and altered mental status. "Vasogenic" and "vasospasm" mechanisms have been considered to be responsible for the syndrome. Cerebral edema and petechial cortical hemorrhages are common autopsy findings. Eclampsia and its associated complications may be prevented by good obstetric care, early detection of preeclampsia, and the use of magnesium sulfate., ">
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.241364
Source of Support: None, Conflict of Interest: None
Posterior reversible encephalopathy syndrome is characterized by acute headache, visual impairment, seizures, and altered mental status; neuroimaging may show cerebral edema affecting the parietal and occipital lobes of the brain. The objective of this article is to review the current understanding of posterior reversible encephalopathy syndrome in eclampsia. Literature was searched from PubMed, Scopus, and Google Scholar databases. The search terms included “eclampsia”, “eclampsia and posterior reversible encephalopathy syndrome”, and “pregnancy and posterior reversible encephalopathy syndrome”. We reviewed all published original articles with the search term “posterior reversible encephalopathy syndrome”. Up to 100% of eclamptic patients may have reversible posterior leukoencephalopathy syndrome. Two putative mechanisms – “vasogenic” and “vasospasm” – are considered to be responsible. Cerebral edema and petechial cortical hemorrhages are common autopsy findings. Clinical and neuroimaging manifestations are reversible in the majority of patients. Prompt correction of increased blood pressure and treatment of seizures are the cornerstones of treatment. Magnesium sulfate is the drug of choice for seizures. Some survivors may have permanent vision loss and other disabling sequelae. In conclusion, posterior reversible encephalopathy is a devastating complication of eclampsia. Early recognition helps in preventing some of its devastating sequelae.
Keywords: Epilepsy, hypertensive encephalopathy, magnetic resonance imaging, pregnancy
Preeclampsia or eclampsia is a multisystem disorder of pregnancy and puerperium. Preeclampsia is defined by the presence of new-onset hypertension (>140/90 mmHg) and occurrence of proteinuria after the 20th week of gestation. The occurrence of convulsions in a pregnant or recently delivered woman characterizes eclampsia.
Posterior reversible encephalopathy syndrome is a distinctive clinical and imaging syndrome characterized by acute headaches, visual impairment, seizures, and altered sensorium. Neuroimaging is characterized by cerebral edema predominantly affecting the parietal and occipital lobes. In addition to preeclampsia/eclampsia, posterior reversible encephalopathy syndrome has been associated with various systemic conditions such as severe hypertension, transplantation, renal failure, and patients with autoimmune diseases receiving immunosuppressive therapy or high-dose chemotherapy. Reversible cerebral vasoconstriction syndrome, another pregnancy-related complication, is characterized by severe headache and diffuse segmental spasm of the cerebral arteries. The vasospasm usually resolves spontaneously within a few months. Most reported cases of reversible cerebral vasoconstriction syndrome occurred in the postpartum period. Similar afflictions involving large and medium sized cerebral arteries have also been described as postpartum angiopathy to explain ischemic changes occurring as a complication.
The objective of this article is to review the current understanding of posterior reversible encephalopathy syndrome in eclampsia. Literature was searched from PubMed, Scopus, and Google Scholar databases. The search terms included “eclampsia”, “eclampsia and posterior reversible encephalopathy syndrome”, and “pregnancy and posterior reversible encephalopathy syndrome”. We reviewed all published original articles with the search term “posterior reversible encephalopathy syndrome”. Bulk of the information on this subject is available either in the form of case reports or small case series. Information on non-eclamptic posterior reversible encephalopathy syndrome has also been used.
History of posterior leukoencephalopathy syndrome
The term “posterior leukoencephalopathy” was coined by Hinchey et al., in 1996. The authors reported 15 cases of reversible posterior leukoencephalopathy syndrome, of whom 3 patients had eclampsia, and among rest of the patients, 7 were on immunosuppressive therapy, 1 was receiving interferon for melanoma, and 4 had acute hypertensive encephalopathy associated with renal disease. The clinical manifestations included headache, vomiting, confusion, seizures, cortical blindness, and other visual abnormalities and motor signs. Neuroimaging showed extensive bilateral white matter abnormalities suggestive of cerebral edema affecting posterior regions of the cerebral hemispheres. Neuroimaging changes involved other areas of the brain as well, such as the anterior regions of cerebral hemispheres, brainstem, and cerebellum. Majority of the patients improved with reduction of blood pressure or on withdrawal of immunosuppressive therapy. Neurologic deficits resolved within 2 weeks.
