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Aim: To assess whether lamotrigine (Lamictal), when used in antiseizure medication (ASM) monotherapy, is a teratogen., Materials/methods: Analysis of data from 490 LTG monotherapy treated pregnancies and 214 pregnancies in women with epilepsy not exposed to any antiseizure medications during at least the first half of pregnancy., Results: The LTG-treated and the untreated pregnancies were well matched in nearly all regards apart from ASM exposure. There was a foetal malformation (FM) occurrence rate of 4.49 % in the LTG-exposed pregnancies and 3.27 % in the untreated pregnancies (Risk Ratio = 1.37; 95 % C.I. 0.60, 3.16). Logistic regression produced no evidence that the extent of the LTG-associated malformation occurrence hazard was LTG dose related. However, the malformation-affected body regions tended to differ between the LTG-treated and untreated pregnancies., Conclusion: The above findings do not reach a statistically significant level (P < 0.05) but, taken overall, they do not necessarily exclude the possibility that LTG may be a weak teratogen. If LTG monotherapy-associated foetal malformation occurrence rates are used as the comparator against which to evaluate the foetal malformation hazards associated with other ASMs, the findings may possibly be open to the risk of falsely reassuring outcomes., Competing Interests: Declaration of competing interest Frank Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Epilepsy Action Australia, Sanofi-Aventis, Eisai, UCB Pharma, Sci-Gen, and JAZZ Australia Mervyn Eadie: none Simon Vajda: none, (Copyright © 2025. Published by Elsevier Ltd.)

Purpose: To investigate the risk of teratogenesis occurring in relation to intrauterine exposure to infrequently used antiseizure medications in Australia., Methods: Analysis of data contained in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs., Results: There was statistically significant evidence that zonisamide, but not any other of nine infrequently used antiseizure medications in Australia, was associated with a risk of teratogenesis related to the maternal dose of the drug taken in at least the earlier half of pregnancy., Conclusions: The teratogenesis associated with zonisamide, like that associated with topiramate and possibly acetazolamide, may be an expression of a class effect shared among sulphonamide-derived carbonic anhydrase inhibitors that possess anti-seizure activity., Competing Interests: Declaration of competing interest FJE Vajda has received research support for the Australian Pregnancy Register from Epilepsy Action Australia, the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, Eisai, UCB Pharma, and Sci-Gen. T O'Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, and Sci-Gen and Eisai. P Perucca is supported by the Australian National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, The University of Melbourne, Monash University, Brain Australia, and the Weary Dunlop Medical Research Foundation. He has also received speaker honoraria or consultancy fees provided to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. JE Graham, AA Hitchcock, CM Lander, and MJ Eadie have no relevant conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To assess the role of antiseizure medication (ASM) regimens and other factors in relation to the occurrence of intrauterine foetal death (IUFD) in pregnant women with epilepsy (WWE) enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (APR)., Results: IUFDs occurred in 70 (3.01 %) of 2,323 prospective pregnancies from WWE with known outcomes in the APR. Factors associated with IUFD occurrence included older maternal age, enrolment in the APR at an earlier stage of pregnancy, history of pregnancies which did not result in livebirths, parental history of foetal malformations, and maternal use of carbamazepine, lamotrigine or ethosuximide. Individual ASM dosages were not associated with IUFD occurrence. Relative to no exposure, the risk of IUFD increased with the increasing number of ASMs used in combination (2 ASMs: relative risk, RR = 5.45 [95 % CI: 0.73-41.80]; 3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), >3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), but this finding was attenuated after adjusting for other factors implicated in IUFD occurrence. Several ASM pairs were associated with an increased risk of IUFD relative to no exposure, but these associations were lost after accounting for confounders., Conclusions: Although it is possible that prenatal ASM exposure may increase the risk of IUFD, other non-pharmacological factors are more relevant to the occurrence to IUFD in pregnant WWE., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [FJE Vajda has received research support for the Australian Pregnancy Register from Epilepsy Action Australia, the Epilepsy Society of Australia, the NHMRC, the RMH Neuroscience Foundation, Sanofi-Aventis, Eisai, UCB Pharma, and Sci-Gen. T O’Brien has received research support from the Epilepsy Society of Australia, the NHMRC, the RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, and Sci-Gen and Eisai. P Perucca is supported by an Emerging Leadership 2 Investigator Grant from the NHMRC (APP1163708), the Epilepsy Foundation, The University of Melbourne, Monash University, Brain Australia, and the Weary Dunlop Medical Research Foundation. He has also received speaker honoraria or consultancy fees provided to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. JE Graham, AA Hitchcock, CM Lander, and MJ Eadie have no relevant conflicts of interest to declare]., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

