Pregnancy, a unique condition in clinical medicine, involves simultaneous treatment of both the woman and her fetus(es). When a pregnant woman has a neuro-ophthalmic problem, many neuro-ophthalmologists hesitate about diagnostic studies and therapeutic interventions. My interest in this subject began during my fellowship at the University of Iowa—in part, thanks to my husband, a high-risk obstetrician. My fellowship project was examining pregnant women with severe preeclampsia and eclampsia for neurologic and neuro-ophthalmologic findings. My colleague, Dan Jacobson, shared my interest, and together we published a case of spontaneous orbital hemorrhage (1). Dan went on to report a cranial neuropathy occurring in pregnancy (2) and to become a masterful clinician, teacher, and writer. Our mutual interest in neuro-ophthalmic complications in pregnancy inspired my Jacobson Lecture.
Here, I review normal changes in pregnancy, which can affect the eye and brain. I also describe evaluation of neuro-ophthalmic conditions in pregnancy, and I discuss common problems, including vascular complications, papilledema, eclampsia, cranial neuropathy, and postpartum neuro-ophthalmic events.
WHAT ARE THE NORMAL CHANGES IN PREGNANCY THAT COULD AFFECT THE EYE OR BRAIN?
All physiologic changes in pregnancy are mediated by the fetus and placenta and are designed to optimize development in utero and facilitate a safe birth. Blood volume and cardiac output are increased by 30%–50% at term in order to adequately perfuse mother's uterus (and fetus). An increase in extraellular fluid (approximately 2 L by term) results from a decrease in serum osmolality (3). In anticipation of controlling blood loss during delivery, plasminogen, fibrinogen, and factors I, V, VII, IX, and X are increased while fibrinolysis is decreased. Smooth muscle hyperplasia helps accommodate the enlarging uterus, and fragmentation of reticular fibers within blood vessel walls occurs, resulting in an increased risk for vascular complications (4).
Immunologic changes in pregnancy, primarily in cellular immune function, occur because the fetus is immunologically distinct from its mother (5,6). Many immune-mediated problems, like rheumatoid arthritis and ankylosing spondylitis, can improve in pregnancy. In the postpartum state, immunologic problems may worsen. For example, women with multiple sclerosis are more likely to have a demyelinating attack postpartum (7,8).
Although normal human pregnancy is approximately 38–40 weeks in duration, approximately 12% of births in the United States occur more than 3 weeks before the due date. While three-quarters of these are “late preterm” (34–36 weeks) and have relatively few complications, approximately 3% are less than 34 weeks and are at an increased risk for perinatal and long-term morbidity and mortality. Most obstetricians and neonatologists predict rapidly improving survival rates for babies born at or beyond 24 weeks (9). Treatment and intervention decisions during pregnancy must always consider the fetal risks from continued in utero residence versus delivery.
CHANGES IN THE EYE IN PREGNANCY
Excellent reviews summarize normal changes in the eye and ophthalmic complications (10–13). Pregnant women report refractive changes, thought to be partially due to progesterone-mediated changes in corneal fluid content. These same fluid shifts may contribute to the common complaint of blurred vision and poorly fitting contact lenses during pregnancy (14,15). A myopic shift of less than 1 diopter often occurs (16). Myopia-related reduction in night vision can happen; if it is pronounced, the clinician should consider vitamin A deficiency. Intraocular pressure decreases during pregnancy (17). The cause is attributed to reduced episcleral venous pressure, greater aqueous outflow, and effects of progesterone. There are no known retinal or optic nerve changes in normal pregnancy.
NEUROLOGIC CHANGES IN PREGNANCY
Volumetric MRI techniques have shown that the brain becomes somewhat smaller and the ventricles slightly larger. These changes may be related to alkalosis and hormones. Brain volume decrease seems to reverse itself postpartum (18,19). Biochemical and hormonal changes in the brain during and after pregnancy prepare a woman for motherhood (20). Prolactin levels are increased, and cerebrospinal fluid (CSF) prolactin is elevated. Prolactin may have an effect on maternal-newborn bonding and feeding (21).
The pituitary gland increases in size approximately 0.08 mm/week, its weight increases 30%, and its volume increases 2-fold. The pituitary gland often appears enlarged on MRI and returns to normal approximately 1–2 weeks postpartum, whether the woman is nursing or not (22). While normal enlargement rarely causes problems, chiasmal compression has been reported (23).
