Episode 4: Preeclampsia and Cerebrovascular Consequences - RCVS and PRES

Grace is 26 years old and just delivered a healthy baby girl... then suddenly, days later, severe pain hits her head like a thunderclap. What is the workup for "thunderclap headache" in the postpartum period? We talk with obstetrician Dr. Jane Sharp, maternal fetal medicine specialist Dr. Erika Werner and stroke specialist Dr. Shadi Yaghi. Dr. Julie Roth hosts.

Key Takeaways:

• Preeclampsia is a multisystem, vascular disorder of pregnancy defined by the new onset of hypertension and proteinuria after 20 weeks of gestation. However, preeclampsia can also occur in the early postpartum period.
• Neuroimaging is indicated in any individual experiencing the "first or worst" headache of one's life, to exclude subarachnoid hemorrhage as can be seen in cerebral aneurysm rupture.
• There is substantial overlap between reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES); both neurological disorders reflect abnormal cerebral vasculature and both can be seen within or outside of pregnancy and the postpartum period. 

Written Case: Preeclampsia and Its Cerebrovascular Consequences - RCVS and PRES

By Dr. Niharika Mehta and Dr. Julie Roth

A 26 year old G1P0 woman experiences hypotension and presyncope during pregnancy, with mild peripheral edema shortly before delivery; her pregnancy is otherwise normal and she delivers a healthy baby girl at full term. Three days after delivery, she returns to the ER after experiencing a sudden-onset, severe, “thunderclap headache.” Her blood pressure in the ER is 170/90, normal liver function tests, serum creatinine of 1.2. She is diagnosed with postpartum preeclampsia and treated with intravenous magnesium, which quickly resolves the headache. Her blood pressure returns to normal within 24 hours and she is discharged.

QUESTIONS:

What is preeclampsia? How is it clinically defined, and what is the pathophysiology?

Preeclampsia is a heterogeneous, multisystem disorder of pregnancy defined by the new onset of hypertension and proteinuria after 20 weeks of gestation. The ACOG[1] recommends the following diagnostic criteria to establish diagnosis of preeclampsia:

New onset BP elevation after 20 wks:  >/= 140/90 on at least 2 occasions 4 hours apart or >/=160/110 confirmed by 2 measurements a few minutes apart

AND

Proteinuria: >300mg in 24 hours or UPCR >/=0.3 or Urine Dipstick with 1+ proteinuria

OR (in the absence of proteinuria, New onset HTN and any of the following)

1. Thromboctyopenia: Plt <100k/ml
2. Renal insufficiency: Creat >1.1mg/dl
3. Impaired liver function: Liver enzymes at least 2x upper limit of normal
4. Pulmonary edema
5. Cerebral or visual symptoms

Preeclampsia is felt to result from an imbalance between proangiogenic and antiangiogenic factors in the placenta resulting in systemic endothelial dysfunction. Production of placental anti-angiogenic factors, specifically soluble fms-related tyrosine kinase 1 and soluble endoglin, have been shown to be upregulated in preeclampsia. These placental anti-angiogenic factors are released into the maternal circulation; their actions disrupt the maternal endothelium. Clinical features of preeclampsia can be explained by this endothelial dysfunction[2]: hypertension results from disturbed endothelial control of vascular tone, proteinuria and edema are caused by increased vascular permeability, and coagulopathy is the result of abnormal endothelial expression of procoagulants.

Risk factors for preeclampsia include older age (>34 years), nulliparity, preeclampsia in prior pregnancy, family h/o preeclampsia, multiple gestation, preexisting medical conditions including diabetes, hypertension, renal disease, SLE, antiphospholipid antibody syndrome, obesity[3].

Endothelial damage resulting from preeclampsia may explain subsequent increased risk of cardiovascular and end stage renal disease in these women.

What screening tests are performed throughout pregnancy?

