J Neurol Neurosurg Psychiatry 1998;64:711–725 717 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

NEUROLOGY AND MEDICINE

The neurology of

Guy V Sawle, Margaret M Ramsay

The neurology of pregnancy can be split into headache, visual disturbances (typically pho- two. On the one hand, there are women who topsia), epigastric pain, or vomiting. This pro- develop neurological symptoms during preg- dromal state is typical, but the convulsions of nancy. Some have simple neurological disor- may arise apparently unheralded ders such as carpal tunnel syndrome, which are and at what seems to be normal pressure. more common during pregnancy. Others have Eclampsia is most common during the third disorders that are either peculiar to or very trimester of pregnancy or during labour, but much commoner during pregnancy, such as can also occur after delivery, typically within eclampsia, pelvic neural compression, or even the first 48 hours. tumours arising from the . The most common, serious, and important of these con- ditions is eclampsia. Other women have PRODROMAL FEATURES AND DIAGNOSIS Certain clinical features, indicating pre- neurological problems such as epilepsy or eclampsia of significant severity, are typical in myasthenia first and then become pregnant. patients who subsequently develop generalised For these patients, pregnancy may aVect the convulsions. It is di cult to know whether and course of the disease, and there may be impor- Y over what time scale this progression may occur tant issues with respect to investigation, in an individual patient. Such patients typically treatment, and prognosis. have high and rapidly rising or extremely labile , (sometimes in the Eclampsia nephrotic range), visual disturbances (especially Eclampsia is one of the commonest causes of photopsia or cortical blindness), headache, . In the United Kingdom, recent malaise, new onset of peripheral oedema (espe- figures show that 15.5% of direct maternal cially periorbital or facial), oliguria, restlessness, deaths were due to the hypertensive disorders shivering, and clonus. Laboratory evidence of of pregnancy, and more than half of these multisystem disease (such as hyperuricaemia, women had eclampsia.1 As many as 50 000 thrombocytopaenia, raised liver enzymes, or maternal deaths annually world wide are haemolysis) is also common. thought to be as a consequence of eclampsia.2 Other patients fail to show these warning http://jnnp.bmj.com/ The incidence of eclampsia during a recent signs and clinicians may not recognise impend- nationwide survey in the United Kingdom was ing eclampsia or may even fail to make the about one in 2000 maternities, with a case diagnosis when convulsions ensue. Examples fatality ratio of almost one in 50.3 We do not include patients who present during the second know how many women presenting with the trimester of pregnancy or in association with fulminating features described below will go on molar degeneration of the placenta. In other to have convulsions, or whether drug treatment cases the prodromal features are distracting, Division of Clinical can reduce the chance of progression. In one such as predominantly epigastric pain and on October 1, 2021 by guest. Protected copyright. Neurology GVSawle observational study, only one in 75 women vomiting, rather than headache and visual dis- with severe pre-eclampsia developed eclamptic turbance. The diagnosis may also be missed 4 Department of convulsions. when patients present in labour or the early and puerperium, when the blood pressure has , Queens DEFINITIONS always been normal (but beware rapidly rising Medical Centre, Pregnancy induced hypertension (also known blood pressure or onset of proteinuria peripar- Nottingham NG7 2UH, UK as pre-eclampsia and pregnancy toxaemia) tum). In other cases the blood pressure may M M Ramsay develops after 20 weeks of gestation in not be particularly raised or else there may be previously normotensive women and resolves no information about the patient’s “normal” Correspondence to: by three months postpartum; the pressure is prepregnancy blood pressure. Sometimes the Dr GV Sawle, Division of Clinical Neurology, Queens considered raised if greater than 140/90 mm patient or her medical attendants do not know Medical Centre, Nottingham Hg, or if the diastolic blood pressure rises that she is pregnant; other times the convul- NG7 2UH, UK. 15–25 mm Hg above prepregnancy values.5 sions begin late in the puerperium (>48 hours Telephone 0044 115 970 9792; fax 0044 115 970 When such a patient has a convulsion, they after delivery). Rarely, in an obtunded patient, 9738. should be considered to have eclampsia unless the seizures may not have been witnessed. proved otherwise. Such patients are likely also Important diVerential diagnoses in a preg- Received 22 May 1997 and to have significant proteinuria (>0.5 g/24 nant woman having her first seizure are intrac- in final revised form 2 March 1998 hours, or at least + with urine dipstick testing), erebral (particularly subarachnoid) haemor- Accepted 3 March 1998 facial or generalised oedema, and symptoms of rhage and cerebral venous thrombosis. Other 718 Sawle, Ramsay J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

possibilities are tumours, intracerebral infec- which show increased T2 signals on MRI.14–17 tion, metabolic disturbances, and autoimmune Abnormalities are more common in patients disorders (particularly systemic lupus with eclampsia.16 There is a predilection for erythematosus).6 abnormalities in the occipital and parietal lobes, in the watershed area between middle PATHOPHYSIOLOGY and posterior cerebral artery territories.15 16 It is always diYcult to know how best to treat or The distribution of lesions shows good correla- prevent a disease when its underlying patho- tion in most cases with the patient’s clinical physiology is incompletely understood. Our features, such as occipital pole lesions in understanding of the cerebral changes occur- women with cortical blindness.14 15 Enhance- ring in pre-eclampsia and eclampsia has ment of T1 signals after injection of gadolin- changed with the improvement of neuroradio- ium has been documented in regions with logical techniques. The traditional view was increased T2 signals.17 The lesions are inter- that eclampsia was due to intracerebral haem- preted as indicating areas of abnormal water orrhage, because that is what was typically content—that is, focal cerebral oedema. There 6 found postmortem. Yet proposed pathophysi- is much debate about whether such oedema is ological mechanisms must provide explana- intracellular, indicating areas of focal ischae- tions for several clinical findings: firstly, that mia, or whether it is extracellular, secondary to eclamptic convulsions can arise suddenly in a capillary leakage and breakdown of cerebral patient with little or no prodrome; secondly, autoregulation.14–17 that eclampsia does not always occur with It is, however, important to determine which extremely high blood pressure or prolonged is the more important mechanism, as this will increase in blood pressure; and thirdly, that determine pharmacological strategies to amel- there may be transient focal neurological iorate or prevent eclampsia. The proponents of defects (such as cortical blindness or hemipare- the breakdown of cerebral autoregulation sis) yet most women who survive eclampsia do theory argue that eclampsia is simply hyperten- so neurologically intact. sive encephalopathy and that the keystone of It has variously been proposed that eclamp- treatment should be good control of blood tic convulsions result from intracerebral haem- pressure.18 This leaves a dilemma in a patient orrhage, hypertensive encephalopathy, cerebral 67 with “normal” or only marginally raised blood oedema, or cerebral vasospasm. DiVerent mechanisms may be operating in diVerent pressure as to what should be the target blood patients, with the compounding eVects of pressure. If focal ischaemic areas develop as a cerebral hypoxia, intravenous