Sleep changes occur in all trimesters. Disrupted sleep breathing is associated with rates of preeclampsia, endothelial damage, and fetal abnormalities (24,25). Pregnancy and the puerperium are stressful life events, and hormonal and biochemical changes increase the frequency of mood changes. Depression occurs within the first week of delivery in 50–70% of pregnancies. In 10–20%, it is serious and requires attention (26).
Cerebrospinal Fluid Pressure in Pregnancy
A pregnant woman has an average normal CSF pressure of 12.7 mm Hg (27) or 167 mm CSF. While 250–300 mL of blood is transfused into the vascular circulation with each contraction, there is no increase in intracranial pressure during a contraction alone. It has been shown that CSF pressure increases during labor, due to muscular contraction in response to pain (28–31). Women can increase pressures to more than 700 mm CSF with Valsalva maneuver (32).
EVALUATING A NEURO-OPHTHALMIC PROBLEM IN PREGNANCY
Evaluation should proceed as it would if the woman were not pregnant. We should assume that if we diagnose the mother correctly and treat her appropriately, she will adequately care for the fetus. We use the same tools as we would to make any diagnosis in neuro-ophthalmology (Table 1).
MEDICATIONS IN PREGNANCY
No studies have prospectively evaluated medication safety in pregnancy. Much of what we know is derived from animal studies and toxicity reports. The major classification of drugs in pregnancy is from the Food and Drug Agency (FDA) classification (Table 2).
VASCULAR DISORDER IN PREGNANCY
Cerebral Stroke and Retinal Vascular Disorders
It used to be thought that pregnancy alone increases the risk of cerebrovascular disease by 3–13 times the expected rate in healthy young women, and it still does in some countries (35). The risk of stroke during a normal healthy pregnancy is approximately 0.7, but stroke risk is definitely increased postpartum to 8.7 (95% confidence interval, 4.6–16.7) (36). Cerebrovascular disease accounts for 0.47%–6% of maternal mortality (37). Retinal vascular events occur; it is important to diagnose their cause. In some cases, simple aspirin (FDA class C) is prescribed; in others, prophylactic anticoagulation with heparin or heparinoids (FDA class B) is indicated. Warfarin (FDA class X) generally is avoided because of associated fetal malformations and abnormalities resulting from concurrent fetal anticoagulation (38).
Embolism from a cardiac source is the most common cause of an acute vascular event in this age group (Table 3). Conditions to consider include rheumatic heart disease, endocarditis (bacterial and nonbacterial), and paradoxical embolism (often worsened by venous stasis in the lower extremities and an undetected patent foramen ovale) (39). Peripartum cardiomyopathy, an uncommon disorder, is poorly understood and causes acute heart failure that may not be reversible. These women often first present with symptoms weeks or months postpartum (40). Amniotic fluid embolism is a catastrophic event with often multiple arterial occlusions and is fortunately a rare cause of retinal or cerebral artery occlusion (41). Evaluation of vascular embolic disorders should proceed as if the woman were not pregnant. Besides evaluation of a cardiac source, consider hematologic disorders, such as lupus anticoagulant, protein C deficiency, Leiden factor V, and prothrombin 20210.
Spontaneous Orbital Hemorrhage
Spontaneous orbital hemorrhages occur in 2 scenarios. The first is in the first trimester when women have severe nausea and vomiting. The second is during labor where Valsalva maneuver is repeatedly performed (1). Symptoms are sudden diplopia, proptosis, and pain (44). Anti-coagulation of the mother constitutes a risk factor (45). The diagnosis can be made by orbital ultrasound, CT, or MRI. Treatment is usually unnecessary since the hemorrhage generally resolves spontaneously.
Orbital varix usually presents with a slowly progressive sense of fullness around the eye. Sometimes bending over increases the fullness. Orbital ultrasound, CT, and MRI are appropriate diagnostic studies. The varix may become symptomatic due to increased blood volume. Little is known about the management (46). Complications resemble those observed in women who are not pregnant: hemorrhage, glaucoma, and thrombosis. Cesarean section is not mandatory; labor can be managed with an epidural and “rest and descent,” with assisted vaginal delivery with vacuum or forceps.
Vascular Events of Pituitary Gland: Sheehan Syndrome or Pituitary Apoplexy
Pituitary apoplexy presents either with lack of menstruation after pregnancy or more dramatically with the sudden onset of a headache and variable visual loss. There are 2 instances where apoplexy can occur: 1) hemorrhage into an unsuspected pituitary tumor during or after pregnancy and 2) after sudden and large hemorrhage or blood volume loss. While most cases present postpartum, looking for this entity under the appropriate circumstances can be important (47,48). Treatment of pituitary apoplexy may be surgical, if vision or life is threatened, or hormone replacement (49,50).
