Neurological Deseases in Pregnancy

Neurological Deseases in Pregnancy
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  Neurological disease inpregnancy  Muna NooriMandish K Dhanjal  Abstract  Neurological diseases are commonly encountered in women of child-bearing age and pregnancy can pose a unique, if not challenging aspectto their management. A number of conditions exist prior to pregnancy andeither the condition itself or its therapy may impact on the pregnancy,labour or delivery. Conversely, pregnancy may interfere with or precludeoptimal treatment of some neurological diseases, which highlights theimportance of multidisciplinary care in such women. This review outlinesthe natural history, diagnostic features and management options of a number of common neurological conditions in pregnancy. Keywords  anti-epileptic agents; cerebrovascular disease; epilepsy;headache; migraine; neurological disease; neuropathy; pregnancy; pre-pregnancy counselling Migraine and tension headache Migraine is a common disorder in women and frequently pres-ents during child-bearing years. It may present  de novo  in preg-nancy and may be difficult to differentiate from tension headacheas migraine can present with or without an aura.Migraine with and without aura may represent separate clin-ical entities. In a study of women who experienced migraine withaura, 20% suffered their first episode during pregnancy, with nopredilection for a specific trimester. Frequency of migraine wasnot significantly altered by pregnancy. Migraine without aura,however, tended to improve or cease during pregnancy, partic-ularly in later pregnancy. Pathogenesis Tension headache is thought to occur as a result of musclecontraction and is often stress-related. Migraine is regarded asa neurovascular disorder in which sensitization and activation of trigeminal ganglia promotes inflammation of nerves supplyingmeningeal blood vessels, thereby causing cerebral vasodilatation.Triggers for migraine include stress, hormonal factors (e.g.premenstrual hormone changes and the combined oral contra-ceptive pill) and dietary factors (e.g. chocolate, cheese and wine). Diagnosis A careful history and neurological examination, particularlylooking for focal signs will aid diagnosis. It is important toconsider secondary causes of headache, such as pre-eclampsia,subarachnoid haemorrhage, cerebral venous thrombosis andmeningitis, and to investigate appropriately if there are concerns.A diagnosis of migraine is more likely if the headache isunilateral and throbbing, and if it associated with visualprodromal symptoms, nausea and vomiting. Migraine may alsobe associated with focal signs including hemianopia and hemi-plegia, although this presentation is rare (0.1% of cases), andoccurs mainly in the third trimester.Migraine is associated with the development of gestationalhypertension or pre-eclampsia, predominantly in women whoseheadachedoesnotimprovewithpregnancyandhasbeenpostulatedto be an important risk factor for maternal ischaemic stroke.Migrainehasnotbeenassociatedwithadversefetaleffectsincludingmiscarriage, malformations, stillbirth and low birthweight. Treatment options for migraine in pregnancy  Inadequate treatment of migraine may have a serious impact onmaternal wellbeing. Effective management of migraine in pre-gnancy includes:   avoidance of triggers   treatment of acute episodes   prevention of future attacksNon-pharmacological measures to avoid migraine such asadequate sleep, stress management, relaxation techniques,biofeedback, acupuncture, and massage may be of benefit.Among therapeutic options in an acute migraine attack, par-acetamol is the first-line therapy and can be given with an anti-emetic. Codeine phosphate may be of benefit if paracetamol isineffective. Migraleve  (paracetamol, codeine    buclizine orsumatriptan) is a useful combination drug. Non-steroidal anti-inflammatory agents such as ibuprofen are effective but shouldnot be used in the third trimester due to the risk of prematureclosure of the ductus arteriosus and oligohydramnios. Ergotderivatives(e.g. ergotamine) cause placental ischaemia throughvasoconstriction and should be avoided in pregnancy. Manywomen who experience severe migraine have been managed atone time or another with triptans (5-HT agonists). Triptans(sumatriptan, naritriptan), are useful in treating acute attacks butare of limited benefit in prevention of future migraine. Triptansbind to 5-HT receptors, causing vasoconstriction and inhibitionof neuronal inflammation. Population studies