Neurological conditions during pregnancy can be pregnancy related or can be caused by exacerbation of pre-existing neurological disorders. Knowledge of pre-existing epilepsy or myasthenia gravis in women of childbearing age requires preconception counselling by neurologist and planned pregnancy. Possible adverse effects of medication on the foetus should be balanced with the risk of uncontrolled symptoms. Interdisciplinary management before, during and after pregnancy is recommended.
New acute neurological symptoms in pregnant or postpartum women should lead to an urgent neurological review. Patients need a thorough diagnostic evaluation that targets a range of serious pathological conditions that are either unique to (e.g. eclampsia) or arise more frequently (e.g. cerebral venous thrombosis) in this population. Most of these conditions are infrequent and require a specialized and multidisciplinary management. Treatment is challenging due to risks to the unborn child.
Introduction
In pregnant and post-partum women several neurological symptoms and conditions may occur. Some are caused by exacerbation of pre-existing disorders others are pregnancy related disorders. Understanding the physiological changes during pregnancy is important for the diagnosis and management of the neurological conditions. Mediated by hormonal changes several organ systems are affected from the first trimester until postpartum. For example, increased production of procoagulant factors and fibrinogen leads to a hypercoagulate state, while concentration of factors important for fibrinolysis is decreasing. These changes result in increased risk of venous thrombosis, e.g. cerebral venous thrombosis (CVT). Pharmacokinetics of various drugs, e.g. antiepileptic drugs (AEDs), maybe influenced by alterations to renal clearance and altered liver metabolism. Increased renal blood flow and glomerular filtration rate may cause shift of plasma protein and in particular albumin concentrations. Increased hepatic glucuronidation may result in decreased serum levels of drugs metabolised by this pathway. Hence, treatment of epilepsy during pregnancy is complex and challenging . Changes to connective tissue can cause peripheral nerve compression syndromes, for example carpal tunnel syndrome. Symptoms often improve with conservative management and resolve after delivery . Knowledge of pre-existing disorders (e.g. epilepsy, myasthenia gravis, or previous CVT) and its treatment is particularly important and requires special consideration before, during and after pregnancy .
Frequent neurological symptoms
Headache is a common neurologic symptom in pregnancy. The most common primary headaches in general population are tension type headache and migraine. They occur amongst adults with a prevalence of 20 to 30% and 10 to 12% respectively, both with an increased prevalence in women . Among pre-existing primary headaches, migraine is more sensitive to ovarian hormones. Increased oestrogen levels and the lack of hormonal fluctuations are associated with an amelioration of migraines without auras . New onset headaches that are associated with increasing symptom severity and/or frequency should lead to the suspicion of secondary causes (e. g. CVT or preeclampsia) and should lead to a prompt and careful neurological assessment and diagnostic investigation .
Seizures may occur either as new onset or as a result of a pre-existing epilepsy. With regards to the latter, epilepsy is the most common chronic neurological disorder affecting 0.7% of population, with the similar prevalence in pregnant women. New onset epilepsy in pregnancy (e.g. cryptogenic focal epilepsy, idiopathic generalised epilepsy) is less common due to the fact that there are two peaks in the incidence, one in childhood and one in older age . It is more likely that new onset seizures in epilepsy are acute symptomatic, i.e. they occur as a result of acute brain damage or disease. Therefore, pregnant and post-partum women with a new-onset seizure require urgent neurology review and should undergo thorough investigation to establish the cause of the seizure. Non-pregnancy related causes include hypoglycaemia, an undiagnosed brain tumour or encephalitis. Pregnancy related causes include CVT, intracranial haemorrhage or posterior reversible encephalopathy syndrome. Although these conditions are more frequent during pregnancy, they occur also in non-pregnant individuals . Eclamptic seizures are unique to pregnancy .