Epidemiology of preeclampsia and eclampsia
Preeclampsia and eclampsia are associated with significant maternal and perinatal morbidity and mortality. Approximately 10–15% of maternal deaths are associated with preeclampsia and eclampsia. However, the incidence of eclampsia and its complications have significantly reduced in developed countries. For example, in Finland during the years between 2006–2010, 295,447 deliveries were registered and eclampsia was identified in 46 women; there were no maternal deaths during this period. In Yorkshire, a total of 210,631 women delivered between 1999 and 2003. One thousand and eighty-seven women (5.2 per 1000) had severe preeclampsia or eclampsia. Eighty-two women had eclamptic seizures. In the United States, the incidence of eclampsia decreased from 8.0 cases per 10,000 deliveries in 2001 to 5.6 cases per 10,000 deliveries in 2007. On the contrary, in poor countries, the incidence of eclampsia is still exceptionally high. In Nepal, among 8,066 deliveries, an incidence of 13.8 per 1000 deliveries was projected after 112 women were diagnosed with eclampsia. Importantly, more than 90% were unbooked and a significant proportion (41%) of them were <19 years of age. The incidence of eclampsia in India is around 1.5%. From 1980 to 2015, the data analysis showed no reduction in its incidence. Poor obstetric care is largely responsible for the high rates of eclampsia in low-resource countries. A systemic review analyzing 59 publications (from 26 countries) noted that, out of 18,488 eclamptic women, the proportion of antepartum, intrapartum, and postpartum eclampsia was 59%, 20%, and 21%, respectively.
Incidence of posterior leukoencephalopathy syndrome in preeclampsia and eclampsia
Vision loss is a frequent complaint in eclampsia. In a systematic review, 66% and 27% women (a total of 2163 eclamptic women), respectively, had headache and vision loss before the seizure onset. In many eclamptic women, vision loss is expected to remain unnoticed because of altered sensorium.
In preeclampsia and eclampsia, the incidence of posterior leukoencephalopathy syndrome is not precisely known. Many smaller studies recorded that almost 100% of eclamptic patients had reversible posterior leukoencephalopathy. Brewer et al., noted that 98% (46 of 47) of patients with eclampsia had reversible posterior leukoencephalopathy. Reversible posterior leukoencephalopathy was observed both in antepartum and postpartum eclampsia. In another study, among 39 patients with eclampsia and preeclampsia with neurologic symptoms, the magnetic resonance imaging (MRI) revealed that 12 of 13 (92.3%) patients with eclampsia had reversible posterior leukoencephalopathy, whereas 5 of 26 (19.2%) patients with preeclampsia had posterior reversible encephalopathy syndrome. Fisher et al., noted that a lesser proportion of eclamptic women developed posterior reversible encephalopathy syndrome. They observed that out of 46 patients (8 with eclampsia and 38 with preeclampsia), 9 patients (5 with eclampsia and 4 with preeclampsia) developed posterior leukoencephalopathy syndrome. A younger age, thrombocytopenia, proteinuria, and higher peak systolic and diastolic blood pressures predicted the occurrence of reversible posterior leukoencephalopathy.
The Indian data are not different from the western data as Indian eclamptic women have been shown to develop posterior leukoencephalopathy syndrome in the same proportion. For example, in a large prospective Indian cohort of 104 eclamptic women, 74 (71%) developed posterior encephalopathy syndrome. On univariate analysis, the predictors of posterior encephalopathy syndrome were primigravida and an unbooked status; the presence of altered sensorium, vision loss, vomiting, and status epilepticus; and, abnormal laboratory parameters viz. lactate dehydrogenase, uric acid, low platelet count, and kidney and liver functions. An unbooked pregnancy, the primigravida status, and the presence of visual impairment, however, were the only ones found significant on multivariate analysis.
Postpartum eclampsia and posterior leukoencephalopathy syndrome
Posterior leukoencephalopathy syndrome is frequent in the postpartum period as well. Most cases of posterior leukoencephalopathy syndrome are part of postpartum eclampsia, and the manifestations develop within 48 hours after delivery. Eclampsia occurring after 48 hours but within 4 weeks of delivery is known as late postpartum eclampsia. In many cases, postpartum eclampsia may present without prior preeclampsia.
Posterior reversible leukoencephalopathy syndrome associated with late-onset postpartum eclampsia is uncommon, with postpartum hemorrhage as a possible triggering factor. Hormone fluctuations, increased blood pressure, and massive blood transfusion may also be inciting events for the development of posterior reversible leukoencephalopathy syndrome.
