Neurological factors and Cesarean section in Australian women with epilepsy.

OBJECTIVES: To analyze the records of the pregnancies of 2283 Australian women with epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy database to identify neurological factors relevant to the Cesarean sections carried out in these pregnancies. RESULTS: The Cesarean section rate in Australian women overall increased by an average of 0.59% annually over 20 years, from 26.0% to its calculated 2020 value of 37.3%. For the operations in women with epilepsy, the corresponding figures were 0.71% annually, and 34.4% and 48.7%. The average annual rate of increase for pre-labor operations was 0.89% to a 2020 value of 39.1%, the annual rate for operations during labor showing no statistically significant change. Multivariate regression analysis identified a number of characteristics of women with epilepsy that were statistically significantly associated with an increased likelihood of Cesarean section, but of these only seizures continuing to occur in the third trimester and having chronic illness, in particular migraine, were neurological ones. In 70 migraine-affected women, the Cesarean section rate was 51.4%, compared with 39% in the remaining pregnancies (P < 0.05). CONCLUSIONS: Having seizures in the final trimester of pregnancy and having chronic neurological illness, especially migraine, favored Cesarean section being carried out in Australian women with epilepsy, but did not adequately account for the increasing rates of occurrence of the operation over the past 20 years.

Anti-epileptic drug exposure and risk of foetal death in utero.

OBJECTIVE: To clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death. METHODS: Analysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy. RESULTS: The relative risk (6.46; 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure. CONCLUSIONS: Intrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy.

Antiepileptic drug polytherapy in pregnant women with epilepsy.

OBJECTIVE: To study seizure control and rates of foetal malformation in pregnancies of women with epilepsy treated with antiepileptic drug polytherapy. METHODS: The use of conventional statistical methods to analyse the Australian Pregnancy Register records of 1810 pregnancies in women with epilepsy, 508 treated with antiepileptic drug polytherapy. RESULTS: Polytherapy-treated pregnancies were less often seizure free than monotherapy-treated ones, for both focal (36.0% vs 51.9%: P < .05) and primary generalized epilepsies (41.1% vs 69.3%; P < .05). Drug combinations with dissimilar and similar mechanisms of action achieved similar rates of seizure freedom during pregnancy (36.3% vs 38.3%). The increased rate of malformed foetuses in polytherapy pregnancies depended on valproate or topiramate being in the drug combinations. The combinations of lamotrigine and levetiracetam offered the chance of seizure control and foetal safety. CONCLUSIONS: In pregnancy, the use of antiepileptic drug combinations is not necessarily disadvantageous to mother and foetus if valproate and topiramate are avoided.

Predicting epileptic seizure control during pregnancy.

OBJECTIVE: The objective of the study was to assess whether the type of seizure disorder present in the prospective mother with epilepsy, her use of antiepileptic drugs (AEDs) in early pregnancy, and her seizure control before pregnancy help predict her prospects for seizure freedom throughout pregnancy. METHODS: This paper is based on data accumulated in the Australian Pregnancy Register (APR) between 1998 and late 2016. Information was analyzed concerning epileptic seizure occurrence and AED therapy taken before and during pregnancy, using simple statistical and confidence interval (C.I.) methods, mainly relative risk (R.R.) calculations. RESULTS: After excluding pregnancies lost to follow-up, and those that ended prematurely because of spontaneous abortion or stillbirth, 1939 pregnancies were available for study. Seizures had occurred during pregnancy in 829 (42.8%), and convulsive seizures in 385 (19.9%). Seizures of any type occurred in 78.4% of pregnancies where seizures had occurred in the previous year (active epilepsy) and in 22.3% of those associated with inactive epilepsy. Seizures of any type had occurred in 54.9% of pregnancies initially unexposed to AEDs and in 45.5% of those treated with AEDs throughout. The corresponding figures for convulsive seizures during pregnancy were 31.7% and 22.3%. There was statistically significant evidence that, in women with epilepsy (WWE), having a seizure disorder that was active in the prepregnancy year and one untreated in early pregnancy was associated with decreased prospects of seizure freedom during pregnancy. Decreased chances of seizure-free pregnancies in women with focal epilepsies and those treated with multiple AEDs were probably explained by greater frequencies of active seizure disorders in these patient categories. CONCLUSIONS: Women with epilepsy who experience seizures in the year prior to pregnancy appear 3 or 4 times more likely to continue to have seizures during pregnancy than women whose seizures are fully controlled prior to pregnancy. Not taking AEDs in early pregnancy also increases the hazard for seizure occurrence in pregnancy.