Pregnancy related neurological conditions
Eclampsia
Hypertensive disorders of pregnancy (preeclampsia and eclampsia) are the cause of 12% of maternal deaths globally . Preeclampsia is a multisystem disease characterized by impaired organ perfusion resulting from vasospasm and activation of the coagulation system. It is defined as hypertension and proteinuria appearing after the 20th week of gestation and resolving within 6 to 12 weeks after delivery. It occurs in 2 to 3% of all pregnancies and is more common in primigravida or the first pregnancy with a particular partner . The aetiology is not clear, but abnormal trophoblastic invasion and alterations in the immune response are implicated . This may lead to vascular, renal, hepatic and hematologic dysfunction. The constellation of haemolysis, elevated liver enzymes, and low platelet counts is known as HELLP syndrome . The hallmark of eclampsia is seizures, which are usually tonic-clonic and last for about one minute. Other symptoms such as coma or focal neurological deficits may occur. In most cases preeclampsia precedes eclampsia . 44% of seizures in eclampsia occur in the postnatal period, the remainder being antepartum (38%) or intrapartum (18%) . Symptoms including persistent frontal and occipital headache, blurred vision, scotoma, photophobia and altered mental status can precede a seizure . The pathogenesis is not clear, but convulsions are believed to result from severe intracranial vasospasm, local ischemia, intracranial hypertension and endothelial dysfunction associated with vasogenic and cytotoxic edema . Magnetic resonance imaging of the brain may reveal cortical and subcortical hyperintense lesions predominantly in the posterior cerebral region. These lesions may resolve with appropriate treatment. Such changes are classified as the posterior reversible encephalopathy syndrome . Women with eclampsia require prompt intervention. The first priority is to prevent maternal injury, maintain a patent airway, and ensure cardiorespiratory stability . Further convulsions should be prevented with intravenous or intramuscular magnesium sulphate, which is superior to phenytoin and benzodiazepines . The suggested mechanism is its antivasospastic effect, which results in an increase in cerebral blood flow . Blood pressure should be reduced to a safe range. Significant hypotension should be prevented to avoid compromise to cerebral perfusion or jeopardizing uteroplacental blood flow . If eclampsia occurs pre-partum, urgent delivery of the foetus should be considered. In postpartum eclampsia more active treatment can be advocated, which is directed at terminating the cause of focal deficits and managing raised intracranial pressure, malignant hypertension, seizures and ischemic or haemorrhagic stroke . There has been a significant decrease in the mortality associated with eclampsia over the years, and mortality is often attributable to hepatic complications .
Eclampsia:
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Women with eclampsia require prompt intervention.
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Management in a high-dependency care setting should be considered. Cardiorespiratory support may be required, and high blood pressure should be gradually reduced to a safe level.
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Prevention of further convulsions with intravenous or intramuscular magnesium sulphate.
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In case of pre-partum eclampsia urgent delivery of the foetus should be considered.