fluid and drug consequence of cerebral vasospasm, then administration, and varying degrees of hyper- specific vasodilator agents are likely to be more tension. The women who die are likely to be at beneficial and lowering blood pressure in some the worst end of the range. Those who die of circumstances could further aggravate ischae- eclampsia have significantly higher blood pres- mic processes. sure, but no worse renal function or more pro- An increasing body of evidence points to the teinuria than those who survive.8 presence of cerebral vasospasm in eclampsia and Typical postmortem cerebral findings are also in severe pre-eclampsia. Cases have been fibrinoid necrosis of vessels, thrombosed pre- reported where cerebral angiography and mag- 19 20 http://jnnp.bmj.com/ capillaries, perivascular ring haemorrhages, netic resonance angiography, performed subarachnoid, intraventricular, and intracer- after eclamptic seizures, have shown diVuse ebral haemorrhages (including patches of vasospasm. Similar images have also been noted 21 22 petechial haemorrhage in the cerebral cortex), in women with severe pre-eclampsia. Follow hypoxic-ischaemic damage, and perivascular up images documented resolution of vasospasm microinfarcts.67910 Studies with CT have in association with clinical recovery. Is cerebral shown that eclamptic patients with evidence of vasospasm a primary feature of eclampsia, caus- cerebral haemorrhage are likely to die as a con- ing focal or generalised ischaemic areas, which sequence of their condition;10 11 such patients give rise to seizure foci and impaired neuronal on October 1, 2021 by guest. Protected copyright. may have a profound coagulopathy. Surviving function? Or, is the vasospasm a secondary phe- patients are more likely to have either normal nomenon, protecting the brain from the damag- scans or patchy, low density areas.11 ing eVects of raised arterial pressure? Generalised cerebral oedema has been docu- In experimental hypertension in animal mented in eclampsia postmortem,67 found on models, pial arteriolar constriction has been CT in unconscious eclamptic patients,12 and directly observed, including a “sausage-string” has been suggested in patients in whom intra- pattern.7 Cerebral blood flow is stable over a cranial pressure was directly monitored and wide range of systemic arterial pressures. Once found to be raised;10 but it is not a universal the upper limit of this autoregulation is finding.911Many such patients may have iatro- achieved, blood flow increases. Damage occurs genic fluid overload or oedema may be a in capillaries, allowing escape of plasma consequence of prolonged cerebral ischaemia. and blood cells into the perivascular Other studies have found the brain in pre- spaces. This is the important pathophysiologi- eclampsia and eclampsia to be of similar cal basis of hypertensive encephalopathy.718 weight9 or even smaller13 than normal. These processes indubitably occur in some Brain MRI may identify abnormalities where patients with eclampsia, particularly in those in CT has failed to do so. The characteristic neu- whom high arterial blood pressure has per- roradiological features of severe pre-eclampsia sisted untreated for a considerable period of and eclampsia are hypodense lesions on CT time. However, the concept that eclampsia is The neurology of pregnancy 719 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

simply hypertensive encephalopathy does not titratable against level of consciousness, but fit all the available facts. often involves administration of large volumes Patients with pre-eclampsia and eclampsia of fluid; a dangerous practice in an oliguric exhibit increased sensitivity to vasoactive patient. For all these reasons, maintenance use agents such as catecholamines and angiotensin of sedative anticonvulsants should be avoided. II, and vasospasm has been proposed as the Phenytoin was introduced in the 1980s as a underlying mechanism causing multiple organ good non-sedative anticonvulsant drug for the dysfunction.523 Optic arteriolar vasospasm treatment and prevention of eclampsia.26 How- and nail bed vessel spasm are clinical features ever, with increasing use it has become appar- in some patients. Epigastric pain, of an ent that eclamptic convulsions may occur angina-like quality, is a sinister feature which despite plasma phenytoin concentrations in the may herald eclamptic seizures. Some patients therapeutic range.27 28 experience relief from epigastric pain after the Magnesium sulphate has been the drug administration of vasodilating drugs. Rapid treatment of choice for eclampsia and pre- improvement occurred in the neurological sta- eclampsia in the United States for more than tus of a woman with recurrent eclamptic 80 years, although its initial use was on an seizures and MR evidence of widespread empirical basis. Only recently have large cerebral ischaemia, after administration of studies compared its use with other agents nimodipine, a cerebral vasodilator.24 That (phenytoin and diazepam).228 In a study of abnormal electrical activity arises in ischaemic 1680 women with eclampsia,2 those treated areas of the brain due to focal or widespread with magnesium sulphate had a 52% lower risk cerebral vasospasm is an attractive hypothesis. of recurrent convulsions than those given It explains the unpredictable nature of eclamp- diazepam and a 67% lower risk of recurrent tic seizures, their association with localising convulsions than those given phenytoin. In signs in some patients and non-specific another study,28 more than 2000 women who features in others (headache, reduced con- presented in labour with hypertension (blood scious level etc), the potential for full recovery pressure=140/90 mm Hg) were randomly allo- without neurological deficits or radiological cated to treatment with either magnesium sul- signs, and the fact that seizures may occur with phate or phenytoin. Those who had already or without increases in systemic arterial had eclamptic seizures were excluded, but oth- pressure. erwise the study had broad inclusion criteria. Hydralazine was used to control diastolic blood MANAGEMENT pressure that exceeded 110 mm Hg. The trial A bitter debate has taken place about the opti- was discontinued when an interim analysis mal prophylaxis or treatment for eclampsia, found that eclampsia developed in 10 of 1089 between obstetricians and neurologists, and women given phenytoin prophylaxis, but none between practitioners from North America and of 1049 women given magnesium sulpha- those in the rest of the world.18 25 Should man- te.The authors noted that the expected inci- agement of eclampsia consist of giving anticon- dence of eclampsia in similarly hypertensive vulsant drugs (such as phenytoin) or antihyper- women given magnesium sulphate prophylaxis, tensive agents? Would magnesium sulphate based on findings at their hospital over many prove valuable if tested scientifically in a proper years, was one in 750. clinical trial against other agents? Fortunately, These studies yield persuasive evidence for http://jnnp.bmj.com/ clinical studies have now provided answers to the eYcacy of magnesium sulphate in the man- some of these questions, but other uncertain- agement of women with severe pre-eclampsia or ties remain. eclampsia, compared with phenytoin or di- A woman experiencing a generalised ec- azepam. What should be borne in mind, lamptic convulsion should be managed initially however, is that there is a range of severity for the with whatever anticonvulsant agents are to underlying condition (“pre-eclampsia” or “tox- hand and with which a practitioner is familiar. aemia”) and that there is not the same risk of The important thing is to terminate the seizure developing eclamptic convulsions in an asymp- on October 1, 2021 by guest. Protected copyright. because both mother and may become tomatic woman with a blood pressure of hypoxaemic if the fit is prolonged. The more 150/100 mm Hg as in another with the same diYcult issue is whether drug