On November 8, 1923, William John Adie described an unusual disorder to the Section of Neurology of the Royal Society of Medicine. The condition comprised frequent momentary stereotyped impairments of consciousness that occurred in children, did not respond to antiseizure medications, and did not develop into epilepsy, as that term was then commonly understood, since no convulsive seizures occurred. After some time, the episodes terminated spontaneously, leaving the sufferer unhandicapped and neurologically intact. Almost certainly, Adie had described the present-day entity of childhood absence epilepsy. He termed it "pyknolepsy," knowing that the name "pyknolepsie" had been used for a similar disorder in Germany from 1916 onwards, though not reported elsewhere. Following Adie's account, published in 1924, reports of the disorder appeared in the English and French-language literature and continued to be published in German. It became increasingly accepted that pyknolepsy was a form of epilepsy that was part of Lennox's petit mal triad. The word pyknolepsy itself never became widely used and is now largely forgotten. Adie never took up the topic in print again. However, he had awakened English-language readers to one component in a broadening of the concept of what constituted epilepsy.

Purpose: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy)., Results: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy., Conclusion: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option., Competing Interests: Conflicts of Interest FJE Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Epilepsy Action, Sanofi-Aventis, Eisai, UCB Pharma, and Sci-Gen. T O’Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, and Sci-Gen and Eisai. P Perucca is supported by the Australian National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, The University of Melbourne, Monash University, Brain Australia, and the Weary Dunlop Medical Research Foundation. He has also received speaker honoraria or consultancy fees given to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. JE Graham, AA Hitchcock, CM Lander, and MJ Eadie have no relevant conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objective: The Raoul Wallenberg Australian Pregnancy Register (APR) was established to collect, analyze, and publish data on the risks to babies exposed to antiseizure medications (ASMs) and to facilitate quality improvements in management care over time. It is one of the seveal prospective observational pregnancy registers of ASMs that has been established around the world. Although the APR and other registries have contributed to knowledge gain that has been applied to decrease adverse pregnancy outcomes, their cost-effectiveness remains unknown. Here, we aimed to evaluate the economic impacts of the APR from both societal and health care system perspectives., Methods: Using decision analytic modeling, we estimated the effectiveness (prevention of adverse pregnancy outcomes) and costs (costs of adverse pregnancy outcomes and the register itself) of the APR over a 20-year time horizon (2000-2019). The comparator was set as the adverse pregnancy outcomes collected by the APR between 1998 and 2002 (i.e., no APR derived improvements in care). In the scenario analysis, we conservatively assumed a 2.5% and 5% contribution of the APR to the savings in health care and societal costs. Adverse pregnancy outcomes included stillbirth, birth defects, and induced abortion. All cost data were derived from published sources. Health and economic outcomes were extrapolated to the total target Australian epilepsy population. The primary outcomes of interest were the return of investment (ROI) for the APR and incremental cost-effectiveness ratio (ICER) for cost per adverse outcome avoided., Results: Over the 20-year time horizon, the ROI from the APR from a societal perspective was Australian dollars (AUD) 2,250 (i.e., every dollar spent on the program resulted in a return of AUD2,250). Over this time, it was estimated that 9,609 adverse pregnancy outcomes were avoided, and health care and societal costs were reduced by AUD 191 million and AUD 9.0 billion, respectively. Hence, from a health economic point of view, the APR was dominant, providing cost saving ICERs from both perspectives., Discussion: Following its inception 20+ years ago, the APR has represented excellent value for investment for Australia, being also health-saving and cost saving from a societal and a health care perspective. With the growing number of marketed ASMs, the APR is expected to continue to have a major impact in the foreseeable future., (© 2022 American Academy of Neurology.)

