was beginning to emerge, particularly in England. His experimental work was concerned with the electrical properties of frog muscle and nerve. Early in his career he related his experimental findings to the phenomenon of rigor mortis and concluded that, contrary to the general belief of the time, muscle contraction depended on the cessation of nerve input, and muscle relaxation on its presence. He adhered to this counter-intuitive interpretation throughout his life and, based on it, produced an epileptology that was very different from those of his contemporaries and successors. His interpretations were ultimately without any direct influence on the advance of knowledge. However, his idea that withdrawal of an inhibitory process released previously suppressed muscular contractile powers, when applied to the brain rather than the periphery of the nervous system, permitted Hughlings Jackson to explain certain psychological phenomena that accompany or follow some epileptic events. As well, Radcliffe was one of the chief early advocates for potassium bromide, the first effective anticonvulsant.

Lamotrigine concentrations were measured simultaneously (as far as was feasible) in stimulated and unstimulated saliva samples, and in plasma, from seven adult volunteers over a 32 h period following a single 50 mg dose of the drug, and in 20 children and adolescents during the course of routine antiepileptic therapy. In individuals there was a close correlation between the measurements at least 2 h after ingestion of the drug. Concentrations in stimulated and unstimulated saliva were similar; the stimulation produced little change in the saliva secretion rate. The saliva-to-plasma concentration ratio increased linearly by 0.78% for each 1 mg/L plasma lamotrigine concentration, with a mean value of 48.8% at a plasma lamotrigine concentration of 10 mg/L. With appropriate precautions as to the timing of saliva collections, and a single plasma lamotrigine concentration measurement to calibrate the salivary values in the individual, salivary lamotrigine concentration measurement appears to be a practicable approach to therapeutic drug monitoring. This has significant implications for the elucidation of the pharmacokinetics of lamotrigine in the paediatric population.

The modern understanding of the pathogenesis of migraine, based on the concept that it is a neurovascular disorder, is often thought to have emerged from the work of Harold Wolff in the period 1932-1962. However, over the preceding 300 years, from William Harvey onwards, various hypotheses of the pathogenesis of migraine had been proposed, a few bearing reasonably strong resemblances to Wolff's ideas, though based on less adequate evidence. Many of these earlier hypotheses regarded migraine either primarily as a vascular (e.g., Willis, Wepfer, Latham) or as a neural disorder (e.g., Harvey, Lieving and his 'nerve storms'). There were also variations around these two major themes and in the 19th Century a number of neurovascular type hypotheses emerged assigning a major role in migraine pathogenesis to the autonomic nervous system. In addition, during the three centuries there were a number of other hypotheses based on different postulated pathogenic mechanisms, some quite ingenious, which had relatively brief vogues. No hypothesis has yet proved capable of explaining all the features of migraine satisfactorily.

Unlabelled: To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different anti-epileptic drugs (AED) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study., Methods: A voluntary, Australia-wide, telephone-interview-based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy; with epilepsy not taking AEDs; taking AEDs for a non-epileptic indication. Four hundred and fifty eligible women were enrolled over 40 months. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes., Results: 354 (87.8%) pregnancy outcomes resulted in a healthy live birth, 26 (6.5%) had a FM, 4 (1%) a death in utero, 1 (0.2%) a premature labour with stillbirth, 14 (3.5%) a spontaneous abortion and 4 lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (16.0%) compared with those exposed to all other AEDs (16.0% vs. 2.4%, P < 0.01) or no AEDs (16.0% vs. 3.1%, [Formula: see text] ). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (1,975 vs. 1,128 mg, P < 0.01). The incidence of FM with VPA doses >or= 1,100 mg was 30.2% vs. 3.2% with doses <1,100 mg (P <0.01)., Conclusions: There is a dose-effect relationship for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy.

Since it was written about the middle of the 1st Century AD, and up to comparatively recent times, the great Herbal, or Materia Medica, of Dioscorides provided medicine with its chief source of information about what were then considered therapeutic substances. The work contained data on various materials of botanical, biological and mineral origin which were claimed to provide benefit to sufferers from epilepsy, though often with no clear underlying rationale for their use. Some of these materials continued to be used as antiepileptic remedies over many centuries till they were finally recognised to be without useful effect in the disorder. The longest survivor amongst the Dioscoridean antiepileptic remedies was a rather esoteric one, viz. two stones taken from the belly of a young swallow during the rising phase of the moon and also whilst the swallow's parent birds were absent from the nest. The stones, or one of them, were worn against the skin of the seizure sufferer. The use of the swallow stones for epilepsy was recommended as late as in the writings of Thomas Willis (1675).

Over the past decade the various triptan derivatives have been accepted as the most effective available agents for relieving migraine attacks. Prior to that, for a period of half a century, ergotamine was the only 'specific' available for this purpose. In 1918, Stoll had isolated it from the various alkaloids present in extracts of the sclerotia of the fungus Claviceps purpurea (ergot), which grow on rye and, to a lesser extent, on other grasses. By 1925 ergotamine was beginning to be used to treat migraine attacks. However, as ergotamine was present in extracts of ergot, which had been used to treat migraine first in Italy in 1862, and then by Edward Woakes (1868) in England, and after him by Albert Eulenburg in Germany (1883), the drug had actually come into unrecognised use for the disorder more than half a century before ergotamine itself was known to exist. Unfortunately, because of ergotamine's chemical and pharmacokinetic properties, extracts of ergot of rye were incapable of producing consistent therapeutic results, so that general acceptance that the first specific substance for migraine treatment existed had to wait until pure ergotamine was available for administration.