In the first half of pregnancy, antenatal management consists of risk factor identification and treatment with low-dose aspirin (81 mg/d) as preventive medication after 12 weeks of gestation in women who are at high risk for preeclampsia (USPSTF recommendation)[4] . Many experts recommend checking levels of creatinine, liver enzymes, platelets and a urine protein-to-creatinine ratio (UPCR) in the first trimester, to identify any abnormalities at baseline that might confuse the picture later on in pregnancy when preeclampsia is suspected.

A BP check and screening for proteinuria with dipstick is performed at every antenatal visit and management of abnormal values is guided by the gestational age. Before 20 weeks, an elevated BP is usually the result of a chronic or pregnancy-unrelated cause and management is guided by suspected diagnosis. After 20 weeks gestation, the finding of hypertension should prompt a search for proteinuria or other features of preeclampsia as listed above. 

During pregnancy, how is preeclampsia managed?

Once preeclampsia is identified, close monitoring to establish severity of disease and rate of progression is important. Delivery is the only definitive treatment for preeclampsia. Timing of delivery is dictated by presence of “severe features”- which include severe hypertension (>160/110), pulmonary edema, HELLP syndrome, severe intractable headache, seizures or altered mental status, progressive renal insufficiency (creatinine >1.1 mg/dl). Intravenous magnesium for seizure prophylaxis is initiated in these patients as soon as severe preeclampsia is identified and is continued until 24 hours after delivery.

In the absence of severe features, conservative management with close in-patient or out-patient monitoring with frequent lab evaluation (CBC, LFTs, Creatinine, UPCR), treatment of hypertension, assessment of fetal wellbeing and growth is indicated. For patients managed conservatively, delivery is indicated at 37 weeks of gestation or as soon as they develop preeclampsia with severe features.

What is postpartum preeclampsia? Why might it occur?

Occasionally, preeclampsia/eclampsia can present in the postpartum period. Delayed postpartum preeclampsia can be defined as signs and symptoms of the disease leading to readmission more than two days but less than six weeks after delivery[5]. Most patients tend to present in the first week after delivery and have no antecedent diagnosis of hypertensive disorders of pregnancy.  It is unclear whetherthe pathology of preeclampsia in the postpartum period is different from those that occur in the antepartum and the peripartum periods. One proposed pathophysiologic mechanism for postpartum preeclampsia includes the presence of circulating placental factors in maternal blood that have yet to be cleared.

Following resolution of her headache, she returns home and does well initially. However, 24 hours later, she notes a gradual buildup of bifrontal throbbing pain, which becomes increasingly severe (to 10/10) in spite of treatment at home with acetaminophen and ibuprofen. She has a history of rare, mild headaches prior to her pregnancy that resolved on their own, but no strong history of migraine. Her headaches fail to respond to acetaminophen.

What concerns are there in this patient with known postpartum preeclampsia who presents with severe headache? What further workup is needed?

While the overwhelming majority of postpartum headaches are from benign causes such as migraine or tension headaches exacerbated by lack of sleep and fatigue, certain features in presentation should prompt further work up for secondary causes.  Post dural puncture (“spinal”) headache should be considered in women who received epidural analgesia or spinal anesthesia for delivery and who present with positional variance in headache – in other words, worse standing up and resolved when lying down. However, the opposite pattern (worse lying down and improved standing up) suggests a secondary cause of headache, possibly related to increased intracranial pressure. Severe, sudden onset headache – sometimes called “thunderclap headache” – can be the result of intracranial hemorrhage from ruptured blood vessel anomaly like aneurysm or arteriovenous malformation or associated with other pathology such as cerebral venous thrombosis or pituitary apoplexy. Two other causes of headache in pregnancy and the postpartum period include reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES), which will be discussed further, below.

It is therefore important to pursue neuroimaging in patients who present with severe headache in the postpartum period with concerning features in their clinical history.