therapy can be blood pressure but also 2 g/24 hour proteinuria used to prevent eclamptic seizures in the first or another with escalating symptoms (head- place or reduce the risk of recurrent seizures. aches, vomiting, etc). Is it appropriate to give Sedative anticonvulsant drugs (diazepam, bar- prophylactic treatment to women with mild and biturates, chlormethiazole) have been used moderate degrees of pre-eclampsia, or should it extensively in the management of patients with be reserved for the more truly “at risk” group severe pre-eclampsia and eclampsia. However, with severe increase in blood pressure and heavy sedation does not necessarily prevent evidence of multiorgan disease (from symptoms convulsions in these patients. Maternal respira- or laboratory findings)? Not enough is known tory depression caused by sedative agents can yet about whether magnesium sulphate reduces result in hypoxaemia and hypercapnia and or enhances the survival chances of the fetus, possible aggravation of cerebral injury. Such which may be both premature and growth patients are also at risk of aspiration pneumo- restricted.5729 nia. Deterioration in the conscious state cannot It is also diYcult to know the relative necessarily be attributed to worsening of their importance of a particular pharmacological clinical condition. Short term intravenous treatment (for example, magnesium sulphate) chlormethiazole has the advantage of being compared with other issues of management, 720 Sawle, Ramsay J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

such as time taken to eVect delivery of the fetus someone familiar with all the potential haema- and control of blood pressure.8 Women who die tological, cardiovascular, renal, hepatic, and of severe pre-eclampsia or eclampsia do not all obstetric as well as neurological problems. have intracerebral haemorrhage; some have “Treating the underlying cause” of the prob- adult respiratory distress syndrome, dissemi- lems means expediting delivery of the fetus and nated intravascular coagulation, or congestive placenta; other care is generally supportive in heart failure.13Correct recognition of the con- nature. It is important to ensure that iatrogenic dition, and involvement of experienced doctors problems such as fluid overload do not compli- in the management of women with severe pre- cate recovery.15The signs of recovery are her- eclampsia or eclampsia is likely to be as impor- alded generally by a spontaneous diuresis and tant for the eventual outcome for mother and lowering of blood pressure, ahead of improve- fetus as the actual drugs used. The develop- ment in measured haematological or biochemi- ment of special interest teams for the manage- cal factors. ment of severe pre-eclampsia and eclampsia has been recommended after the recent confi- dential inquiry into maternal deaths in the Other neurological symptoms arising United Kingdom.18 during pregnancy In pre-eclampsia, our own practice (modi- Almost any medical disorder which can occur fied from reference30) is to give 5 g magnesium in a woman of childbearing age can occur dur- sulphate intravenously over 20 minutes (by ing pregnancy. Most are probably no com- adding 10 ml 50% magnesium sulphate moner than would be expected by chance. solution to 200 ml normal saline). We then There are, however, neurological disorders infuse magnesium sulphate at 2 g/h. We meas- which occur more commonly during preg- ure the magnesium concentration after 30–60 nancy than at other times, or which demand minutes and then every six hours to maintain a special treatment at this time and some of these therapeutic range of 2–3 mmol/l. If the blood are briefly mentioned here. pressure falls below 110/70 mm Hg, the respi- ratory rate falls below 16, urine output is below MINOR NEUROLOGICAL DISORDERS 30 ml/h, or areflexia occurs, we reduce the Several minor neurological disorders occur infusion rate to 1 g/h and measure the magne- more often during pregnancy than at other sium concentration urgently. times; Bell’s palsy and the carpal tunnel If patients have seizures on this regime, we syndrome are common examples. take blood for an urgent magnesium concen- The incidence of Bell’s palsy is higher during tration and give a further bolus of 2 g pregnancy and the puerperium (38–45 women magnesium sulphate over two to three minutes. per 100 000 v 17 per 100 000 If fits continue after five minutes, we give a women-years in non-pregnant women of child- benzodiazepine. bearing age31). Recovery is usual. Some neu- One of the criticisms levelled against magne- rologists prescribe a short course of steroids if sium sulphate, before there was clear evidence patients are seen early after the development of for its eYcacy in the management of eclampsia, facial weakness (whether or not they are preg- was that it did not have true anticonvulsant nant). Such treatment probably does no harm properties.718 Magnesium, however, has been in pregnancy (see below), although the evi- shown to have vasodilator properties and it may dence that it is beneficial is by no means http://jnnp.bmj.com/ be that its action in eclampsia is due to reduc- secure.32–34 Rarely, patients have recurrent tion in cerebral vasospasm.25 28 If this is so, then Bell’s palsy in successive pregnancies.35 36 other specific cerebral vasodilators including The carpal tunnel syndrome is also more nimodipine deserve further investigation for common in pregnancy. Estimates of incidence the management of eclampsia. vary between almost ridiculous extremes (1– 50%). Conservative management is almost CONCLUSIONS always appropriate because resolution after Eclampsia is an uncommon condition in the pregnancy is the rule,37 although surgical treat- on October 1, 2021 by guest. Protected copyright. developed world, but is associated with a ment may be necessary38 and the condition may disproportionate degree of maternal and fetal recur in subsequent pregnancies. Not all pain mortality.3 For this reason, it is important to in the hand during pregnancy is due to the car- improve our recognition of patients at risk for pal tunnel syndrome; de Quervain’s tenosyno- the condition and their subsequent manage- vitis is also more frequent.39 The incidence of ment. The report on the confidential enquiry meralgia paraesthetica is also increased. Con- into maternal deaths in the United Kingdom servative management is best. It may recur in has a sobering chapter about how easily things successive pregnancies.40 can go wrong.1 Each case of severe pre- eclampsia and eclampsia should be assessed GUILLAIN-BARRÉ SYNDROME individually and managed in a specialist unit The Guillain-Barré syndrome is no more according to carefully thought out protocols, common in pregnancy than at other times41. dealing with issues such as fluid balance, Both plasma exchange42 and immunoglobulin seizure control, conduct of delivery, and anaes- therapy have been used in pregnant patients thesia. There should be clear guidelines for with successful outcome. Fetal survival is usual. laboratory investigations, including radiologi- Rarely, the newborn child of an aVected mother cal imaging and access to information allowing may also be aVected.43 The course of the mater- interpretation of the tests. Advice for those nal neuropathy is unaVected by termination or managing patients must be available from delivery. The neurology of pregnancy 721 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