evaluating therisks of triptan use during pregnancy have not demonstrated anincreased risk in congenital malformations. Minimal amounts of triptans have been measured in breast milk and they are there-fore considered to be safe during breastfeeding.Frequent migraine attacks warrant prophylaxis. Low-doseAspirin (75 mg daily) is a first-line agent and is safe in pregnancy. b -blockers (propranolol 10 e 40 mg three times aday) are effectivein80%ofcasesandcanbeusedinthosewithoutasthmaifaspirinis ineffective. Tricyclic anti-depressants (amitriptyline 25 e 50 mgat night), calcium channel blockers (Verapamil 40 e 80 mg atnight), and cyproheptadine (2 e 4 mg at night) may be useful in Muna Noori   BSc MRCOG PhD  is a Sub-specialty Trainee in Maternal and Fetal Medicine at Imperial College Healthcare Trust, Queen Charlottesand Chelsea Hospital, Du Cane Road, London, UK. Conflicts of interest:none declared. Mandish K Dhanjal  BSc MRCP MRCOG   is a Consultant Obstetrician and Gynaecologist at Imperial College Healthcare Trust, Queen Charlottesand Chelsea Hospital, Du Cane Road, London, UK. Conflicts of interest:none declared. REVIEW OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 21:6  158    2011 Elsevier Ltd. All rights reserved.  resistant cases. There are insufficient data regarding safety of Pizotifen(Sanomigran  )forpreventionofmigraineinpregnancy. Treatment for tension headache Stress relieving techniques, massage and simple analgesia workbest for alleviating tension headaches. Postpartum headache Migraine attacks can recur postpartum in 34 e 55% of cases, butare more likely to be milder than usual attacks, and less likely tobe unilateral. Breastfeeding appears to protect women frommigraine recurrence. In one study, migraine recurred in the firstmonth following delivery in 43% of women who were breast-feeding and in 100% of women who were not.Othercausesofapostpartumheadachemustbeconsidered,andif persistent may require more detailed investigation with neuro-imaging. If the patient received a spinal or epidural anaestheticduring labour and delivery, a dural puncture must be ruled out. Post-dural puncture headache A post-dural puncture headache (PDPH) arises due to loss of cerebrospinal fluid and reduction in cerebrospinal pressure. Itoften presents in the days following delivery as a fronto-occipital,throbbing headache which occurs abruptly on standing andimproves almost immediately on lying flat again. It may beassociated with visual symptoms, nausea and vomiting andwarrants review by an anaesthetist. An epidural blood patch isoften highly effective in relieving this form of headache. Epilepsy  Epilepsy, which occurs in 0.5 e 1% of women, is the mostcommon neurological disease to complicate pregnancy and isone of the leading causes of indirect maternal deaths in the UK. Classification Epilepsy is classified according to the clinical type of seizures,electroencephalographic (EEG) appearances, and whether theyare partial or generalized. The most common forms are:   tonic-clonic (grand-mal)   absence (petit mal)   temporal lobe seizures (complex partial seizures)   myoclonic seizuresThe majority of cases of epilepsy are idiopathic although a familyhistory exists in up to 30% of patients. Secondary epilepsy mayoccur in subjects who have had previous neurosurgery, anintracranial mass lesion or antiphospholipid syndrome.Furthermore, while most women with epilepsy are diagnosedprior to pregnancy, some may have their first fit in pregnancy.The differential diagnosis for a seizure in pregnancy includeseclampsia, intracranial mass lesion, cerebral thrombosis, stroke,metabolic (hypoglycaemia) and electrolyte imbalances (hypo-natraemia, hypocalcaemia).  Anti-epileptic drugs Anti-epileptic drugs (AEDs) cross the placenta and are terato-genic. The major malformations seen include:   Neural tube defects   Orofacial clefts   Congenital heart defects   Minor malformations(dysmorphic facies, hypertelorism,hypoplastic nails, midface hypoplasia)Associated malformations and absolute risks are summarized inTables 1 and 2.Sodiumvalproateisthemostteratogenicanti-epilepticagentandis responsible for 2% of neural tube defects. Polytherapy, particu-larly regimes including valproate, increases the risk of congenitalmalformation,increasingfurtherwitheachadditionalagent.Thereislikelytobeadose-dependenteffectofmalformationswithsodiumvalproate and lamotrigine so limiting the dosage of these agentsduringthefirsttrimestershouldbeconsidered.Thecombinationof valproate and lamotrigine has also been shown to be