Objectives: To investigate control of epileptic seizures during pairs of successive pregnancies in antiseizure medication (ASM)-treated women with epilepsy., Materials and Methods: Analysis of seizure freedom rates during 436 pairs of successive pregnancies in Australian women with epilepsy, in nearly all instances long-standing epilepsy., Result: There was a higher rate of seizure-free second pregnancies compared with first paired pregnancies (63.1% vs. 51.4%; Relative Risk (R.R.) = 1.2277; 95% CI 1.0930, 1.3789) and of seizure-free pre-pregnancy years before second as compared with first paired pregnancies in the same women (63.6% vs. 52.4%; R.R. = 1.2616; 95% CI 1.1337, 1.4040). In 108 women whose ASM therapy was unaltered throughout both of their pregnancies, the seizure-freedom rate was higher in the second of the paired pregnancies (82.4% vs. 69.4%; R.R. = 1.1867, 95% CI 1.0189, 1.3821)., Conclusions: Altered ASM therapy after the first of a pair of successive pregnancies did not fully account for the better overall seizure control in the corresponding second pregnancies. Some additional factor may have been in operation, possibly a greater preparedness to undertake a further pregnancy if seizures were already fully controlled., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Edward Henry Sieveking (1816-1904) was a professionally successful and well respected nineteenth-century London physician who, over the span of some half a century, continuously held appointment to British royalty, including Queen Victoria and King Edward VII. In 1858, he published a monograph On Epilepsy and Epileptiform Seizures , with a second edition in 1861. In both editions, he described an entity cephalalgia e pileptica that comprised the occurrence of headache in association with phenomena that resembled the premonitory symptom of some epileptic seizures. However, the sufferers did not have epilepsy, in that they did not experience generalized convulsions. Sieveking, like most of his British contemporaries, had little awareness of the existence of the variety of migraine phenomena apart from headache itself. In retrospect, it seems likely that migraine with aura probably was the main basis of the disorder Sieveking designated, one that later may have been termed migralepsy .

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., Competing Interests: Conflicts of interest F.J.E. Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Epilepsy Action, Sanofi-Aventis, Eisai, UCB Pharma, and Sci-Gen. T. O’Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, and Sci-Gen and Eisai. P. Perucca is supported by an Early Career Fellowship from the National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, the Royal Australasian College of Physicians, The University of Melbourne, Monash University, the Weary Dunlop Medical Research Foundation, Brain Australia, and the Norman Beischer Medical Research Foundation. He has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. J.E. Graham, A.A. Hitchcock, R. Kuhn, C.M. Lander, and M.J. Eadie have no relevant conflicts of interest to declare. They have not received any personal funding from outside bodies in relation to their roles in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To study factors that affected previous epileptic seizure control throughout pregnancy, during labour, and in the post-natal weeks., Materials & Methods: Analysis of data concerning seizure freedom that was available at various stages of 2337 pregnancies in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs, mainly employing multiple variable logistic regression techniques., Results: Based on data available at the outset of pregnancy, the risk of seizure-affected that is, not seizure-free pregnancy was statistically significantly (p < .05) higher in pregnancies where there was previously uncontrolled epilepsy (78.1% vs. 20.8%) and focal epilepsy (51.3% vs. 39.7%), and decreased with later onset-age epilepsy (41.8% vs. 52.2% with onset before age 13 years), The risk did not differ between initially antiseizure medication (ASM)-treated or untreated pregnancies. For epilepsy receiving ASM therapy, 90.6% of 160 pregnancies of women with uncontrolled focal epilepsy that began before the age of 13 were seizure-affected. None of the above factors influenced the risk of seizures during labour, though having seizures during pregnancy increased the hazard (3.93 vs. 0.6%). Either ASM-treated pregnancy or labour being seizure-affected increased the risk of post-partum period seizures (33.0% vs. 6.67% for both stages being seizure-free). Use of particular ASMs had no statistically significant effect on the seizure control situation at any of the pregnancy stages studied., Conclusions: Obtaining full seizure control before pregnancy appeared to be the main factor in maintaining seizure freedom during