STROKE IN PREGNANCY types similar to those of non-pregnant women Although it has been thought for many years of similar age. There is probably no greater that pregnant women carry a considerably overall incidence of primary brain and spinal increased risk for the development of stroke, a tumours in pregnant women than in age recent critical appraisal of the data suggested matched non-pregnant women.55 that the risk of ischaemic stroke due to presumed arterial occlusion may well have Gliomas been exaggerated because of referral and selec- Management decisions in pregnant patients tion bias.44 In a recent retrospective case- with gliomas are diYcult. With low grade control study of 497 women with “a reliable tumours, it may be possible to defer all cerebral thromboembolic diagnosis”, preg- treatment until after delivery whereas higher nancy only carried a small and non-significant grade lesions often require surgical resection increase in risk with an odds ratio of 1.3 (non- during pregnancy. Radiotherapy during preg- significant), in comparison to an odds ratio of nancy may cause , mental retardation, 5.4 for diabetes, 3.1 for hypertension (both and congenital defects56 and p<0.001), and 2.8 for migraine (p<0.01).45 may also lead to fetal malformations. Both are When stroke does occur in pregnancy, it is as best deferred until after delivery. Steroids may likely to be due to haemorrhage as to be used when necessary (see below). infarction, and there is an increase in the proportion of cases related to venous thrombo- Pituitary tumours sis (particularly in the third trimester and Many (perhaps most) women with pituitary puerperium). In women with an unruptured tumours are looked after by endocrinologists, arteriovenous malformation, the risk of a first rather than neurologists. In patients with haemorrhage during pregnancy is about 3.5%. microadenomas or presumed microadenomas This risk is no higher than over a similar period measuring 1cm or less, the risk of developing outside pregnancy.46 We do not recommend visual loss after as many as four full term preg- surgery for arteriovenous malformations dur- nancies is very small, whereas six of eight ing pregnancy. About 1 in 10 000 pregnancies women with larger tumours ran into visual is complicated by rupture of an intracranial problems during pregnancy.57 aneurysm.47 Unruptured cerebral aneurysms are common, with an incidence of around Meningiomas 5%;48 the risk of rupture of a previously asymp- The hormonal eVect of pregnancy, with high tomatic aneurysm during pregnancy must be oestrogen leading to accelerated or even explo- low, though this has not, to our knowledge, sive growth of meningiomas, is well known. been formally studied. We do not recommend Even so, unless the tumour has reached a criti- prophylactic surgery (for an incidentally dis- cal size such that serious neurological impair- covered asymptomatic cerebral aneurysm) ment is present or imminent, treatment can during pregnancy. When aneurysmal rupture often be delayed until after delivery, by which does occur, the aneurysm should be operated time the tumour size and severity of symptoms on before delivery.49 Aneurysmal rupture is may be reduced.55 more likely in the second and third trimesters (30% and 55% of ruptures respectively), than Tumours peculiar to pregnancy in the first trimester or puerperium (6% and is the commonest systemic http://jnnp.bmj.com/ 9% respectively).50 In those women who do not associated with pregnancy. It may follow require neurosurgery during pregnancy, cae- a molar pregnancy, abortion, ectopic preg- sarean section may not aVord any better nancy, or term pregnancy. Brain metastases are maternal or fetal outcome than vaginal common and untreated mortality is high. Sur- delivery.49 vival is improved by early diagnosis and For women who require anticoagulants dur- treatment; patients usually require chemo- ing pregnancy, heparin (which does not cross therapy and cranial radiotherapy.58 the placenta) is generally preferable to warfa- on October 1, 2021 by guest. Protected copyright. rin. The only exception is in patients with MOVEMENT DISORDERS BEGINNING IN prosthetic heart valves in whom heparin does PREGNANCY not give suYcient anticoagulation and warfarin refers to chorea occurring should be used until around 37 weeks of during pregnancy. Recognised causes of chorea gestation51 and then full dose heparin to term. starting at this time include hereditary, drug Heparin carries a low risk of maternal osteope- related, immune, and vascular disorders. That nia. Low molecular weight heparin has the chorea gravidarum is less common than it used advantages of sparing calcium and ease of use to be is probably a reflection of the reduced (it is given once daily as a subcutaneous injec- incidence of rheumatic fever (Sydenham’s cho- tion). Daily aspirin in low dose (60 to 150 mg) rea) due to the widespread use of antibiotics. has been used by obstetricians in the second Treatment may be unnecessary. If the chorea is and third trimesters without evidence of fetal disabling, haloperidol may provide the best harm.52 The use of aspirin in the first trimester balance between eYcacy, mild teratogenesis, remains controversial because of uncertainty and propensity to induce tardive dyskinesia.59 about whether it is teratogenic.53 54 The restless legs syndrome is almost cer- tainly the commonest movement disorder in NEOPLASTIC DISEASE pregnancy, occurring in up to 20% of pregnan- Most types of tumours have been reported in cies. There is an association with pregnant women, with the range of tumour deficiency, and if folate concentrations are low 722 Sawle, Ramsay J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

this should be corrected. If further drug treat- pranolol, although beta blockers do reduce ment is necessary, levodopa/carbidopa in low placental perfusion which may result in intrau- dose is probably the least teratogenic of the terine growth restriction. Despite these caveats, agents reported eVective in this condition. For- beta blockers are generally considered as tunately, it usually remits in the puerperium. appropriate first line prophylactic drugs in the treatment of disabling and frequent migraines Pregnancy in patients with neurological during pregnancy.64 As an alternative, tricyclic disease antidepressants (such as imipramine and am- Common neurological conditions in young itriptyline) are useful for prophylaxis of both women include migraine, other forms of head- migraine and tension headache. No significant ache, and epilepsy. Less commonly, patients increases in birth defects have been reported.65 with multiple sclerosis and muscle and neu- Infantile tachycardia and urinary retention romuscular junctional disease may require spe- have rarely been reported and it may be sensi- cial advice and treatment. The enormous range ble to reduce the dose during the last few weeks of neurological diagnoses obviously precludes a of pregnancy.66 Unlike beta blockers and tricy- detailed consideration of the special problems clic antidepressants (in which most of the pre- posed by any but the most common. scribing in pregnancy is for indications other than headache), there is little information MIGRAINE AND OTHER HEADACHES available on which to base decisions about The commonest causes of troublesome head- using pizotifen. Data collected by the manufac- ache in young women are migraine and tension turers up to September 1994 include 30 obser- headache. Migraine usually becomes less fre- vations on outcome of pregnancy. Eighteen quent during pregnancy,60 but it is such a com- pregnancies resulted in normal babies. Seven mon condition that there are still many women had (all diVerent) malformations. Five aborted with bad (and even worsening) migraines during (four spontaneously). (Data on file, Sandoz pregnancy. Less commonly, migraine may occur Pharmaceuticals.) These few abnormal obser- for the first time during pregnancy. The diagno- vations are all retrospective and many more sis is usually straightforward, but it pays to mothers must have taken this drug in the first remember that other important causes of head- few weeks of pregnancy even before knowing ache have a slightly increased incidence in preg- they were pregnant. Nevertheless, the manu- nancy, particularly benign intracranial hyperten- facturers recommend its use in pregnancy only sion, tumours (including pituitary adenomas), in “compelling circumstances” and cerebral venous thrombosis. When the headaches are bearable, many women prefer to avoid medication altogether during pregnancy. MULTIPLE