particularlyteratogenic when compared to a combination of carbamazepineand lamotrigine. Data regarding types of malformations and rateswithuseoflamotrigine,topiramateandlevetiracetaminpregnancyarelimited.Thereisnoevidencetosuggestanincreasedriskoffetalmalformations in women with untreated epilepsy in pregnancy.In the last decade, an increasing number of studies haveaddressed the long-term safety of AEDs on child development butresults have been conflicting. While maternal IQ has an influenceon offspring IQ, meta-analysis data have shown significantlyreduced verbal IQ in children whose mothers were treated withsodium valproate during pregnancy. These effects were notevident after maternal carbamazepine use.Recent meta-analysis data have shown that epilepsy, withoutthe use of AEDs in pregnancy, is not associated with an increasedcognitive impairment in their offspring. Pre-pregnancy management  Pre-pregnancy counselling should be routine practise in womenwithepilepsy.Priortopregnancy,seizuresshouldbewell-controlledon the least number of AEDs and with the lowest possible dose. Arecent meta-analysis has shown that freedom from seizures for9 months prior to pregnancy is associated with a high likelihood(84 e 92%) of remaining seizure-free during pregnancy. Womenwho have been seizure-free for 2 years prior to pregnancy, mayconsiderdiscontinuationoftheiranti-epilepticmedication,althoughthisshouldbeaninformeddecision,particularlyasreturnofseizureactivitycouldrisklossoftheirdrivinglicence.Womenwithjuvenilemyoclonic epilepsy should not discontinue their medication.Women treated with sodium valproate should be counselledregarding reducing their dose or switching to an alternative AED.If this is not deemed appropriate, divided doses or a slow releasepreparation (EpilimChrono  ) are preferable, as peak plasmaconcentrations are lower and the risk of neural tube defects isreduced. Malformations associated with anti-epileptic drugs Phenytoin  Cleft palate Carbamazepine  Posterior cleft palate; neural tube defects Sodium Valproate  Neural tube defects; facial clefts, hypospadias Phenobarbitone  Cardiac malformations; orofacial clefts Lamotrigine  Neural tube defects; facial clefts;hypospadias  e  limited data Topiramate  Orofacial clefts; hypospadias  e  limited data Table 1 REVIEW OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 21:6  159    2011 Elsevier Ltd. All rights reserved.   Antenatal management  The consequences of uncontrolled epilepsy for mother and babymust be balanced against the risks of teratogenesis and childhoodneurocognitive development that are associated with use of AEDs. Although short periods of hypoxia occurring duringseizures are not known to be harmful for the developing fetus,more prolonged or recurrent episodes of hypoxia may beharmful.While women with uncontrolled epilepsy prior to pregnancyare more likely to experience an increase in seizure frequencyduring pregnancy, other causes for poor control include:   a lack of drug compliance (due to concerns regardingteratogenesis)   decreased drug levels as a result of vomiting in earlypregnancy   lower circulating free drug levels (carbamazepine andlamotrigine)   decreased gastrointestinal absorption   lack of sleepThe option of discontinuing AEDs warrants very careful consid-eration as in doing so, seizure activity may resume or increase.SomewomenchoosetodiscontinuetheirAEDswhentheybecomepregnant due to concerns about teratogenesis. It may be appro-priate to counsel restarting AEDs in women with regular seizures,especially after the first trimester when the risk of teratogenesishas passed. However, long-term neurocognitive effects of sodiumvalproate are likely to be associated with exposure throughoutpregnancy, particularly in the third trimester.Women on AEDs should commence folic acid (5 mg daily)pre-conception and to continue this throughout pregnancy.Those on carbamazepine, valproate or lamotrigine, which exhibitlittle protein binding, may need to increase their doses withadvancing pregnancy as free drug levels tend to fall. This fall ismost marked with lamotrigine. A baseline serum AED level maybe useful in establishing compliance and for adjusting futuredoses, particularly in women who have regular seizures. VitaminK (10 e 20 mg daily) should be prescribed from 36 weeks gesta-tion, to women taking enzyme-inducing AEDs (phenytoin, car-bamazepine, phenobarbitone, and primidone), to increasevitamin K-dependent clotting factors in the baby and reduced theincidence of haemorrhagic disease of the newborn.Women should be