The pathophysiology of preeclampsia/eclampsia is not properly understood. Possibly, maternal, fetal, and/or placental factors are collectively responsible for it. Varied mechanisms such as placental abnormalities, altered immune mechanisms, endothelial cell dysfunction, oxidative stress, genetic susceptibility, and dietary factors have been thought to be involved in the pathogenesis of preeclampsia/eclampsia.,,
The exact etiopathogenesis of posterior reversible encephalopathy syndrome in eclampsia is not precisely known. Two important mechanisms – disordered cerebral autoregulation and endothelial damage – are possibly causal in the pathogenesis of posterior leukoencephalopathy. Two widely accepted theories – “vasogenic theory” and “vasospasm theory” – are considered responsible for the clinical and imaging manifestations of posterior reversible encephalopathy syndrome. According to the vasogenic theory, a rapid rise in blood pressure results in autoregulatory failure of cerebral vasculature and subsequently dilatation of cerebral arterioles, producing brain hyperperfusion. There is opening of endothelial tight junctions and extravasation of fluid and blood products into the brain parenchyma, causing vasogenic cerebral edema. As per the vasospasm theory, severe vasospasm occurs secondary to sudden and severe rise in blood pressure. Vasospasm of cerebral vessels results in hypoperfusion of the brain parenchyma. The resultant ischemia leads to the development of cytotoxic edema with or without actual cerebral infarction. Vasoconstriction induces hypoxic change leading to endothelial cell damage. The cerebral white matter is dominantly constituted by myelinated fiber tracts in a cellular matrix of glial cells, arterioles, and capillaries. This unique structure makes brain more vulnerable to fluid accumulation in the extracellular spaces.,,
Adrenergic sympathetic innervation of cerebral vessels autoregulates cerebral blood flow. Vessels of the carotid system are adequately supplied with sympathetic adrenergic nerves in comparison to the vertebro-basilar system. This inherent deficiency of adrenergic innervation in the vertebro-basilar system results in loss of vasoconstrictor properties. As a result, there are edematous changes in the parieto-occipital lobes, following the rapid rise in blood pressure.
In eclampsia, cerebral edema and multiple petechial cerebral parenchymal hemorrhages are the hallmark pathological findings. Petechial cortical hemorrhages are seen all over the brain but occipital lobes are dominantly affected. A large cerebral hematoma is infrequent. In addition, abnormalities of the cerebral venous system are common. Brain biopsy done in a patient with posterior leukoencephalopathy syndrome revealed extensive edematous white matter abnormalities without definite evidence of vessel wall damage or infarction.
In eclampsia, headache, seizures, altered sensorium, and vision loss are cardinal symptoms of posterior reversible encephalopathy syndrome. Brewer et al., in a study (47 patients) noted that seizures and headache were the most common presenting symptoms in 87.2% of the patients. The presence of an altered mental status, involvement of vision, and nausea/vomiting was noted in 51.1%, 34%, and 19.1% patients, respectively. Focal neurological deficits other than cortical blindness are infrequent. Patients with eclampsia and posterior reversible encephalopathy syndrome may have concomitant metabolic abnormalities such as raised serum creatinine, liver enzymes abnormalities, a low mean platelet volume, and a higher amount of proteinuria.
Seizures in eclampsia are usually of generalized tonic–clonic convulsive type and self-limiting. In patients with occipital lobe seizures, visual auras and visual hallucinations precede generalized convulsions. Many eclamptic patients experience multiple seizures in clusters. Typically, eclamptic seizures do not last for more than 3 to 4 minutes. Most patients become responsive within 10 to 20 minutes.,, Unusually, prolonged postictal unresponsiveness usually indicates associated metabolic abnormalities.
Headache is often a heralding symptom of posterior reversible encephalopathy syndrome in eclampsia. Headache is frequently diffuse and dull aching. A thunderclap headache in eclampsia often indicates reversible cerebral vasoconstriction syndrome. A thunderclap headache is a severe headache that peaks within seconds-to-minutes to reach its maximum intensity.
Visual disturbances such as decreased visual acuity, field defects, cortical blindness, and hallucinations are common in a patient with eclamptic encephalopathy. Cortical vision loss is characterized by total or partial loss of vision in a normal-appearing eye and is caused by damage to the visual cortex. In cortical blindness, fundus and pupillary examinations reveal no abnormality. Patients may even be unaware of their blindness or even deny having visual impairment (Anton's syndrome). Vision loss is frequently acute or sudden.
In eclampsia, altered sensorium ranges in severity from mild confusion to deep coma. Altered sensorium is often sudden or acute and frequently follows a bout of seizure. Unusually prolonged unconsciousness may be associated with status epilepticus or severe metabolic alterations such as uremia.