SCLEROSIS The eVect of pregnancy on multiple sclerosis If simple analgesia is necessary, then paraceta- has been a subject of much debate over many mol is preferable to aspirin, which (as an inhibi- years. In a recent Swedish study, the authors tor of prostaglandin synthesis) may delay the reported a significantly reduced incidence of onset of labour, increase intrapartum blood loss, relapses during pregnancy, with no rebound impair neonatal haemostasis, and cause prema- increased risk in the puerperium.67 Our own ture closure of the ductus arteriosus.61 Paraceta- interpretation of the literature is that whereas mol does cross the placenta, but no increase in the rate of new relapses falls a little in http://jnnp.bmj.com/ birth defects has yet been attributed to its use. pregnancy, there is a similar increase in the Non-steroidal anti-inflammatory drugs such as puerperium. So whereas pregnancy does not ibuprofen and naproxen are generally safe cause an overall increase in the risk of relapse, during the first two trimesters, but carry similar if one is going to occur it is more likely in the risks to aspirin and because of the risks of puerperium than during the later part of the premature closure of the ductus, decrease in pregnancy.68 69 A recent MR study involving amniotic fluid volume, and inhibition of labour two patients showed a decrease in MR disease and , should be avoided in the third activity during the second half of pregnancy on October 1, 2021 by guest. Protected copyright. trimester.62 Metoclopramide has not been re- and then a return to prepregnancy levels in the ported to cause congenital malformations.63 puerperium.70 Pregnancy probably has little, if Animal studies using sumatriptan have failed to any, eVect on longer term disability.71 72 show teratogenic eVects in rats or rabbits but even so, use in human pregnancy must still be regarded as experimental. In 159 pregnancy EPILEPSY outcomes reported to the manufacturers up to Maternal epilepsy increases the risk of fetal September 1996, 134 were without birth malformation around two to threefold and it is defects. There were six with birth defects (show- assumed that much of this increase in risk is ing no consistent pattern), nine spontaneous due to the drugs taken. The older agents pregnancy losses, eight induced , and (phenytoin, valproate, and carbamazepine) are two . Four of the birth defects included all associated with a similar overall risk. In came from 150 pregnancies in whom exposure patients on valproate and carbamazepine a occurred in the first trimester (data from higher fraction of this risk is accounted for by GlaxoWellcome, April 1997). an increase in the frequency of spina bifida In patients having frequent and disabling (about 1% for carbamazepine and 2% for attacks, prophylaxis may be necessary. Beta valproate).73 74 All of the risks are probably blockers (atenolol and propranolol) have both increased by polytherapy.75 76 The risk of spina been used extensively during pregnancy. There bifida may be reduced if mothers take folate is no evidence of teratogenicity with pro- supplements and our own practice is to The neurology of pregnancy 723 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

prescribe folate supplements from the time of DYSTONIA diagnosis in women of childbearing potential.77 We are not aware of any evidence to suggest that The manufacturers of vigabatrin warn against dystonia is more common in pregnancy than at its use in pregnancy because of an increased other times. Of current interest is the question of incidence of cleft palate in rabbits. Lamotrigine whether botulinum toxin injections confer any and gabapentin have not caused teratogenicity risk to the foetus. Clinical experience suggests in animals, but the available data in humans are that continued use of this agent is probably safe very few. Data on lamotrigine in monotherapy but until we have more data the safest approach and polytherapy collected by the manufacturers must be to defer further injections during up to September 1996 include 6.5% (four of 62) pregnancy.87 pregnancy outcomes with birth defects, with no pattern to the defects seen (data from GlaxoW- PARKINSON’S DISEASE ellcome, April 1997). The use of these agents as Parkinson’s disease is unusual in young women, preferred therapy in pregnancy is thus (at least but can occur and may require special consid- for the time being) an act of faith. Topiramate eration. Levodopa crosses the placenta (as does 88 has been shown to be teratogenic in animal carbidopa in smaller concentration), but even studies. though published experience with the use of There is a grand tradition of monitoring levodopa in pregnancy is limited, its eYcacy in anticonvulsant concentrations during preg- treating Parkinson’s disease probably outweighs any potential for fetal harm or maternal nancy and adjusting doses to maintain concen- 59 trations in the hope that this will prevent complications. Bromocriptine has been used seizures. In favour of the monitoring strategy, it more widely in pregnancy (for the treatment of is true that women who have seizures during pituitary disease) without problems, but is pregnancy often have low anticonvulsant con- usually less potent in its antiparkinsonian eVect. centrations. But we also know that compliance is often poor (sometimes patients deliberately PERIPHERAL NERVE DISORDERS reduce or stop their pills, to “protect” their Chronic inflammatory demyelinating polyneuropathy child) and that some tablets are swallowed and Women with chronic inflammatory demyeli- vomited back up again. Monitoring concentra- nating polyneuropathy probably have more tions in pregnancy has not been shown to be relapses during pregnancy than at other better than reappraising the need for ongoing times.89 Intravenous immunoglobulin treat- medication, counselling about compliance, and ment has been used for therapy in non- adjustments to dosage if necessary on the basis pregnant women with chronic inflammatory of clinical features. If they are to be monitored, demyelinating polyneuropathy. It has also been then free drug concentrations should be used over several years in pregnant women with followed, as bound and free concentrations recurrent fetal loss associated with the an- may change in opposite directions during tiphospholipid syndrome, without obvious ill 78–80 pregnancy. eVects.90 Generalised tonic-clonic seizures can lead to 78 81 profound fetal bradycardia. Fetal cerebral Hereditary sensorimotor neuropathy haemorrhage and death have been reported Patients with hereditary sensorimotor neu- 82 http://jnnp.bmj.com/ after a series of seizures during pregnancy. ropathy type I have a similar rate of obstetric This underscores the need for good seizure complications to other pregnant women.91 control during pregnancy in the interests of Eight of 21 (38%) in one study reported fetal wellbeing. Rarely (non-eclamptic) epi- increasing weakness during pregnancy. With lepsy occurs only during pregnancy; recurring childhood onset disease, there is no obvious 83 with successive pregnancies. Status epilepti- way of predicting whether deterioration will cus is a serious complication of epilepsy and occur in any person.91 Deterioration may be death of the child or mother have both been severe enough to require artificial ventilation.92 reported as a consequence. It should be treated on October 1, 2021 by guest. Protected copyright. 84 along conventional lines. MYASTHENIA GRAVIS Mothers taking enzyme inducing drugs Around a third of women with myasthenia should receive orally 20 mg vitamin K1 daily for gravis deteriorate neurologically during or after a week before delivery. If the exact date of pregnancy. Pyridostigmine appears safe, also delivery is not known in advance (the usual plasma exchange and steroids (see below). 93 situation), it seems sensible to start K1 a month Thymectomy is possible during pregnancy, before the expected delivery date.85 Alterna- but probably better performed earlier.