Cerebral venous thrombosis (CVT)
Patients with CVT present most commonly with acute (within hours), subacute (within days or weeks) or hyperacute (thunderclap) headache. It is typically described as a diffuse pain, which often progresses in severity over days to weeks. In addition to headache, the most common symptoms and signs are seizures, focal neurological deficits, altered consciousness and papilloedema . The incidence of CVT in the general population is 1.32 per 100 000 per year, which is probably higher than previously believed . The incidence of CVT during the peripartum period is estimated at 12 per 100 000 deliveries. The higher incidence in this population is due to hypercoagulability with the highest risk during the third trimester and the first four postpartum weeks . In addition to a thorough history and physical examination, testing of D-dimer level may help in the diagnosis, but if there is strong clinical suspicion of CVT a normal D-dimer level should not preclude further evaluation . Early and accurate diagnosis is possible with the help of magnetic resonance imaging venography, which is considered to be the technique of choice for diagnosis and follow-up . Further thrombophilia screening may be indicated, particularly if there is history of previous thrombotic events (e.g. CVT, deep venous thrombosis, and pulmonary embolism) in the patient or her family . In accordance with the guidelines of European Federation of Neurological Societies the first line treatment of CVT is anticoagulation in order to prevent further clot propagation and allow resolution of the existing clot. Patients without contraindications for anticoagulation should be treated either with subcutaneous low-molecular-weight heparin (LMWH) or with intravenous heparin . Intracranial haemorrhage secondary to the CVT is not an absolute contraindication for anticoagulation. Anticoagulation with LMWH should be continued throughout pregnancy for a further 6 weeks postpartum, for a total duration of at least 6 months. Postpartum therapy with LMWH or warfarin is recommended. It is reasonable to advice women with a history of CVT that future pregnancy is not contraindicated, but a prophylaxis with LMWH during future pregnancy and the postpartum period is recommended . Adjunctive therapy for associated complications includes the use of antiepileptic drugs (AEDs), management of increased intracranial pressure, the control of psychomotor agitation and analgesia . Prophylactic AED therapy may be considered in patients with focal neurological deficits indicating cerebral involvement and/or focal cerebral lesions on imaging. The optimal duration of AED treatment for patients with seizures is unclear . The risks of epileptic seizures against possible adverse effects to the fetus need to be balanced . Patients with CVT who develop raised intracranial pressure are at risk of loss of vision. A therapeutic lumbar puncture with removal cerebrospinal fluid to achieve normal CSF pressure should be considered. Anticoagulation should be started 24 hours after lumbar puncture. General principles of management of raised intracranial pressure including head elevation at about 30°, intravenous application of osmotic diuretics are recommended for short periods . Management in an intensive care unit is required to facilitate sedation, and intracranial pressure monitoring. Hyperventilation with a target PaCO 2 pressure of 4.5–5.0 kPa (30–35 mmHg) is effective to reduce intracranial pressure but should be applied with caution to pregnant women with respect to uterine vasoconstriction. Patients with a large haemorrhagic infarction are at particular risk of brainstem herniation and should be considered early for a decompressive craniectomy . The prognosis is very variable, though generally favorable among the obstetric population as compared to the general population . The individual prognosis is difficult to predict. Two-thirds of patients recover without sequelae .
Cerebral venous thrombosis:
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First line treatment is anticoagulation with subcutaneous LMWH or intravenous heparin.
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Treatment should be continued for a minimum duration of six months and for at least 6 weeks postpartum.
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Symptomatic therapy includes the use of antiepileptic drugs, management of increased intracranial pressure, the control of psychomotor agitation and analgesia.
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Prophylaxis with LMWH during future pregnancy and the postpartum period is recommended.
Pre-existing disease requiring special consideration
Myasthenia gravis (MG)
MG is a neurological disease that is associated with functional loss of the nicotinic acetylcholine receptors (AChR) that initiate muscle contraction, caused by autoantibodies of the IgG isotype . Prevalence rates are estimated at 40 cases per million. The incidence is twice as high in women compared to men, with the peak incidence in the third decade of life . The cardinal feature of MG is a fluctuating muscle weakness that is worsened by fatigue and improves when resting. Symptoms usually increase as the day progresses. At onset of the illness muscles controlling eye movements are frequently affected. This results in diplopia, gaze paresis or often asymmetrical and incomplete ptosis. All voluntary muscles can be affected. Although pelvic floor muscle weakness can compromise pregnant women in delivery, involuntary muscles like the uterus are not involved . The presence of a thymoma, an epithelial tumor of the thymus gland, is the most prevalent association with MG . Hence, imaging of the anterior mediastinum is always required, either by computed tomography or magnetic resonance imaging . The clinical diagnosis is confirmed by positive AChR antibody titre in serum and decremental responses to 2–3 hertz stimulation of hand or proximal muscles as determined by electrophysiology. If the diagnosis is in doubt, a Tensilon test (intravenous injection of edrophonium chloride) should be considered. However, its safety in pregnant patients has not been established . Worsening of symptoms may be caused by several drugs, infections, hypothyroidism, surgery with general anaesthesia, physical or emotional stress, but also by pregnancy and postpartum. Any worsening may result in myasthenic crisis, which is defined as an insufficiency of the respiratory muscles and may become severe enough to require assisted ventilation . In accordance with the recommendations of the European Federation of Neurological Societies for the treatment of MG, anticholinesterase drugs should be given as first line treatment. If thymoma is diagnosed, thymectomy is indicated. Immunosuppressive medication should be considered in all patients with progressive MG symptoms. Prednisolone is often used as the first line immunosuppressant. When long-term immunosuppression is indicated, adding azathioprine allows minimising the dose of steroids. Intravenous immunoglobulin and plasma exchange are effective for the treatment of MG exacerbations and crisis . Women with MG have an increased risk of pregnancy complications and adverse pregnancy outcome. Increased awareness of the risks associated with pregnancy and delivery should not discourage woman from giving birth. However, management of such patients will need well coordinated interdisciplinary care by obstetricians, neurologists, and paediatricians in order to optimize the treatment and minimize the risks .