offered first trimester ultrasound screeningand a detailed anomaly scan, including fetal echocardiography todetect fetal malformations. The woman’s family members needto be aware of how to place her in the recovery position in theevent of a seizure and the woman should be advised to eithershower, or to bathe in shallow water. Intrapartum management  Epilepsy is not a contraindication to vaginal delivery andCaesareansectionshouldbeperformedforobstetricindicationsorin the event of recurrent generalized seizures in labour. Seizurerecurrence is higher during labour and in the first 24 h afterdelivery. When in labour, women should be offered an earlyepidural as pain and anxiety can trigger seizures. Anti-epilepticdrugs shouldbe continued throughout labourin suppository formif necessary. In the event of a seizure, women should be managedwith facial oxygen, intravenous lorazepam or rectal diazepam. Postpartum care Sleep deprivation lowers seizure threshold so women oftenrequire additional supervision and support postpartum. Theyshould be advised about ways of minimizing risk to herself andthe baby, such as not to bathe their babies unaccompanied and tochange nappies on the floor rather than on a changing table.Theneonateshouldbegiven1mgofintramuscularvitaminKtoprevent haemorrhagic disease of the newborn. Women should beencouraged to breastfeed as in most cases, AEDs cross into breastmilk in minimal amounts(3 e 5% of maternal levels). Lamotrigineandphenobarbitonecrossinlargeramounts(30 e 50%)sowomentreated with these agents should be advised to breastfeed prior totaking their AEDs to minimize neonatal exposure. Multiple sclerosis Multiplesclerosis(MS)isachronicinflammatoryconditionaffectingthe central nervous system. Onset is typically in the second or thirddecadeoflifeanditistwiceasprevalentinfemalesasmales.Multiplesclerosis tends to run a relapsing and remitting course and mostcommonlypresentswithopticneuritis,diplopia,sensoryimpairmentor motor weakness of the limbs. Disease progression is extremelyvariable with complete resolution between relapses in some cases,and progressive neurological deterioration in others. Multiple scle-rosis is unlikely to present for the first time during pregnancy. Pathogenesis The pathogenesis of MS is incompletely understood but involvesa maladaptive humoural and cell-mediated (predominantly Thelper cell type I) response to an antigen that has yet to becharacterized. The autoimmune inflammatory cascade thatensues results in CNS conduction block, demyelination, andaxonal damage which may be reversible or persistent. Areas of demyelination within the spinal cord and brain can be demon-strated using Magnetic Resonance Imaging (MRI). Pregnancy and MS The prospective PRIMS (Pregnancy in Multiple Sclerosis) studyreported a reduction in MS relapse during pregnancy, particularlyin the third trimester (70% reduction), and a compensatoryincrease in relapse rates in the first 3 months postpartum (40%relapse rate), with a subsequent decline in relapse rates to pre-pregnancy levels by 10 months postpartum. Pregnancy andbreastfeeding do not appear to have an adverse effect on futuredisease course or MS progression, and MS does not appear tohave an effect on pregnancy outcome and is not a contraindica-tion to vaginal delivery or epidural anaesthesia.WomenwithadvancedMSmayexperiencedeteriorationintheirmobility and worsening spasticity as pregnancy advances, due to  Absolute risks of congenital malformations arising fromanti-epileptic drug monotherapy  Carbamazepine  900 2.2 (1.4 e 3.4) Lamotrigine  647 3.2 (2.1 e 4.9) Phenytoin  82 3.7 (1.3 e 10.2) Sodium valproate  715 6.2 (4.6 e 8.8) Table 2 REVIEW OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 21:6  160    2011 Elsevier Ltd. All rights reserved.  increasing weight and an altered centre of gravity. Patients shouldbe warned against falls and may require additional physiotherapyduring pregnancy. As pregnancy is a prothrombotic state, throm-boprophylaxis with compression stockings, aspirin or low molec-ular weight heparin should be considered in immobile patients.Patients with a pre-existing neurogenic bladder are atincreased risk of recurrent urinary tract infections, which requireprompt treatment with antibiotics, or more frequent self-cathe-terizations to minimize infections. Treatment  Relapses of MS can be managed with rehabilitation but severe,acute relapses may warrant treatment with high dose corticoste-roids during pregnancy and breastfeeding. Agents that reducerelapses such as  b -interferon and Glatiramer