pregnancy, labour and the post-natal weeks., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To investigate possible factors that influenced whether pregnancy in women with epilepsy resulted in the desirable outcome of a live-born non-malformed infant and a mother whose pregnancy had been seizure free., Results: The desirable outcome, as defined, occurred in 46.3% of unselected pregnancies in the database of the Australian Register of Antiepileptic Drugs in Pregnancy (APR). The only factor investigated that had a statistically significant (P < 0.05) effect, increasing the chance of such a desirable outcome, was freedom from seizures in the pre-pregnancy year. However, anti-seizure medication (ASM) doses, particularly valproate doses, had been reduced prior to 15.6% of the pregnancies, and this may have concealed factors that otherwise may have adversely affected the desirable outcome rate. Analysis of data for monotherapy with the more commonly used ASMs appears to suggest that employing levetiracetam at the outset of antiseizure therapy may offer a better chance of a desirable outcome to future pregnancies than monotherapy with other ASMs, but this finding is not confirmed statistically., Conclusions: In pregnancies where valproate use has already been minimized, seizure control throughout the pre-pregnancy year was associated with the best chance of a desirable outcome, as defined above. In most Australian women starting therapy for epilepsy initiating treatment with levetiracetam monotherapy may offer the best chance of such a desirable outcome to a future pregnancy, yet to be confirmed., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy., Results: Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P < 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P < 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P < 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy., Conclusions: The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Over the past 50 years, published studies have provided quantitative data on the control of epileptic seizures during pregnancy. The studies have varied in quality, and particularly in the ways in which seizure control has been assessed. However, most studies have shown that seizure occurrence rates are more likely to worsen than improve during pregnancy, though in most pregnancies the rates have been unaltered. Nearly all of the studies have involved women with antiseizure medication-treated epilepsy, but there is a little evidence that seizure control also tends to worsen in pregnancies of women with untreated epilepsy. The factors likely to contribute to the seizure worsening are (i) patient non-compliance, (ii) increased antiseizure medication clearance during pregnancy resulting in lower circulating drug concentrations relative to dose, (iii) the effects of the higher female sex hormone levels during pregnancy, oestrogens being pro-epileptogenic and progesterone anti-epileptogenic, and (iv) reluctance to use the potential teratogen valproate in women capable of pregnancy, depriving them of the most effective drug for certain types of epilepsy. Compliance can be encouraged, but at the present time only one other factor is readily correctable, i.e. the increased drug clearance. This can be compensated for by raising antiseizure medication dosage during pregnancy, guided by measurement of circulating drug concentrations. This course of action appears to reduce the chance of seizure disorder worsening during pregnancy, but so far it has not provided a complete solution to the issue., (© 2021. The Author(s).)

Objective: To ascertain whether epileptic seizure control during pregnancy differed between Australian women with previously surgically treated epilepsy, and those with only medically treated epilepsy., Materials/methods: Analysis of data for 74 pregnancies of women with surgically treated focal epilepsy, compared with that from 1013 pregnancies in women with medically treated focal epilepsy, both groups drawn from the Australian Register of Antiepileptic Drugs in Pregnancy between 1999 and 2020., Results: Seizures of all types, and also convulsive seizures, were less well controlled during pregnancy in the previously surgically treated cases, the difference for seizures of all types (68.9% versus 50.1%) being statistically significant (p < .05). This result was contrary to the outcome of a previously published study of the same question carried out in India., Conclusions: At present, it may be premature to conclude that previous epilepsy surgery will be associated with a better chance of seizure-free, or seizure-controlled, pregnancy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To assess the possible contribution of factors in additional to intrauterine anti-seizure medication (ASM) exposure in the occurrence of fetal malformation in