tively, the mother can be given 10 mg K1 Myasthenia has little eVect on pregnancy. parenterally during labour. Administration of The (being smooth muscle) is unaf-

vitamin K1 to the newborn (which is almost fected, although the striated muscles used dur- universal practice anyway, to prevent the rare ing the expulsive phase of labour may be but serious condition of haemolytic disease of aVected and assisted (forceps) delivery may be the newborn) is recommended in these cir- necessary. Caesarean section is necessary only cumstances. for obstetric indications. Magnesium sulphate Whereas most anticonvulsant drugs pass and neuromuscular blocking agents are impor- into breast milk, they do so in low concentra- tant members of the “drugs to avoid” list for tions and yield only a tiny fraction of the lowest pregnant myasthenic mothers. recommended daily dose for an infant.86 Breast Up to 20% of infants born to mothers feeding can therefore be encouraged. with myasthenia will have transient neonatal 724 Sawle, Ramsay J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

myasthenia; symptoms typically start in the first 18 Donaldson JO. Eclamptic hypertensive encephalopathy. Semin Neurol 1988;8:230–3. one to four days. Small doses of anticholineste- 19 Will AD, Lewis KL, Hinshaw DB, et al. Cerebral rase drugs are usually needed for a few days. vasoconstriction in toxaemia. Neurology 1987;37:1555–7. 20 Kanayama AN, Nakajima A, Maehara K, et al. Magnetic resonance imaging angiography in a case of eclampsia. THE USE OF STEROIDS IN PREGNANCY Gynaecol Obstet Invest 1993;36:56–8. 21 Ito T, Sakai T, Inagwa S, et al. MR angiography of cerebral Dexamethasone is not known to be linked with vasospasm in preeclampsia. American Journal of Neuroradi- congenital defects. Its short term use to stimu- ology 1995;16:1344–6. 22 Matsuda Y, Tomosugi T, Maeda Y, et al. Cerebral magnetic late fetal lung maturation in patients with pre- resonance angiographic findings in severe preeclampsia. mature labour is not associated with long term Gynaecol Obstet Invest 1995;40:249–52. 23 Zaret GM. Possible treatment of pre-eclampsia with fetal harm. Dexamethasone crosses the pla- calcium channel blocking agents. Med Hypotheses 1983;12: centa, however, and infants may have short 303–19. 94 24 Horn EH, Filshie GM, Kerslake RW, et al. Widespread cer- lived leukocytosis. Prednisolone also seems to ebral ischaemia treated with nimodipine in a patient with have little eVect on the developing fetus; there eclampsia. BMJ 1990;301:794. 25 Sadeh M. Action of magnesium sulfate in the treatment of have been little more than anecdotal reports of preeclampsia-eclampsia. Stroke 1989;20:1273–5. newborn immunosuppression or fetal deform- 26 Slater RM, Smith WD, Patrick J, et al. Phenytoin infusion in ity and the available evidence supports the use severe pre-eclampsia. Lancet 1987;i:1417–21. 27 Slater RM, Wilcox FL, Smith WD, et al. Phenytoin in of prednisolone to control various maternal pre-eclampsia. Lancet 1989;ii:1224. diseases.95 Because prednisolone is metabolised 28 Lucas MJ, Leveno KI, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of before crossing the placenta it is preferred to eclampsia . N Engl J Med 1995;333:201–5. dexamethasone when steroids must be given 29 Reynolds JD, Chestnut DH, Dexter F, et al. Magnesium sul- 96 fate adversely aVects fetal lamb survival and cerebral blood for more than a few days during pregnancy. flow response during maternal hemorrhage. Obstetric High dose steroids in pregnancy may be Anesthesia 1996;83:493–9. 30 Sibai BM, Graham JM, McCubbin JH. A comparison of associated with mineralocorticoid side eVects intravenous and intramuscular magnesium sulfate regi- (oedema and rising blood pressure) which may mens in pre eclampsia. Am J Obstet Gynaecol 1984;150: 728–33. mimic pre-eclampsia. 31 Rosenbaum RB, Donaldson JO. Peripheral nerve and neuromuscular disorders. Neurol Clin 1994;12:461–77. 32 Prescott CAJ. Idiopathic facial nerve palsy. (The eVect of POSTSCRIPT treatment with steroids). J Laryngol Otol 1988;102:403–7. Finally, although there are a few reports on 33 Falco NA, Eriksson E. Idiopathic facial palsy in pregnancy and the puerperium. Surgery Gynecology and Obstetrics delusions of pregnancy in men, this is usually 1989;169:337–40. symptomatic of a prior cerebral disorder.97 34 Devriese PP, Schumacher T, Scheide A, et al. Incidence, prognosis and recovery of Bell’s palsy. A survey of about Some men experience symptoms such as 1000 patients (1974–83). Clinical Otolaryngology and Allied weight gain, nausea, and toothache during Sciences 1990;15:15–27. 35 Gbolade BA. Recurrent lower motor neurone facial paraly- their partner’s pregnancies (Couvade syn- sis in four successive pregnancies. J Laryngol Otol drome). But most men actually come to medi- 1994;108:587–8. 36 McGregor JA, Guberman A, Amer J, et al. Idiopathic facial cal attention less often when their wives are nerve paralysis (Bell’s palsy) in late pregnancy and the early 98 pregnant than at other times. We are unaware puerperium. Obstet Gynecol 1987;69:435–8. 37 Wand JS. Carpal tunnel syndrome in pregnancy and of any study of specific neurological symptoms lactation. JHandSurgery1990;15:93–5. in the partners of pregnant women. 