are usually dis-continued during pregnancy due to a paucity of safety data. Themainstay of MS relapse prevention is  b -interferon. Recent caseseriesofwomenwithfirsttrimesterexposuretoeither b -interferonorGlatiramerdidnotdemonstrateanincreasedmiscarriagerateorcongenital malformation rate compared to women who were nottreated with these agents. Treatment with  b -interferon washowever associated with lower birthweight. As data are limited,use of either  b -interferon or Glatiramer should be restricted tomore complicated cases, where benefits outweigh potential risks.Additional drugs that are occasionally used warrant consid-eration. Azathioprine is safe in pregnancy, but methotrexate isassociated with miscarriage and malformations and should beavoided. Drugs used to relieve spasticity (baclofen), paroxysmalpain or dysaesthesiae (carbamazepine and gabapentin) may alsobe used. Depression is sometimes encountered in MS sufferers soanti-depressants may be required during pregnancy. Stroke Stroke in pregnancy occurs in 34.2 per 100,000 deliveries, andcontributes to more than 12% of maternal deaths. Pre-eclampsiaand eclampsia are associated with 25 e 45% of pregnancy-relatedstroke, including haemorrhagic and non-haemorrhagic causes.Most pregnancy-related strokes occur in the third trimester orpostpartum and this is especially true of venous thrombosis. Thecommon causes of stroke out with pregnancy, including hyper-tension, and diabetes and smoking are less common in preg-nancy so rarer causes need to be considered. Risk factors areoutlined in Table 3. Ischaemic stroke Most pregnancy-related ischaemic strokes occur in the distribu-tion of the carotid and middle cerebral arteries, and predomi-nantly occur postpartum. Haemorrhagic stroke Haemorrhagic stroke is rare in women of child-bearing ageoutside pregnancy but is as common as ischaemic stroke duringpregnancy. It accounts for two to four maternal deaths annuallyin the United Kingdom.Haemorrhage occurring in pre-eclampsia and eclampsia isthought to occur secondary to cerebral vasospasm, loss of cere-bral autoregulation and breakthrough of the vessel wall. Ruptureof vascular malformations may also contribute to maternal strokerates and may occur in any trimester. Subarachnoid haemorrhage Subarachnoid haemorrhage (SAH) occurs in two per 10,000pregnancies which is a two to three fold increase from non-pregnant rates. In the puerperium, rates of SAH are up to 20-foldhigher. Presenting signs and symptoms include:   Headache, which is often sudden-onset and occipital   Vomiting   Altered consciousness or sudden collapse   Neck stiffness   Papilloedema   Focal neurological signsSubarachnoid haemorrhage may occur due to rupture of anarterial (Berry) aneurysm or an arterio-venous malformation(AVM). Pregnancy-related ruptured aneurysms have been shownto occur antenatally in 90% of cases (most commonly in latepregnancy), in the puerperium in 8% of women, and duringlabour in the remaining 2% of cases. Investigation Investigation of stroke in pregnancy should proceed as in thenon-pregnant state, but pregnancy-specific causes require specialconsideration. Magnetic resonance imaging (MRI) or computedtomography (CT) can confirm ischaemic stroke and differentiatehaemorrhage from infarction. Lumbar puncture, echocardiog-raphy and carotid artery Dopplers may also help to establish anunderlying cause. CT angiography may also be useful and shouldnot be withheld in pregnancy. Management  Management of ischaemic stroke includes anti-platelet therapy(Aspirin 75 mg daily), which should be continued postpartum.Some patients require anticoagulation with unfractionated or lowmolecular weight heparin. Warfarin crosses the placenta and isteratogenic, so its use requires careful consideration. Throm-bolysis for stroke is generally contraindicated in pregnancy and Risk factors for stroke during pregnancy  MigraineHaematological Sickle cell disease, thrombophilia, Cardiovascular  Hypertension, mitral valve disease, infective endocarditis,peripartum cardiomyopathy, paradoxical embolus, aortic dissection Endocrine Diabetes, electrolyte disturbances  Antiphospholipid syndrome Vasculitis Systemic lupus erythematosus (SLE), TTP Black ethnicity  Age > 35 yearsPregnancy-related Pre-eclampsia, eclampsia, multiple pregnancy, multiparity,Caesarean section Lifestyle Smoking, alcohol and substance abuse Table 3 REVIEW OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 21:6  161    2011 Elsevier Ltd. All rights reserved.


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