women with ASM-treated epilepsy., Results: Logistic regression analysis showed that maternal age over 31 years, family histories of fetal malformation, and conception after assisted fertility treatment, and also dosage of valproate, carbamazepine, and topiramate, made statistically significant (P<0.05) contributions to the fetal malformation rate in 2223 pregnancies in Australian women with epilepsy. The malformation rates were lower in pregnancies where the non-ASM-associated contributory factors were not present: statistically significantly so for all ASM-exposed pregnancies, and those pregnancies exposed to the more potent teratogenic drugs., Conclusion: It is important to consider the possible roles of identified, and also possible non-identified, non-ASM factors in relation to the occurrence of fetal malformations in the pregnancies of women with ASM-treated epilepsy., Competing Interests: Declaration of Competing Interest F J E Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, RMH Neuroscience Foundation, Epilepsy Action, Sanofi-Aventis, UCB Pharma, Eisai, and Sci-Gen. T O’Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, Eisai and Sci-Gen C M Lander, JE Graham, AA Hitchcock and MJEadie have no relevant conflicts of interest to declare. No personal funding from outside bodies has been involved in their roles in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: New disease modifying therapies (DMT) to control relapsing-remitting multiple sclerosis (RRMS) have been introduced to the market in the past few years and are now widely used in Australia., Objective: To analyse the dispensed use of government subsidised RRMS DMTs in Australia from 1996 to 2019., Methods: We obtained data of dispensed use of DMTs from the Australian Government's Pharmaceutical Benefits Scheme (PBS) administered by Medicare Australia. We measured use as defined daily dose (DDD) per 100,000 population per day. We obtained jurisdictional population data from the Australian Bureau of Statistics., Results: Total DMT use increased by an average of 18% annually, from 2.4 (in 1996) to 69.9 DDD/100,000/day in 2019. Interferon β1B was the most commonly used medicine between 1996 and 2000, Interferon β1A between 2001 and 2014, and fingolimod subsequently. Among Australian states, Tasmania (the southernmost state) had the highest dispensed DMT use of 94.6 DDD/100,000/day in 2019. Concession beneficiaries under the Government's PBS had both lower use and cost per patient than general beneficiaries did. Fingolimod and ocrelizumab accounted for 55% of total expenditure on MS drug therapy in 2019., Conclusion: The use of oral DMTs might increasingly replace parenteral treatments in the near future. Given the current substantial government expenditure on oral DMTs, it will be imperative to examine the real world effectiveness of DMTs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy., Methods: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy., Results: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409)., Conclusions: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We report data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) to see if there are significant differences in relation to the courses and outcomes of the twin pregnancies contained in the register, as compared with the singleton ones., Methods: The APR has been under the oversight of Melbourne institutional Human Ethics Research Committees; all women enrolled in the APR have provided written informed consent. Data from the APR were transferred to a spreadsheet and then analyzed using simple statistical techniques including logistic regression., Results: The population studied comprised 44 twin and 2261 singleton pregnancies; thus, twin pregnancies accounted for 1.91% of all pregnancies studied. The women carrying twins tended to be older than the women with singleton pregnancies to a statistically significant extent, their pregnancies more often originated from assisted fertilization techniques, and their babies were more often delivered by cesarean section. There were no statistically significant differences in relation to antiepileptic drug (AED) therapy. Individual twins had statistically significantly lower mean birthweights than singleton babies and they were statistically significantly more often involved structurally malformed foetuses. In the first year of life, the twin pregnancies statistically significantly more often produced offspring that were affected by seizures in infancy., Significance: The data suggest that there may be an increased hazard of fetal malformation in the offspring of twin pregnancy in women with epilepsy, but that with contemporary standards of management of epilepsy and pregnancy, there is unlikely to be an increased hazard of seizure-affected pregnancy., (© 2020 International League Against Epilepsy.)