There are a few clinical differences between the eclamptic and the non-pregnant posterior reversible encephalopathy syndrome. Women with eclamptic or preeclamptic encephalopathy with posterior reversible encephalopathy syndrome had a higher incidence of headache and visual complaints. Non-eclamptic or preeclamptic women, compared with non-pregnant posterior reversible encephalopathy syndrome, were less likely to be confused., Eclamptic patients with posterior reversible encephalopathy syndrome were younger and had a higher incidence of thrombocytopenia, a higher amount of proteinuria, and higher peak systolic and diastolic blood pressures.
The characteristic neuroimaging abnormality in eclampsia with posterior reversible encephalopathy syndrome is the presence of white matter signal changes localized to the parieto-occipital regions of the brain. White matter signal changes are usually symmetric and tend to spare the calcarine and paramedian parts of the occipital lobes [Figure 1]. Many atypical structures such as the frontal lobes, temporal lobes, basal ganglia, cerebellum, brainstem, and thalamus may also be involved, but in lesser frequency.
MRI is the imaging modality of choice. It characteristically shows hypointense or isointense signal changes on T1-weighted images. High signal changes are visualized on T2-weighted images. On fluid-attenuated inversion recovery (FLAIR) sequences, the lesions appear hyperintense. Amongst the various MRI sequences, FLAIR is considered to be the most sensitive technique for detecting lesions of posterior reversible encephalopathy syndrome [Figure 2], [Figure 3], [Figure 4].
Diffusion-weighted imaging (DWI) is another commonly performed magnetic resonance sequence and is usually meant for evaluation of acute ischemic stroke. DWI is highly sensitive for the detection of small and early infarcts and can differentiate cytotoxic edema from vasogenic edema., Cytotoxic edema appears hyperintense on DWI with a low signal intensiy image on the corresponding apparent diffusion coefficient sequence. A predominantly low signal on DWI and a high signal on apparent diffusion coefficient image indicates vasogenic edema. High apparent diffusion coefficient values are consistent with highly mobile water in vasogenic edema. Vasogenic edema and cytotoxic edema can coexist in eclampsia [Figure 2], [Figure 3], [Figure 4].
Occasionally, parenchymal cerebral and subarachnoid hemorrhage are seen. Varied forms of cerebral hemorrhages have been described in posterior reversible encephalopathy syndrome. Small punctate hemorrhages are most frequent. Subarachnoid hemorrhage within the cortical sulci, or a large intraparenchymal hematoma have occasionally been described. Susceptibility-weighted magnetic resonance sequences are more sensitive than gradient recall echo magnetic resonance sequences in identifying small brain hemorrhages [Figure 3]., Gyriform signal enhancement can rarely be noted. Meningeal and cortical enhancement, if present, indicates breakdown of the blood–brain barrier.
Severe posterior reversible encephalopathy syndrome is defined as edema extending from the cortex to the periventricular white matter, a midline shift/herniation, or the involvement of cerebellum, brainstem, and basal ganglia. In its mild form, imaging shows a few areas of vasogenic edema or may even reveal a normal brain [Figure 2], [Figure 3], [Figure 4].
On comparing the neuroimaging characteristics of posterior reversible encephalopathy syndrome between patients with preeclampsia and eclampsia, and with patients having other conditions, it was noted that preeclampsia and eclampsia patients had less cytotoxic edema, hemorrhage, and contrast enhancement, with more frequent complete resolution of edema and less frequent residual structural lesions on follow-up.
In patients with posterior reversible encephalopathy syndrome, angiograms are usually normal. In pregnancy-related reversible cerebral vasoconstriction syndrome, angiography reveals multifocal segmental arterial constriction. Typically, angiography shows segmental narrowing and dilatation (the string of beads appearance). Mayama et al., noted that approximately 8% of patients with preeclampsia had both the cerebral vasoconstriction syndrome and the posterior reversible encephalopathy syndrome simultaneously. Angiographic abnormalities resolve spontaneously within a few months [Figure 2].
Reversibility of lesions
Reversibility of neuroimaging abnormalities following institution of treatment is a characteristic feature of posterior reversible encephalopathy syndrome. Complete or near-complete resolution of imaging abnormalities is noted in approximately 70% of the cases [Figure 2]. The reversal of neuroimaging abnormalities is seen within 1 or 2 weeks. Infrequently, reversal may take a little longer and the resolution of lesions is complete within a month's time.,, In a series, the follow-up neuroimaging was done in 74 patients manifesting with posterior reversible encephalopathy syndrome, and an improvement in the imaging features was noted in 65 (88%) cases with complete or near-complete resolution of abnormalities in 52 (70%) of them. Thirteen (18%) patients had partial resolution of neuroimaging abnormalities. Only in 9 (12%) patients, no change was recorded. This series included 7 patients of preeclampsia or eclampsia, and complete resolution was noted in all the patients. A recently published study noted a complete reversal of neuroimaging abnormalities of posterior encephalopathy during follow-up imaging. In this study, 76 patients of eclamptic encephalopathy with posterior reversible encephalopathy syndrome were included, and all patients underwent a follow-up MRI scan within 1-month post-delivery.