Triptan use in Australia 1997-2015: A pharmacoepidemiological study.

OBJECTIVE: This study examined the use of triptan derivatives in Australia between 1997 and 2015, based on a national drug reimbursement database, and compared patterns of use with available international data. METHODS: We obtained publically available data on the number of prescriptions for triptans marketed in Australia (sumatriptan, eletriptan, rizatriptan, zolmitriptan, naratriptan). Dispensed use was measured as defined daily dose (DDD per 1000 population per day) for Australia's concessional beneficiaries (low-income earners, people with disabilities, and seniors). RESULTS: Total triptan use increased at an average annual rate of 112% over the 18-year period. Sumatriptan was the preferred triptan throughout (average annual increase 45%). Zolmitriptan and naratriptan use peaked in 2004, then decreased. Rizatriptan and eletriptan became available in 2010. There were 3.2-fold and 5.9-fold annual increases in their use from 2011 to 2105. There was some evidence suggesting that pattern of triptan use in concessional beneficiaries probably reflected pattern of overall triptan use in Australia. CONCLUSIONS: The use of triptan derivatives in Australia per head of population for treating migraine attacks continued to increase over the 18-year period studied, with use of recently introduced derivatives more than substituting for decreased use of older triptans. This suggests that the available treatments of migraine attacks had achieved what were considered less than adequate therapeutic outcomes.

Antiepileptic drugs, foetal malformations and spontaneous abortions.

BACKGROUND: Some recent studies have found an association between foetal malformations in earlier antiepileptic drug (AED)-exposed pregnancies and an increased hazard of such malformations in subsequent pregnancies. We investigated this matter further, and also considered the possible role of spontaneous abortions in previous pregnancies, in this situation. METHODS: Analysis of foetal malformation data for current and previous pregnancies in women taking AEDs and women with untreated epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy (APR) from 1999 to late 2014. RESULTS: Antiepileptic drug-treated women with either a malformed foetus or a spontaneous abortion in their previous pregnancy had a statistically significant twofold to threefold increased risk of foetal malformation in their next pregnancy, compared with similarly treated women with normal offspring in their previous pregnancy. This was not seen in the same circumstances in women with untreated epilepsy. On AED treatment, the women were more likely to have spontaneous abortions than in their previous untreated pregnancies. Possibly some of the increased abortion rate resulted from drug-related malformations that were incompatible with continuing intrauterine survival. CONCLUSIONS: In assessing the hazard of an AED-treated woman having a malformed foetus, it is important to know both the AEDs being taken and, if there had been a previous pregnancy, whether a foetal malformation or a spontaneous abortion occurred in it.

Does pregnancy per se make epilepsy worse?

OBJECTIVE: To determine whether being pregnant in its own right alters epileptic seizure control. MATERIALS/METHODS: Study of 148 pregnancies in women who took no antiepileptic drugs before pregnancy and in at least the earlier half of pregnancy, 69 taking none throughout pregnancy. RESULTS: More women (P < 0.01) had seizures of any type during pregnancy (45.9%) than in the prepregnancy year (34.5%), and also convulsive seizures (30.4% vs 12.3%). After excluding potential confounding factors, viz. late prepregnancy drug withdrawal, treatment resumption in pregnancy possibly preventing seizure recurrence, the figures became seizures of any type 56.6% during and 35.5% before pregnancy and convulsive seizures 39.4% during and 18.2% before pregnancy (both P < 0.01). There was a non-statistically significant greater tendency for seizure control to be lost during pregnancy in genetic generalized than in focal epilepsies (54.2% vs 35.5%). CONCLUSIONS: Irrespective of its effects on antiepileptic drug disposition, being pregnant per se seems to impair epileptic seizure control.