38 Al Quattan MM, Manktelow RT, Bowen CVA. Pregnancy- induced carpal tunnel syndrome requiring surgical release longer than 2 years after delivery. Obstet Gynaecol 1994;84: 1 Department of Health . Report on confidential enquiry into 249–51. maternal deaths in the United Kingdom 1991–3. London: Sta- 39 Schumacher HRJr, Dorwart BB, Korzeniowski OM. Oc- tionary OYce, 1996:1–31. curence of De Quervain’s tendinitis during pregnancy. Arch 2 Eclampsia trial collaborative group . Which anticonvulsant Intern Med 1985;145:2083–4. http://jnnp.bmj.com/ for women with eclampsia? Evidence from the collaborative 40 Daw E, Ogbonna B. Recurrent Bell’s palsy, carpal tunnel eclampsia trial. Lancet 1995;345:1455–63. syndrome and meralgia in pregnancy. J Obstet Gynaecol 3 Douglas KA, Redman CWG. Eclampsia in the United 1984;5:102–3. Kingdom. BMJ 1994;309:1395–400. 41 Rodin A, Ferner RE, Russell R. Guillain Barré syndrome in 4 Chua S, Redman CWG. Are prophylactic anticonvulsants pregnancy and the puerperium. J Obstet Gynaecol 1988;9: required in severe pre-eclampsia? Lancet 1992;i:250–1. 39–42. 5 Ramsay MM. Hypertension in pregnancy. In: Studd J, ed. 42 Hurley TJ, Brunson AD, Archer RL, et al. Landry Guillain- The yearbook of the Royal College of Obstetricians and Gynae- Barré Strohl syndrome in pregnancy: report of three cases cologists. London: RDOG Press, 1995:251–61. treated with plasmapheresis. Obstet Gynaecol 1991;78:482– 6 Barton JR, Sibai BM. Cerebral pathology in eclampsia. Clin 5. Perinatol 1991;18:891–910. 43 Luijckx GJ, Vles J, de Baets M, et al. Guillain-Barré 7 Donaldson JO. Eclampsia. In: Neurology of pregnancy. syndrome in mother and newborn child. Lancet 1997;349: on October 1, 2021 by guest. Protected copyright. London: WB Saunders, 1989:269–310. 27. 8 Redman CWG. Eclampsia still kills. BMJ 1988;296:1209– 44 Grosset DG, Ebrahim S, Bone I, et al. Stroke in pregnancy 10. and the puerperium: what magnitude of risk? J Neurol Neu- 9 Sheehan HL, Lynch JB. Pathology of toxaemia of pregnancy. rosurg Psychiatry 1995;58:129–31. Baltimore: Williams and Wilkins, 1973:524–53. 45 Lidegaard O. Oral contraceptives, pregnancy and the risk of 10 Richards A, Graham D, Bullock R. Clinicopathological cerebral thromboembolism: the influence of diabetes, study of neurological complications due to hypertensive hypertension, migraine, and previous thrombotic disease. disorders of pregnancy. J Neurol Neurosurg Psychiatry 1988; Br J Obstet Gynaecol 1995;102:153–9. 51:416–21. 46 Horton JC, Chambers WA, Lyons SL, et al. Pregnancy and 11 Milliez J, Dahoun A, Boudrea M. Computed tomography of the risk of haemorrhage from cerebral arteriovenous the brain in eclampsia. Obstet Gynaecol 1990;75:975–80. malformations. Neurosurgery 1990;27:867–72. 12 Richards AM, Moodley J, Graham DI, et al. Active manage- 47 Barrett JM, Van Hooydonk JE, Boehm FH. Pregnancy- ment of the unconscious eclamptic patient. Br J Obstet related rupture of arterial aneurysms. Obstet Gynecol Surv Gynaecol 1986;93:554–62. 1982;37:557–66. 13 Williams EJ, Oatridge A, Holdcroft A, et al. Posterior 48 Sekhar LN, Heros RC. Origin, growth and rupture of leucoencephalopathy syndrome. Lancet 1996;347:1556–7. saccular aneurysms: a review. Neurosurgery 1981;8:248–60. 14 Duncan R, Hadley D, Bone I, et al. Blindness in eclampsia: 49 Dias MS, Sekhar LN. Intracranial haemorrhage from aneu- CT and MR imaging. J Neurol Neurosurg Psychiatry rysms and arteriovenous malformations during pregnancy 1989;52:899–902. and the puerperium. Neurosurgery 1990;27:855–66. 15 Sanders TG, Clayman DA, Sanchez-Ramos L, et al. Brain in 50 Hunt H, Schifrin B, Suzuki K. Ruptured berry aneurysms eclampsia: MR imaging with clinical correlation. Radiology and pregnancy. Obstet Gynecol 1974;43:827–36. 1991;180:475–8. 51 de Swiet M. Heart disease. In: Calder AA, et al,eds. 16 Digre KB, Varner MW, Osborn AG, et al. Cranial magnetic High-risk pregnancy. Oxford: Butterworth Heinemann, resonance imaging in severe preeclampsia v eclampsia. 1992:139–64. Arch Neurol 1993;50:399–406. 52 CLASP (collaborative low-dose aspirin study in pregnancy) 17 Schwartz RB, Jones KM, Kalina P, et al. Hypertensive collaborative group . CLASP: a randomised trial of encephalopathy: findings on CT, MR imaging, and SPECT low-dose aspirin for the prevention and treatment of imaging in 14 cases. American Journal of Radiology pre-eclampsia among 9364 pregnant women. Lancet 1994; 1992;1559:379–83. 343:619–29. The neurology of pregnancy 725 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.6.717 on 1 June 1998. Downloaded from

53 Hertz-Picciotto I, Hopenhayn-Rich C, Golub M, et al. The 77 Sawle GV. Epilepsy and anticonvulsant drugs. In: Rubin P, risks and benefits of taking aspirin during pregnancy. ed. Prescribing in epilepsy. London: BMJ Publishing Group, Epidemiol Rev 1990;12:108–48. 1995:121–35. 54 Bremer HA, Wallenburg HCS. Aspirin in pregnancy. Fetal 78 Yerby MS. Problems and management of the pregnant and maternal medicine review 1992;4:37–57. woman with epilepsy. Epilepsia 1987;28(suppl 3):S29–36. 55 Roelvink NCA, Kamphorst W, van Alphen HAM, et al. 79 Tomson T, Lindbom U, Ekqvist B, et al. Disposition of car- Pregnancy-related primary brain and spinal tumours. Arch bamazepine and phenytoin in pregnancy. Epilepsia 1994; Neurol 1987;44:209–15. 35:131–5. 