PAPILLEDEMA IN PREGNANCY
Papilledema discovered in pregnancy poses significant challenges (51). Increased intracranial pressure may be primary (idiopathic intracranial hypertension [IIH]) or secondary (mass lesion, cerebral venous thrombosis, meningitis, eclampsia). MRI and magnetic resonance venography or CT venography is required to rule out cerebral venous sinus thrombosis, a long-recognized cause of stroke in pregnancy. Incidence of cerebral venous sinus thrombosis in pregnant women is between 1/1000 and 1/10,000. Symptoms may be indistinguishable from those of IIH (52). However, more serious neurologic complications may occur, including seizures and hemiplegia (53). Possible etiologies are outlined in Table 4. Leiden factor V (protein C resistance) is increased 8-fold. Other genetic factors, such as protein C and S deficiencies, prothrombin gene, and homocysteinemia, may be symptomatic. Women are more prone to autoimmune diseases, which could promote venous sinus thrombosis, such as anticardiolipin antibodies or systemic lupus erythematosis. While venous sinus thrombosis most commonly occurs postpartum, it can take place during pregnancy.
Cerebral venous thrombosis must be treated. Pregnant women who received heparin had 50% fewer deaths than those not anticoagulated (54,55), with no increase in maternal or perinatal complications. Enoxaparin (FDA class B) is used frequently rather than heparin (FDA class B) because of the ease of administration and lower complication rate. Warfarin (FDA class X) is not used during pregnancy because of possible fetal posthemorrhagic malformations; however, it can be used postpartum including during lactation. Women with papilledema from venous sinus thrombosis should be followed like individuals with IIH (see below).
IIH commonly is seen in women of childbearing age. The use of acetazolamide in pregnancy has not been systematically studied. This is an FDA class C drug, and no evidence of teratogenicity has been reported (56). Because fetal structural development is essentially complete by the end of the first trimester, concerns about teratogenesis are generally nonissues later in pregnancy. Other diuretics could be considered: chlorthalidone (FDA class B), furosemide (FDA class C), or hydrochlorothiazide (FDA class B). Other treatments include limitation of weight gain (57).
If vision is threatened, simple CSF drainage may temporize the situation. Optic nerve sheath fenestration should be considered. Lumbar-peritoneal and ventricular peritoneal shunts may be challenging (51,58–61).
Because 50% of pregnancies in the United States are unplanned, preconceptional counseling is encouraged whenever IIH diagnosis is established in a woman of reproductive age. Weight control before and during pregnancy may be helpful.
Headache management of IIH in pregnancy is challenging. Early on, nonsteroidal anti-inflammatories are FDA class B; later, they become FDA class C because of the possible risk of premature closure of the ductus arteriosus and decreased fetal renal perfusion. Optimal treatment is usually a diuretic, such as acetazolamide, and a migraine headache preventative (β-blockers, calcium channel blockers, tricyclic antidepressants, rarely anticonvulsants—all FDA class C or D) (62).
PREGNANCY-SPECIFIC NEURO-OPHTHALMOLOGIC CONDITIONS: SEVERE PREECLAMPSIA AND ECLAMPSIA
The hallmarks for these pregnancy-specific conditions are hypertension and proteinuria, with initial onset in the second half of pregnancy. Preeclampsia is diagnosed with persistent blood pressures above 140/90 mm Hg and greater than 300 mg proteinuria/24 hours. Signs of severe preeclampsia that mandate delivery include blood pressure > 160/110 mm Hg, proteinuria > 5 g/24 hours, and oliguria (<500 mL/24 hour). Other signs and symptoms include persistent visual disturbances, pulmonary edema, congestive heart failure, thrombocytopenia (<100,000/mm3) and elevated liver function tests. The HELLP syndrome (Hemolysis, Elevated Liver function tests, Low Platelets) frequently accompanies the condition.
Eclampsia is defined by the development of convulsions and/or coma in a previously preeclamptic woman. Other conditions can be confused with severe preeclampsia or eclampsia, including venous thrombosis, systemic lupus erythematosus, thrombocytopenic purpura, arterial occlusion, drug abuse, idiopathic seizures, hyponatremia, reversible cerebrovascular constriction syndrome, and Wernicke encephalopathy (especially after hyperemesis gravidarum) (63).
I have studied the neuro-ophthalmic findings in severe preeclampsia and eclampsia. In 31 patients, “spots” were reported in 11 patients, color defects in 8, blurred vision in 2, headaches in 19, and visual acuity changes in 2. Others have reported similar findings (64). Funduscopic changes in severe preeclampsia and eclampsia include vascular narrowing, segmental retinal artery vasospasm, or occlusion.