The teratogenicity of the newer antiepileptic drugs - an update.

OBJECTIVE: To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate. MATERIALS AND METHODS: Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester. RESULTS: Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure. CONCLUSIONS: Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.

Associations between particular types of fetal malformation and antiepileptic drug exposure in utero.

OBJECTIVE: To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy. METHODS: Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy). RESULTS: There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities. CONCLUSIONS: The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential.

Foetal malformations after exposure to antiepileptic drugs in utero assessed at birth and 12 months later: observations from the Australian pregnancy register.

BACKGROUND: In studies investigating foetal malformations associated with antiepileptic drug exposure during pregnancy, the common practice has been to assess the incidence and nature of the malformations at, or soon after, birth. The adequacy of this approach to determine the true incidence of the malformations has received little attention. AIMS OF THE STUDY: To compare the incidence and natures of the foetal malformations recognized by, or soon after, birth with similar data for malformations recognized in the first post-natal year. METHODS: Analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy. RESULTS: Up to 25% of the malformations recognized by the end of the first post-natal year had not been detected by, or soon after, birth. There was a tendency for the late-recognized malformations to differ from the early-recognized ones in relation to the body parts involved. CONCLUSIONS: Early assessment and delayed assessment of infants for the presence of foetal malformations are complementary, with the latter resulting in finding a higher incidence of malformations. However, omission of an early post-natal assessment may result in biases because of loss of subjects to follow-up.

Changing patterns of antiepileptic drug use in pregnant Australian women.

OBJECTIVE: To trace the pattern of antiepileptic drug (AED) use in pregnant Australian women annually from 1999 to 2007, and correlate it with the pattern of AED use in the wider community. METHODS: Analysis of data from the Australian Register of AEDs in Pregnancy, related to Australian population data for AED prescriptions. RESULTS: Over the study period, prescribing of carbamazepine, phenytoin and valproate for pregnant women decreased, and prescribing of lamotrigine, topiramate and levetiracetam increased. These changes tended to parallel prescribing trends in the wider community, except for valproate, whose prescribing in the overall community increased as its prescribing, and its dosage prescribed, decreased in pregnancy. Concomitant with this, there was a trend towards fewer births of foetuses with abnormalities. CONCLUSIONS: While otherwise following national AED prescribing trends, Australian prescribers are reducing the use and dose of valproate in pregnant women, likely in recognition of the teratogenic hazards of this drug.

James Ross (1837-1892) and his forgotten neurology textbook of 1881.

James Ross (1837-1892) was an Aberdeen medical graduate who, after 13 years in rural general practice, mainly in Lancashire, became a pathologist and then physician to the Manchester Royal Infirmary and professor of medicine at Owens College, Manchester. In mid-career he developed a major interest in clinical neurology and became, apart from Byrom Bramwell in Edinburgh, the only contemporary British physician outside London who had widely recognised neurological expertise. Ross made several notable original contributions to neurological knowledge, particularly in relation to aphasia and peripheral neuritis. He wrote the entire contents of the two editions of the massive two-volume A Treatise on the Diseases of the Nervous System (1881 and 1883), which was very favourably reviewed and commercially successful but which, like its author who died at the height of his powers, was soon forgotten once William Gowers' A Manual of Diseases of the Nervous System became available in the late 1880s.

Hubert Airy, contemporary men of science and the migraine aura.