Definitive management of preeclampsia is delivery. Therefore in a patient presenting in the postpartum period with preeclampsia, the management is only supportive. Blood pressure control to reduce stroke risk with severe hypertension is recommended. Typical agents used to control blood pressure include IV labetalol or hydralazine or PO nifedipine.  A magnesium drip is started for seizure (eclampsia) prophylaxis and continued for 24 hours.

The patient underwent MRI/A/V, which revealed a high convexity subarachnoid hemorrhage in the right hemisphere. There was no evidence of aneurysm or arteriovenous malformation on MRA, later confirmed on CTA, and the MRV demonstrated no thrombus. There were no space-occupying lesions.

What are the possible causes of subarachnoid hemorrhage in the postpartum patient? 

It is unclear whether the risk of bleeding from brain arteriovenous malformations is higher during pregnancy, delivery, or puerperium, with various cohort studies from different geographical regions showing conflicting results[6],[7],[8]. Risk of rupture of aneurysms is also felt to be low/not impacted by pregnancy. However these remain important in the differential diagnosis of a patient presenting with severe, sudden-onset “thunderclap” headache. In a patient presenting with “thunderclap” headache, or worst headache of her life, aneurysm rupture should be excluded urgently by MRA or CTA. Conventional angiogram is the gold standard for diagnosis – and also for management of aneurysm rupture, as the vascular malformation can be treated with the placement of endovascular coils. Aneurysm rupture usually causes subarachnoid hemorrhage around the deep structures or base of the brain, because most aneurysms are found around the Circle of Willis. A “high convexity” (or along the upper surface of the brain) subarachnoid hemorrhage in a young individual can suggest trauma, and therefore, screening for signs of head injury is also important. In an elderly individual, cerebral amyloid angiopathy can also cause subarachnoid hemorrhage in this location, but this would not be expected to occur in a young, postpartum woman.

Finally, reversible cerebral vasoconstriction syndrome (RCVS) can also present as sudden onset, severe (“thunderclap”) headache and hypertension in postpartum women. Also known as postpartum angiopathy, RCVS, can cause acute, spontaneous subarachnoid hemorrhage in postpartum women, in the absence of an aneurysm or underlying vascular anomaly. In RCVS, hemorrhage is typically in the “high convexity” of the brain. This was the diagnosis in this particular patient.

RCVS occurs when there is focal narrowing of the blood vessels of the head (vasoconstriction). This finding can be seen on vascular imaging like MRA and CTA, and it is also detected on transcranial Doppler (TCD) ultrasound as elevated cerebral flow velocities. In addition to severe headaches and subarachnoid hemorrhage, cerebral ischemia, and seizures.[9] Outside of pregnancy, RCVS can be due to the use of vasoactive medications, including stimulants, allergy nasal sprays, serotonergic medications such as those used for depression, and triptan (migraine) medications. It can also be seen in patients with known hypertension or with migraine. In pregnancy and the postpartum period, RCVS can be seen in the context of preeclampsia/eclampsia, as the shared pathophysiology of this disorder is abnormal cerebral vasoconstriction. However, it can also in patients (pregnant or postpartum) who otherwise do not meet the aforementioned criteria for preeclampsia – but nonetheless have cerebral vasoconstriction. Treatment for RCVS involves calcium channel blockers like verapamil and nimodipine, and occasionally oral magnesium supplementation,[10] as well as pain control.

Another vascular cause of headache in pregnancy is known as posterior reversible encephalopathy syndrome (PRES); headaches due to PRES are usually gradual in onset and accompanied by vision changes. The pathophysiology of PRES involves cerebrovascular leakage and resultant edema in the white matter of the brain. As PRES progresses, confusion (encephalopathy) and seizures can occur. The pathognomonic MRI finding for PRES is confluent or patchy T2/FLAIR hyperintensities in the posterior white matter of the brain. Treatment of PRES is supportive and involves treating the underlying condition. 

How do RCVS and PRES relate to pregnancy?