We investigated the outcome of altering antiepileptic drug (AED) therapy in the year before pregnancy on 2233 occasions in Australian women in the 20-year period of functioning of the Raoul Wallenberg Australian Pregnancy Register (APR). Therapy had been altered in 358 instances (16%) in the months prior to the pregnancy (median interval: 18 weeks). Antiepileptic drug doses had been changed in 141 pregnancies (39.4%), being decreased in 94; drugs changed in 151 (42.2%); drugs withdrawn without replacement in 66 (18.4%) but resumed in 40 before pregnancy ended. The main drugs involved were valproate (34%), phenytoin (16.5%), topiramate (12.6%), and carbamazepine (11.4%). Antiepileptic drug doses were increased significantly more often (16.9% vs. 6.4%) when epilepsy before pregnancy was not controlled, and AED treatment ceased significantly less often (13.6% vs. 24.0%). The alterations were more often made in women with generalized epilepsies and in those whose seizure disorders were not fully controlled in the prepregnancy year, suggesting that avoidance of teratogenicity and achieving improved seizure control often motivated the changes. Overall, the alterations did not result in improved rates of seizure freedom during pregnancy, as compared with pregnancies where therapy was unchanged; however, fetal malformation rates were lower 3.6% vs. 5.4%, but this difference did not attain statistical significance. The same trends regarding seizure control and malformations persisted after pregnancies involving valproate exposure were excluded. In conclusion, this analysis of the APR cohort did not demonstrate that altering AEDs before pregnancy produced a significant improvement in seizure control and the reduction in fetal malformation rate that occurred was not statistically significant., Competing Interests: Declaration of competing interest F J E Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, RMH Neuroscience Foundation, Epilepsy Action, Sanofi-Aventis, UCB Pharma, Eisai, and Sci-Gen. T O'Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, Eisai and Sci-Gen. C M Lander, JE Graham, AA Hitchcock and M J Eadie have no relevant conflicts of interest to declare. No personal funding from outside bodies has been involved in their roles in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To assess the possibility that the occurrence of seizures or the use of antiepileptic drug (AED) therapy might have influenced the rate of occurrence of volunteered histories of patient-recognized depression during pregnancy in women with epilepsy., Materials and Methods: Analysis of data from 2039 pregnancies in the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) followed during pregnancy and to the end of the year after its end., Results: Patient-recognized depression occurrence rates during pregnancy were a little lower rather than higher in seizure-affected than in seizure-free pregnancies (5.67% vs 6.41%), though higher in AED-treated than AED-untreated pregnancies (6.24% vs 5.26%; RR = 1.185, 95% CI 0.612, 2.295). Logistic regression analysis showed that carbamazepine dosage had a statistically significant relationship with a decreasing rate of patient-recognized depression occurring during pregnancy and topiramate dosage with an increasing rate., Conclusions: Carbamazepine and topiramate both have established potentials for causing teratogenesis, and it is possible that replacement of carbamazepine with a less teratogenic AED, for example levetiracetam, might result in any subsequent depression that occurs in pregnancy being inappropriately attributed to the newly introduced agent., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy., Methods: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases., Results: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR 0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR 1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant., Significance: Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy., (© 2020 International League Against Epilepsy.)

Data from 2182 pregnancies in the Australian Register of antiepileptic drugs in pregnancy that were followed to term, with 1965 followed for another year, were analyzed to ascertain whether preexisting illness influenced i. the hazard of fetal malformations, and ii. seizure control during pregnancy. Fetal malformation occurred in 74 of the 842 pregnancies associated with preexisting illness (8.8%) and in 84 of the 1340 comparator pregnancies (6.27%), Relative Risk (R.R.) = 1.402 (95% Confidence Interval (C.I.) = 1.038, 1.893). Logistic regression showed statistically significant effects of preexisting maternal drug-treated psychiatric illness, untreated psychiatric illness, and use of citalopram, carbamazepine, valproate, and topiramate in increasing hazard of fetal malformation. Preexisting nonpsychiatric illness and other antiepileptic drugs and drugs prescribed for psychiatric illness, mainly antidepressants, had no such effect. Seizures occurred during 405 of the 842 pregnancies associated with preexisting illness, and during 593 of 1340 comparison pregnancies (48.1% v 44.3%; R.R. = 1.087; 95% C.I. = 0.991, 1.192). There were no statistically significant relationships between preexisting nonpsychiatric and psychiatric illnesses separately and seizure control during pregnancy. Thus, apart from consequences of antiepileptic drug exposure, preexisting maternal psychiatric illness, in its own right, or when treated with citalopram, appears to be associated with increased hazards of fetal malformation., Competing Interests: Declaration of competing interest F J E Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, RMH Neuroscience Foundation, Epilepsy Action, sanofi-aventis, UCB Pharma, Eisai, Genzyme, and Sci-Gen. T O'Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, sanofi-aventis, UCB