56 Brent RL. The eVect of embryonic and fetal exposure to x 80 Yerby MS, Devinsky O. Epilepsy and pregnancy. In: Devin- ray, microwaves, and ultrasound: counseling the pregnant sky O, et al,eds.Advances in neurology. Vol 64. Neurological and non-pregnant patient about these risks. Semin Oncol complications of pregnancy. New York: Raven Press, 1994: 1989;16:347–68. 45–63. 57 Kupersmith MJ, Rosenberg C, Kleinberg D. Visual loss in 81 Teramo K, Hiilesmaa V, Bardy A, et al. Fetal heart rate dur- pregnant women with pituitary adenomas. Ann Intern Med ing a maternal grand mal epileptic seizure. J Perinat Med 1994;121:473–7. 1979;7:3–6. 58 Weed JCJr, Woodward KT, Hammond CB. Choriocarci- 82 MinkoV H, ScaVer RM, Delke I, et al. Diagnosis of intracra- noma metastatic to the brain: therapy and prognosis. Semin nial haemorrhage in utero after a maternal seizure. Obstet Oncol 1982;9:208–12. Gynecol 1985;65:22S–24S. 59 Golbe LI. Pregnancy and movement disorders. Neurol Clin 83 Knight AH, Rhind EG. Epilepsy and pregnancy: a study of 1994;12:497–508. 153 pregnancies in 59 patients. Epilepsia 1994;16:1–66. 60 Somerville B. A study of migraine in pregnancy. Neurology 84 Shorvon S. Tonic clonic status epilepticus. J Neurol 1972;22:824–8. 1993; :125–34. 61 Rudolph AM. EVects of aspirin and acetaminophen in preg- Neurosurg Psychiatry 56 85 Cornelissen M, SteegersTheumissen R, . Supplements nancy and in the newborn. Arch Intern Med 1981;141:358– et al 63. of vitamin K in pregnant women receiving anticonvulsant 62 Silberstein SD. Headaches and women: treatment of the therapy prevent neonatal vitamin K deficiency. Am J Obstet pregnant and lactating migraineur. Headache 1993;33:533– Gynaecol 1993;168:884–8. 40. 86 O’Brien MD, Gilmour-White S. Epilepsy and pregnancy. 63 Hainline B. Headache. Neurol Clin 1994;12:443–60. BMJ 1993;307:492–5. 64 Donaldson JO. Headache. In: Neurology of pregnancy. 87 Rogers JD, Fahn S. Movement disorders and pregnancy. In: London: WB Saunders, 1989:217–27. Devinsky O, et al,eds.Neurological complications of 65 Crombie DL, Pinsent RJFH, Fleming D. Imipramine in pregnancy. New York: Raven Press, 1994:163–78. pregnancy. BMJ 1972;i:745. 88 Merchant CA, Cohen G, Mytilineous C, et al. Human 66 Webster PA. Withdrawal symptoms in neonates associated transplacental transmission of carbidopa/levodopa. Neurol- with maternal antidepressant therapy. Lancet 1973;ii: ogy 1994;44(suppl 2):S247–8. 318–9. 89 McCombe PA, McManis PG, Frith JA, et al. Chronic 67 Runmarker B, Anderson O. Pregnancy is associated with a inflammatory demyelinating polyradiculoneuropathy asso- lower risk of onset and a better prognosis in multiple scle- ciated with pregnancy. Ann Neurol 1987;21:102–4. rosis. Brain 1995;118:253–61. 90 Spinnato JA, Clark AL, Pierangeli SS, et al. Intravenous 68 Korn-Lubetzki I, Kahana E, Cooper G, et al. Activity of immunoglobulin therapy for the antiphospholipid syn- multiple sclerosis during pregnancy and puerperium. Ann drome in pregnancy. Am J Obstet Gynaecol 1995;172:690– Neurol 1984;16:229–31. 4. 69 Nelson LM, Franklin GM, Jones MC. Risk of multiple scle- 91 Rudnick Schoneborn S, Rohrig D, Nicholson G, et al. Preg- rosis exacerbation during pregnancy and breast-feeding. nancy and delivery in Charcot-Marie-Tooth disease type I. JAMA 1988;259:3441–3. Neurology 1993;43:2011–6. 70 Van Walverdeen MAA, Tas MW, Barkhof F, et al. Magnetic 92 Byrne DL, Chappatte OA, Spencer GT, et al. Pregnancy resonance evaluation of disease activity during pregnancy complicated by Charcot-Marie-Tooth disease, requiring in multiple sclerosis. Neurology 1994;44:327–9. intermittent ventilation. Br J Obstet Gynaecol 1992;99:79– 71 Thompson DS, Nelson LM, Burns A, et al. The eVects of 80. pregnancy in multiple sclerosis: a retrospective study. Neu- 93 Ip MSM, So SY, Lam WK, et al . Thymectomy in myasthe- rology 1986;36:1097–9. nia gravis during pregnancy. Postgrad Med J 1986;62:473– 72 Roullet E, VerdierTaillefer MH, Amarenco P, et al. 4. Pregnancy and multiple sclerosis: a longitudinal study of 94 Briggs GG, Freeman RK, YaVeSJ.Drugs in pregnancy and 125 remittent patients. J Neurol Neurosurg Psychiatry 1993; lactation. Baltimore: Williams and Wilkins, 1994:261/d– 56:1062–5. 4/d. 73 Lindout D, Schmidt D. In utero exposure to valproate and 95 Briggs GG, Freeman RK, YaVeSJ.Drugs in pregnancy and neural tube defects. Lancet 1986;ii:1142. lactation. Baltimore: Williams and Wilkins, 1994:713/p– 74 Rosa FW. Spina bifida in infants of women treated with car- 16p. bamazepine during pregnancy. N Engl J Med 1991;324: 96 Sammaritano LR. Neurologic aspects of rheumatologic dis- 674–7. orders during pregnancy. In: Devinsky O, et al,eds. 75 Lindhout D, Meinardi H, Barth PG. Hazards of fetal expo- Neurological complications of pregnancy. Advances in Neurol- sure to drug combinations. In: Janz D, Bossi L, Dam M, et ogy. Vol 64. New York: Raven Press, 1994:97–130. 97 Chaturvedi SK. Delusions of pregnancy in men. Case report al,eds.Epilepsy, pregnancy, and the child. New York: Raven http://jnnp.bmj.com/ Press, 1982:275–81. and review of the literature. Br J Psychiatry 1989;154:716– 76 Lindhout D, Höppener RJEA, Meinardi H. Teratogenicity 8. of antiepileptic drug combinations with special emphasis 98 Quill TE, Lipkin M, Lamb GS. Health-care seeking by men on epoxidation (of carbamazepine). Epilepsia 1984;25:77– in their spouse’s pregnancy. Psychosom Med 1984;46:277– 83. 83. on October 1, 2021 by guest. Protected copyright.