Both RCVS and PRES are known to be associated with pregnancy. The underlying pathology of PRES is felt to result from disordered (cerebral) vascular autoregulation and endothelial dysfunction – the 2 hallmarks of preeclampsia pathogenesis. Some experts consider this condition as criteria for eclampsia diagnosis even in the absence of hypertension and proteinuria[11].  The clinical features of PRES parallel those along the preeclampsia/eclampsia spectrum, and PRES-like MRI findings would be typical for a patient with known eclampsia.

Although RCVS can occur spontaneously, at least half the cases occur in the postpartum period, with or without preeclampsia/eclampsia. Posterior reversible encephalopathy syndrome and RCVS share many clinico-radiographic features, suggesting overlapping or similar pathophysiological mechanisms.  That overlap occurs within and outside of pregnancy; between 8 and 38% of cases of RCVS also show signs of PRES on neuroimaging.[12] Similar to PRES (and therefore related to preeclampsia), RCVS is also felt to result from a transient disturbance in the control of cerebrovascular tone and is characterized by transient brain edema (endothelial dysfunction -> leaky vessels), vasoconstriction, focal infarction and hemorrhage.

The patient was transferred to the neurology intensive care unit (NICU) and treated with intravenous magnesium and calcium channel blockers, as well as aggressive pain management. Symptoms improved over 24 hours. She was discharged from the hospital with a prescription for magnesium oxide 400mg/day and verapamil 240mg/day. She remained headache free through an 8-week follow-up appointment with her neurologist, who then weaned her off the verapamil by 3 months postpartum.

How long does it usually take for postpartum preeclampsia to resolve after diagnosis? And RCVS?

Both RCVS and postpartum preeclampsia typically resolve within 3 months.

Any advice for future pregnancies?

Whether RCVS is likely to recur in future pregnancies is unclear, as there is no data currently available in the literature. However, preeclampsia can recur in subsequent pregnancies and low dose aspirin during pregnancy is recommended in these patients to reduce the risk of recurrent Preeclampsia [13].  

What do you tell her about breastfeeding?

For most calcium channel blockers, including verapamil, nimodipine and nifedipine, the amount of drug secreted in breastmilk is small and not expected to cause any adverse effect on the nursing infant. Similarly, magnesium oxide supplements at 400mg/day are generally considered acceptable in breastfeeding.

REFERENCES:

[1] Taskforce on hypertension in pregnancy. Accessed at https://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy. Last accessed on 8/1/17

[2] Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda). 2009 Jun;24:147-58.

[3] Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005 Mar 12; 330(7491): 565

[4]https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication. Last accessed 8/8/17

[5] Al-Safi Z, et al. Delayed postpartum preeclampsia and eclampsia: demographics, clinical course, and complications. Obstet Gynecol 2011; 118(5):1102

[6] Relative risk of hemorrhage during pregnancy in patients with brain arteriovenous malformations. Int J Stroke. 2017 Jan 1:1747493017694387. doi: 10.1177/1747493017694387

[7] Hemorrhage Risk of Brain Arteriovenous Malformations During Pregnancy and Puerperium in a North American Cohort. Stroke. 2017 Jun;48(6):1507-1513

[8] Known and unknown cerebral arteriovenous malformations in pregnancies: haemorrhage risk and influence on obstetric management. Neuroradiol J. 2017 Jan 1:1971400917712264.

[9] Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 2(1):91

[10] Mijalski C, et al. Magnesium for Treatment of Reversible Cerebral Vasoconstriction Syndrome: Case Series. Neurohospitalist. 2016 Jul; 6(3): 111–113.

[11] Raps EC, Galetta SL, Broderick M, Atlas SW. Delayed peripartum vasculopathy: cerebral eclampsia revisited. Ann Neurol. 1993;33(2):222

[12] Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012; 11:906-17. 

[13] Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E . The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017;216(2):110.

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