Amsler grid abnormalities strongly predicted retinal vascular changes. In addition, MRI was more likely to be abnormal if the Amsler grid was abnormal. The choroid is frequently affected with choroidal infarctions leading to retinal pigment epithelial changes and serous retinal detachments due to choroidal effusion (65). The optic nerve may be swollen due to intracranial hypertension, systemic hypertension, or anterior ischemic optic neuropathy (66).
MRI findings in severe preeclampsia and eclampsia are characterized by disruptions at the gray white interface in the parieto-occipital region and the basal ganglia. Diffusion-weighted imaging may show an increased signal in the occipital lobes and in corresponding apparent diffusion coefficient maps consistent with vasogenic rather than cytotoxic edema. This appearance is consistent with that of PRES (posterior reversible encephalopathy syndrome) (67,68).
Some type of cerebral blindness occurs in 15% of eclampsia cases, a higher incidence than previously thought (69). It usually resolves completely but may persist if infarction or hematologic stroke occurs. Rare cases of complete blindness have been reported due to bilateral lateral geniculate body infarction (65,70).
Disorders of higher visual cerebral function can occur in eclampsia. These include alexia, alexia without agraphia (69), and simultanagnosia (71).
While the treatment for severe preeclampsia and eclampsia is delivery of the newborn, obstetricians have known for decades that magnesium sulfate is also an effective anticonvulsant. Other anticonvulsants and antihypertensives have been tried; however, magnesium, with the least number of side effects, remains the mainstay of therapy (72,73). Treatment with magnesium can cause neuro-ophthalmic symptoms and signs. Magnesium relaxes accommodation, decreases convergence, and causes ptosis. The Amsler grid is normal if magnesium is the cause of visual blurring (74).
While the etiology of severe preeclampsia and eclampsia remains unknown, one theory involves breakdown of cerebral autoregulation. There is differential innervation of the anterior and posterior circulations. Loss of auto regulation in the posterior circulation would explain involvement of the posterior visual pathways (75–79).
Reversible cerebrovascular syndrome (RCVS), also known as Call–Fleming syndrome, can be confused with eclampsia (80). This syndrome presents with a thunderclap headaches, seizures, and neurologic deficits. Blood pressure may not be elevated, and most patients do not have hypertension or proteinuria. Angiography shows evidence of diffuse irregularity of the cerebral blood vessels, and calcium channel blockers are an effective form of treatment. RCVS can occur postpartum with the use of medications, including bromocriptine, ergonovine, ergotamines, serotonin receptor inhibitors (selective serotonin reuptake inhibitors, serotonin-norepinephrine reputake inhibitors), energy drinks, and sympathomimetics (81–87).
Cranial neuropathies can occur in pregnancy. The most common is facial neuropathy or Bell palsy followed by sixth and fourth involvement (88). Incidence of Bell palsy is 50 in 100,000; more than two third of these are reported in the third trimester (88,89). The etiology of cranial neuropathy is thought to be an increase in interstitial fluid around the nerve, creating compression. The prognosis is usually good; treatment with prednisone generally is not necessary. Jacobson reported a woman with a superior oblique palsy manifested in pregnancy, with excellent recovery (2).
Horner syndrome has been reported following epidural analgesia. It is usually a transient self-limited condition often associated with a high epidural block (90).
Acquired Chiari I malformation has also been reported due to intracranial hypotension, intracranial hypovolemia, or following epidural analgesia with a CSF leak (90). The patient presents with chronic headaches and diplopia often due to a comitant esotropia. Typical findings of intracranial hypotension on MRI can be seen, with low-lying tonsils, flattening of the pons against the clivus, low-lying cerebellum, somewhat enlarged pituitary gland, and gadolinium enhancement of the meninges.
The most important lesson for the neuro-ophthalmologist caring for a pregnant woman is to make the correct diagnosis, using whatever tests are needed. Consider pregnancy-related conditions such as eclampsia and severe preeclampsia and know how to treat them. Finally, remember that what is best for the mother generally will be best for her baby.
The entire slide presentation is available in NOVEL (http://NOVEL.utah.edu/jno). Also, this presentation can be seen from the NANOS Annual Meeting (2011 Jacobson Lecture) on NOVEL (http://NOVEL.utah.edu/NAM).
The author thanks Susan Schulman for her expert editorial assistance and Michael Varner for his suggestions.
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