During the period 1778-1780 the Swiss physician Samuel A A D Tissot (1728-1797) published his Traité des nerfs et de leur maladies, a work which continued to be available and widely influential until at least the middle of the following century. It contained a long chapter dealing with migraine, based on the earlier literature on the topic and on Tissot's own clinical experience. The work appeared at the beginning of the modern era of interest in migraine, and provided the first reasonably adequate and systematic account of the disorder to become widely available. Its descriptions of migraine phenomena have an enduring validity, though Tissot's ideas on the pathogenesis of the disorder, viz. that it usually arose from stomach disturbance, were not founded on satisfactory evidence and are long since superseded.

Thomas Willis (1621-1675), author of the classical work Cerebri Anatome (1664), was arguably the father of the modern era of neurology. His clinical neurology, as described in his Pathologiae Cerebri (1667) and De Anima Brutorum (1672), was largely derived from personal observations and not from traditional authorities and was based around his concept of the animal spirits, a fictitious entity in many ways analogous to the present day idea of the nerve impulse. This concept allowed him to develop a pathology of the animal spirits which embraced the whole content of the clinical neurology and psychiatry of his times. The anatomical and physiological background to Willis' concepts of animal spirit dysfunction, and those disorders he regarded as due to disturbed function of intrinsically normal animal spirits, have been dealt with in the previous part of this paper. The disorders he attributed to intrinsically abnormal animal spirits, dealt with in this part of the paper, comprised two categories. In one, the animal spirits possessed explosive properties, whilst in the other the abnormalities were non-explosive in their nature. The former category included epilepsy, hysteria and hypochondriasis, whilst the latter included mainly disorders now considered psychiatric e.g. delirium, melancholy, madness and stupidity. Willis' ideas about the pathogenesis of nervous system disorder seem never to have been generally accepted, partly because they appeared at a time when others were increasingly calling into question the existence of the animal spirits. Nevertheless, Willis' attempt to record and interpret all nervous system disease on the basis of disorder of function of a single underlying mechanism represents a formidable synthetic intellectual endeavour on the part of a very busy physician.

Thomas Willis (1621-1675), author of the classical work Cerebri Anatome (1664), was arguably the father of the modern era of neurology. As compared with his neuroanatomy, relatively little attention has been paid to Willis' clinical neurology, as described in his Pathologiae Cerebri (1667) and De Anima Brutorum (1672), where he gave a structured account of disease of the nervous system as it was known in his day. His account was largely derived from personal observations and not from traditional authorities and was based around his concept of the animal spirits, a fictitious entity in many ways analogous to the present day idea of the nerve impulse. This concept allowed him to develop a pathology of the animal spirits which embraced the whole content of the clinical neurology and psychiatry of his times. The anatomical and physiological background to Willis' concepts of animal spirit dysfunction, and those disorders he regarded as due to disturbed function of intrinsically normal animal spirits (mainly headache, disorders of consciousness, apoplexy and palsy) are dealt with in the present paper. The disorders he attributed to inherently abnormal animal spirits are considered in a second part of the paper.

The Australian Alfred Walter Campbell (1868-1937) is remembered as one of the two chief pioneers of the study of the cytoarchitectonics of the primate cerebral cortex. He had worked in Britain carrying out neuroanatomical and neuropathological research for almost two decades before his famous monograph on Histological Studies on the Localisation of Cerebral Function appeared in 1905. In that year he returned to his native Australia and practiced for over 30 years in Sydney as a neurologist rather than a neuropathologist, publishing mainly clinical material though he was involved in the investigation of the epidemic of Australian X disease, a viral encephalitis. His abrupt change in both the nature and the location of his career at a time when he was well established in Britain appears to have been a consequence of his marriage and the need to provide for a family. His simultaneous apparent abandonment of research seems not to have really been the case. As judged from the contents of a paper presented to a local medical congress in Sydney in 1911, it appears that, in Australia, Campbell did carry out a major comparative anatomical and histological investigation of the possibility of localization of function in the cerebellar cortex. He never published this work in detail. His investigation let him to conclude that no such localization of function existed, a view contrary to the then topical interpretation of Bolk (1906), but one in accordance with Gordon Holmes' views a decade later. Campbell's circumstances in Sydney, his extremely reticent nature and the essentially negative outcome of his investigation probably explain his failure to make his study more widely known.