Pharma, Genzyme, Eisai, and Sci-Gen. C M Lander, JE Graham, AA Hitchcock, and M J Eadie have no relevant conflicts of interest to declare. No personal funding from outside bodies has been involved in their roles in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To assess (a) the incidence of seizures in the first year of life in infants born to mothers with epilepsy and (b) factors that might contribute to the seizure incidence., Materials & Methods: Analysis of data collected in the Australian Register of Antiepileptic Drugs in Pregnancy during and at the end of the year after pregnancy., Results: By the end of a year following pregnancy, seizures had occurred in the progeny of 47 pregnancies (2.40%), including febrile seizures in 18 (0.92%), the latter rate being higher than the 0.40% and 0.59% rates for the same situation in the general population reported in the recent literature. Seizures in infancy were more likely in the offspring of mothers with generalized as compared with focal epilepsies (3.65% vs 1.56%; RR = 2.332; P < .05) and within the generalized epilepsy mothers in those who were not seizure free during pregnancy (4.83% vs 2.89%). Seizures were also more likely in infants with foetal malformations, especially ones not discovered until after the first post-natal month., Conclusions: These findings may help in advising mothers with epilepsy regarding the chance of their offspring experiencing seizures in the first year of life; they also suggest the desirability of achieving maternal seizure control throughout pregnancy., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: To gain insight into the main advantages and disadvantages that might result from valproate being unavailable for women who intend to become pregnant., Materials and Methods: Analysis of data from the Australian Pregnancy Register concerning pregnancies exposed to valproate (N = 501) and pregnancies where previous valproate intake had been ceased before pregnancy (N = 101)., Results: The risk of foetal malformation associated with valproate exposure during pregnancy was dose-related, and there was a tendency for the more major malformations, including those often managed by therapeutic abortion, for example spina bifida, to occur at higher valproate doses. Had there been no exposure to valproate during pregnancy, some 80% of the foetal malformations that occurred might have been avoided. Cessation of previous valproate therapy before pregnancy was associated with an increased hazard of seizure-affected pregnancy. This was particularly the case for women with generalized epilepsies, in whom the incidence of seizure-affected pregnancy was increased by 50% to nearly 100%., Conclusions: Avoiding valproate intake during pregnancy is likely to reduce the incidence of foetal malformation, but at a cost of worsened maternal epilepsy control. Individualization of treatment is particularly important in considering withdrawal of valproate in the light of the fact that it is much more widely used in generalized epilepsy, there being fewer alternative drugs than for focal epilepsy and withdrawal is not without risk for both mother and baby. This study may provide a quantitative basis for assessing the balance between benefit and disadvantage for individual women with valproate-treated epilepsy who are considering pregnancy., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The literature suggests that cesarean delivery or birth is carried out more often in pregnant women with epilepsy (WWE) than in pregnant women in the general population. Data were utilized from the Australian Pregnancy Register (APR) for Women on Antiepileptic Medication to investigate this issue in Australia. Over almost two decades, the mean CS rate in 1900 APR women was 39.2%, but was only 29.9% in women in the general population (relative risk (R.R.) = 1.31, 95% confidence interval (C.I.) 1.24, 1.39). Rates for forceps and suction-assisted delivery were similar in the two datasets. The 9.3% excess CS rate was almost entirely accounted for by operations carried out prior to the onset of labor. The rates for CS during labor were very similar. Only 11.0% of the WWE knew the indication for their prelabor CS, whereas 69.8% knew why theirs had been carried out during labor (odds ratio (O.R.) = 0.054; 99% C.I. 0.032, 0.089). Slightly older mothers and increased proportions of primipara probably made small contributions to the increased prelabor CS rate in the Australian WWE, but most of the excess could not be accounted for in the Register data. Australian obstetricians may have tended to regard prelabor CS as a preferable course of action in managing delivery in WWE, even in the absence of other indications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Increasing interest into the relationship between Ammon's horn sclerosis (hippocampal sclerosis) and epilepsy seems to have developed after 1880 when Sommer's paper appeared. Bouchet and Cazauvieilh had published the original description of the hippocampal anatomical abnormality in 1825 while attempting to locate the cerebral sites of origin of epilepsy and insanity. However, they offered no interpretation of the significance of the structural change. What has sometimes not been noticed in the subsequent literature is that, after a further investigation, in 1853, Bouchet described the change in 18 of 43 additional brains from persons with epilepsy. Despite this frequency of occurrence of the hippocampal abnormality, he concluded that epileptic seizures had no single site of origin in the brain. Before most of his contemporaries and their successors, he began to propose the idea that all epileptic seizures were symptoms of various, though mostly cerebral, disorders. In doing this, he tended to be reluctant to accept the view that epilepsy was a disease in its own right.