Although there had been occasional references to the visual aura of migraine even in ancient medicine, little attention was given to the phenomenon until the first half of the nineteenth century when French authors began to describe it. In the medicine of English-speaking countries, apart from a few descriptions, it went largely unnoticed until the British Astronomer Royal, Sir George Airy, described his own experience of the visual aura in 1865. Five years later his son, Hubert Airy, also described his experience of it and that of a number of eminent contemporary men of science. The topic of the migraine aura was almost immediately taken up by two of the younger Airy's contemporaries and fellow Cambridge medical graduates, Peter Wallrock Latham and Edward Liveing, in their monographs. Subsequently, migraine with aura quickly became a well-recognised clinical entity in British medicine.

Absinthe, epileptic seizures and Valentin Magnan.

Absinthe is an alcoholic liquor containing extracts from the wormwood plant. It was widely consumed in France in the late nineteenth century. Its production was banned in 1915, partly because it was thought to cause neurological disturbances, including mental changes and epileptic seizures. Modern knowledge of an acceptable content of the convulsant alpha-thujone in absinthe has allowed the lifting of the production bans, and called into question the experimental work of Valentin Magnan in the 1870s, which formed the scientific background to the campaign against absinthe. An examination of Magnan's published investigations suggests that his science was very adequate by the standards of his time, and that he had shown that an alcohol-soluble component of wormwood did produce lapses of consciousness, myoclonic jerks and tonic-clonic convulsions in animals. Whether that component, presumably thujone, was present at convulsant concentrations in some of the available absinthes of Magnan's time cannot now be known.

Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register.

PURPOSE: This paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data. METHOD: Over 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analysed using conventional statistical techniques, confidence interval methods, and logistic regression. RESULTS: By 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy. There were (i) dose-related increased incidences of pregnancies carrying foetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (P < .05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the foetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that pre-conception folate supplementation reduced the hazard of AED-associated foetal malformation. AED polytherapy did not increase foetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard. CONCLUSIONS: If it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.

Marshall Hall, the reflex arc and epilepsy.

Marshall Hall (1790-1857), who graduated from the University of Edinburgh's Medical School in 1812, was considered one of the greatest physiologists of his day. He advanced knowledge in various areas of medicine, in particular elucidating the mechanism of reflex activity in 1833. Hall suggested that convulsive epileptic seizures arose from heightened activity in the afferent limb or the central component of the reflex arc. From 1838 onwards he developed the idea that reflex-mediated neck muscle spasm in seizures obstructed cerebral venous return, congested the brain and thus caused unconsciousness. Associated reflex-mediated laryngeal spasm then caused convulsing. This was the most comprehensive physiologically based explanation of the major features of the convulsive epileptic seizure then available. Hall subsequently advocated and employed tracheotomy to prevent epileptic convulsing. His idea was taken up, modified and made more acceptable by others, and for a generation was the widely acknowledged basis for interpreting epileptogenesis. However, from 1870 onwards it was superseded by John Hughlings Jackson's accumulating evidence that epileptic seizures often arose in the cerebral cortex.

The neurological legacy of John Russell Reynolds (1828-1896).

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.

Rigor mortis and the epileptology of Charles Bland Radcliffe (1822-1889).

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.

Changing Australian prescribing patterns for antiepileptic drugs in pregnancy and their possible consequences.

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.

The epileptology of William Aldren Turner.

William Aldren Turner (1864-1945), in his day Physician to the National Hospital, Queen Square, and to King's College Hospital, London, was one of the major figures in the world of epileptology in the period between Hughlings Jackson in the latter part of the 19th century and the advent of electroencephalography in the 1930s. Although he also made contributions to knowledge in other areas of neurology, and with Grainger Stewart wrote a competent textbook on that subject, Turner's main professional interest throughout his career seems to have been epilepsy. On the basis of a series of earlier, rather heavily statistical, personal publications dealing with various aspects of the disorder, he authored what became a well-accepted monograph entitled Epilepsy - a study of the idiopathic disorder, which appeared in 1907, and he also gave the 1910 Morison lectures in Edinburgh on the topic. His writings on epilepsy over a period of three decades consolidated knowledge rather than led to significant advances, but helped maintain interest in the disorder during a rather long fallow phase in the development of the understanding of its nature.