Robert Whytt (1714-1766), Professor of the Theory of Medicine in the University of Edinburgh from 1745 until his death, was one of the great figures of the early years of the so-called Scottish Enlightenment. His investigations of neurological phenomena and their mechanisms in animals and humans led him to enunciate what was in essence the modern concept of reflex action, although he called the phenomenon 'sympathy'. Whytt recognise the peripheral neural mechanisms of the reflex arc and demonstrated that its central element occurred in a limited segment of the neuraxis, where he invoked an 'inner sentinent principle' to mediate neural activity. In 1751, before he had published his formal analysis of the reflex arc, Whytt described the direct and consensual pupillary response to light and the pupillary response to accommodation. On the basis of some simple, well conceived and controlled observations, Whytt showed that the pupillary response was not due to a direct effect of light on the uvea or pupillary muscles, but involved light acting on the retina, leading to an activation of the optic nerve which caused the sentinent principal within the neuraxis to produce pupillary constriction via the activity of the nerves to the pupillary muscles. Ever since, the pupillary reflex has sometimes been referred to as Whytt's reflex., (Copyright 2000 Harcourt Publishers Ltd.)

The International League Against Epilepsy has devised classifications which subdivide both epileptic seizures and the epilepsies and epileptic syndromes into two main types: generalized and partial. Epileptogenesis in the partial variety is believed to originate in a localized part of the cerebral cortex and results in clinical manifestations which appear to commence in only a restricted part of the sufferer's body. Use of the term 'partial' in relation to these entities has often been said to date back to James Cowles Prichard (1786-1849) who was the author of the second major work on epilepsy to be written in the UK. While Prichard certainly described 'partial epilepsy', he stated that he intended the words to refer to the fact that the disorder he described under that designation was only partly, and not fully, epileptic in nature. He did not refer to the fact that it affected only part of the body as his basis for using the term. In the absence of knowledge of localization of function in the cerebral cortex at Prichard's time of writing, he had no basis for deducing that the underlying epileptic process arose in only part of the brain. However, there is an earlier mention of the use of the word 'partial' in relation to epilepsy. This is to be found in the writings of the great Scottish physician William Cullen (1710-1790), and there is reason to believe that Prichard should have been aware of this. Cullen used 'partial' with an intention similar to the modern one, employing the word to refer to seizures which affected only part of the body. Credit for the origin of the idea of a 'partial' epilepsy should belong to Cullen; not only did he have priority over Prichard but his concept was closer to the modern one than was Prichard's. Copyright 1999 Harcourt Publishers Ltd.

In 1895 Sir James Crichton-Browne lectured on the dreamy mental states that had largely gone unnoticed until his old friend John Hughlings Jackson had first recognized them nearly 20 years earlier as a component of some epileptic seizures. In 1897 Jackson described the association between such dreamy states and pathology in the uncinate gyrus of the brain, thus delineating the phenomenon of uncinate (temporal lobe) epilepsy. Crichton-Browne's account of dreamy states is easier to follow than Jackson's various writings on the subject, and makes it clear that such states are not always epileptic in nature. Jackson believed that epileptic dreamy states were not due to the brain areas responsible being involved by the epileptic discharge itself, but were release phenomena resulting from the discharge inactivating higher levels of brain function. In the century since Jackson, there has been little advance in understanding of the detailed mechanisms of production of the various abnormal psychic experiences which occur in these dreamy states which, following Kinnier Wilson's analysis 1928, are now more usually considered in terms of their individual components.

The relationships between the various epileptic syndromes, which comprise the idiopathic generalized epilepsies that commence after infancy, were explored in 451 patients by comparing the incidences of various clinical and electroencephalographic features in subsets of the patients, determined primarily by their clinical patterns of seizure phenomena (absences, myoclonic and generalized tonic-clonic seizures), and secondarily by their ages at the onset of their seizures. The approach showed a bimodal distribution of ages of onset in the absence epilepsy group only. More subjects whose absences had begun under 10 years of age experienced very frequent episodes (52.0% vs 26.9%) and fewer experienced generalized tonic-clonic seizures (44.0% vs 71.2%). These differences were consistent with the distinction made in the International League Against Epilepsy's Classification between childhood and adolescent onset absence epilepsy. There were no unambiguous age of onset related differences in the incidences of the features studied within each of the myoclonic seizure and the generalized tonic-clonic seizure only groups, although there were differences in the incidences of the features between the two groups. Thus the idiopathic generalized epilepsies studied appeared to comprise a number of discrete entities rather than a smooth continuum of age of onset related epileptic phenomena.

Unilateral motor epileptic seizures occurred in 118 of 1902 persons with seizure disorders referred to a consultant neurological practice over a 30 year period. The unilateral motor seizures were nearly always manifestations of partial (focal, localisation related) epilepsy but, particularly if they occurred on different sides on different occasions, could be due to generalised onset epilepsy (10.2% of cases). The risk of cerebral tumour in those with unilateral motor seizures (10.2%) was greater than that for those with all other forms of seizure disorder (relative risk 3.56 times; 95% C.I. = 1.95 to 6.49 times). Unlike the situation in younger persons, if unilateral motor seizures began after the age of 20 years the chance of an underlying cerebral tumour (23.4%) was significantly higher than in other persons with adult onset partial seizures (relative risk 2.62 times; 95% C.I. = 1.44 to 4.77 times) and was much greater than that in all other seizure sufferers (relative risk 8.35 times; 95% C.I. = 4.66 to 14.9 times).