Preconception
Preconception advice should include a re-evaluation of therapy. Immunosuppressant drugs (e.g. azathioprine, cyclosporine A or mycophenolate mofetil) should be avoided in women with purely ocular symptoms or very mild generalized weakness. These drugs should be discontinued or decreased to a minimum when disease severity allows avoiding potential detrimental effects on the fetus. Withdrawal must be carefully considered and needs to be balanced against the risk of fetus and mother by uncontrolled MG and life threatening exacerbations . Pregnancy should be avoided in women treated with methotrexate, a folic acid antagonist, because of risk of malformations, especially involving the central nervous system, and an associated high rate of spontaneous abortion . Thymectomy is recommended in women with generalized MG considering pregnancy, particularly if they have already given birth to a child with neonatal MG. Lowering the level of AChR antibodies showed a protective effect for the newborn against neonatal MG, but it does not seem to prevent other complications during pregnancy and delivery .
During pregnancy
It is recommended that regular check ups every two weeks is required. Patients on steroids should be closely monitored for infectious complications . Pregnant women should be educated in avoiding unnecessary exertion and eating a well-balanced diet containing food with high potassium. Emotional stress and lack of sleep should be kept to a minimum in order to avoid exacerbation . Treatment of MG during pregnancy is depending on the severity of the disease and the potential side effects to the fetus. Anticholinesterase drugs are considered to be safe in pregnancy. Steroids used in the first trimester have been linked to increased occurrence of cleft palate, but have been considered safe for the rest of the pregnancy . Myasthenic crisis is caused by respiratory failure due to myasthenic muscle weakness. It requires ventilation and is a life threatening condition. This can occur during pregnancy as a result of a worsening disease processes or reduced effects of anticholinesterase drugs. Management of myasthenic crisis requires careful monitoring in an intensive care unit, stabilizing respiratory function and haemodynamics. Treatment with steroids and plasmapheresis is recommended .
Delivery
MG patients may have normal pregnancy and delivery, but deliveries are more often terminated by vacuum extractor to shorten the second stage of labour. A population based cohort study of 127 births from mothers with MG reported a higher total number of caesarean sections in the MG group than in mothers without MG . Transplacental transmission of AChR antibodies, which are IgG isotype, can lead to neonatal MG, which affects 10–20% of infants . Symptoms of neonatal MG consist mainly of transient respiratory problems and difficulties in feeding and swallowing. Due to degradation of the maternally derived IgG, the MG effect upon the infant will be transient. It is important that these children are observed closely to avoid persistent disability due to complications .
Myasthenia gravis and (pre-)eclampsia
Women with myasthenia gravis are particularly difficult to manage if (pre-)eclampsia occurs. Magnesium sulphate, the first line drug for seizure prevention and control in (pre-)eclampsia is inducing myasthenia and carries a high risk of myasthenic crisis. Alternatively, phenobarbital or careful use of anticonvulsant narcotics or sedatives should be used to control seizures in woman with (pre-)eclampsia .
Myasthenia gravis:
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Preconception advice should include reduction in or discontinuation of immunosuppressant drugs. Thymectomy should be considered.
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Throughout pregnancy anticholinesterase drugs are considered safe. Steroids are considered safe after the first trimester. Regular check-ups every two weeks and monitoring for infections are recommended.
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Drugs that precipitate a myasthenic crisis should be avoided (e.g. general anaesthesia, magnesium sulphate). Myasthenic crisis requires careful monitoring.
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Symptoms of neonatal MG are transient.
Epilepsy
Epilepsy is defined as the occurrence of recurrent unprovoked seizures. Most patients with epilepsy are otherwise healthy with normal fertility . Epilepsy is the most common chronic neurological disorder affecting 0.7% of the population. The incidence is 48 per 100 000 per year and will be lower in pregnancy as peak incidence occurs in early life and in older age . The treatment usually comprises a long term antiepileptic drug (AED) regimen. Surgery may be a therapeutic option in patients with drug- refractory epilepsy. Data from EURAP (International Registry of Antiepileptic Drugs and Pregnancy) show that the majority of women with epilepsy remain seizure free throughout pregnancy or having no change in seizure frequency. Seizure control was obtained with monotherapy in 78.7%. Among all pregnant woman with epilepsy one third will have a change in seizure frequency, approximately half have an increase in seizure frequency and half have a decrease in seizure frequency. Status epilepticus is relatively rare (1.8% of pregnancies), with approximately one-third presenting as convulsive episodes and two thirds presenting as non-convulsive episodes . The risk of status epilepticus is not significantly increased in pregnancy .
Preconception
Preconception advice should be given by a neurologist. The most efficacious AED monotherapy with the smallest risk of teratogenic effects needs to be determined. AEDs including lamotrigine, carbamazepine or levetiracetam in monotherapy have the lowest teratogenic risk profile . The AED should be titrated to archive the lowest possible effective dose and the serum concentration should be determined prior to conception . Supplemental use of 5 mg folic acid per day prior to conception and during at least the first trimenon of pregnancy in women on AEDs reduces the risk of neural tube defects .
During pregnancy
The pharmacologic treatment of epilepsy is challenging during pregnancy. The seizure pattern may be influenced by variations in ovarian hormones, blood levels of AEDs and metabolic changes. Physiologic changes associated with pregnancy may alter the serum levels of AED, from absorption, distribution, metabolism to excretion. A significant fall in serum concentrations can be expected for AEDs that are eliminated by glucuronidation (e.g. lamotrigine, oxcarbazepine) or that are primarily cleared by the kidneys (e.g. levetiracetam, gabapentin). In these cases, an increase in dose may be required to maintain the woman’s individual optimal preconception pre-dose serum concentration . Monitoring of serum levels is recommended for AEDs with marked but unpredictable alterations such as lamotrigine, levetiracetam, oxcarbazepine and possibly topiramate , and AED dose adjustment should be considered accordingly.
Post-partum
All neonates born to women taking enzyme inducing AED should receive 1 mg of vitamin K1 administered parenterally . During the postpartum period most of the AED levels increase. This change may be significant and occur within a few days (e.g. lamotrigine, levetiracetam). In general changes to serum AED levels plateau by 10 weeks postpartum. Serum AED levels should be followed closely during this period. Postpartum toxicity can be avoided by tapering the AED to preconception doses . In general, most women taking AED are safe to breast feed . Detailed information on adverse neonatal effects related to breast feeding whilst taking AED is available in drug formularies.
It is important to give mothers advice on how to avoid epilepsy related accidents whilst caring for the newborn. This will also reduce anxiety. The risk of epilepsy related harm to the newborn is low