Headache, vision loss, photophobia, epigastric or right upper-quadrant abdominal pain, and altered sensorium are characteristic clinical manifestations of eclamptic encephalopathy. During pregnancy and the postpartum period, in addition to primary headaches (like migraine), secondary headache syndromes are equally common. Secondary headache syndromes that need to be considered are idiopathic intracranial hypertension, reversible cerebral vasoconstriction syndrome, intracranial hemorrhage, cerebral venous thrombosis, pituitary apoplexy, and post-dural-puncture headache. Patients with thunderclap headache need prompt attention, as the possibility of subarachnoid hemorrhage needs to be ruled out. Seizures are a hallmark feature of eclampsia. The common differential diagnoses of seizures in pregnancy includes cerebral venous thrombosis, intracerebral hemorrhage, brain tumors, and metabolic disorders such as uremia, hypoglycemia, and hyponatremia. In developing countries, infective diseases such as bacterial meningitis, acute viral hepatitis with fulminant hepatic failure, and cerebral malaria are important causes of seizures and coma in pregnancy. Neurocysticercosis should be considered, especially if the patient is a resident of an endemic area or has emigrated from or traveled to an endemic area. Acute vision loss during pregnancy and the postpartum period can occur due to many other reasons, such as pituitary apoplexy and central serous retinopathy.
Imaging characteristics of posterior reversible encephalopathy syndrome in pregnancy are often misinterpreted as encephalitis, posterior circulation stroke, multiple sclerosis, acute disseminated encephalomyelitis, cerebral venous sinus thrombosis, and central nervous system vasculitis. Top of the basilar syndrome with infraction in both the occipital lobes creates considerable confusion. Seizures are often a heralding manifestation in posterior reversible encephalopathy syndrome but not in stroke. This point may be extremely helpful in confirming the diagnosis.,
Prompt recognition of posterior reversible encephalopathy syndrome in patients with eclampsia is crucial. Early treatment often leads to a complete reversal of clinical and imaging manifestations. Delayed treatment may result in permanent disability and even death. Early correction of increased blood pressure and treatment of seizures are the cornerstones of eclamptic encephalopathy treatment. Attention must also be paid to correcting any associated dehydration and electrolyte imbalance. Adequate oxygenation should always be ensured.
Treatment of seizures
In eclamptic encephalopathy, magnesium sulfate is the initial drug of choice for controlling ongoing seizures. Seizures are often terminated immediately after the loading dose of magnesium is administered. Magnesium sulfate is also recommended for seizure prophylaxis in severe preeclampsia and eclampsia. Magnesium sulfate should be given at an intravenous loading dose of 4–6 g (15–20 min) and a maintenance dose of 1–2 g per hour. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommends that magnesium sulfate should not be used for more than 48 hours. If seizures remain uncontrolled with magnesium sulfate, benzodiazepines or phenytoin should be used. Lorazepam (4 mg intravenous over 2–5 minutes) is a good choice for uncontrolled/ recurrent seizures in the acute setting. Diazepam (5–10 mg intravenous slowly) and midazolam (1–2 mg bolus intravenously at a rate of 2 mg/min in repeated boluses) are effective alternatives. In case seizures are still refractory to treatment, intravenous phenobarbitone may be used.
Treatment of hypertension
Prompt lowering of blood pressure is crucial for the management of posterior reversible encephalopathy syndrome. Severe hypertension (more than 160/110 mmHg) should be treated with intravenous antihypertensive drugs such as labetalol, hydralazine, or nifedipine. Hydralazine and labetalol are the initial intravenous drugs of choice in pregnancy. The initial dose of hydralazine is 5 mg given intravenously, followed by a subsequent dose of 5–10 mg every 20 to 30 minutes, based upon the response to treatment. The target blood pressure that needs to be maintained is a systolic blood pressure between 140 and 160 mmHg and a diastolic blood pressure between 90 and 110 mmHg.
Once the patient is stabilized, the delivery of fetus should be prioritized. Symptoms such as headache, visual abnormalities, confusion, and right upper-quadrant pain or epigastric pain should be monitored seriously as these symptoms indicate impending seizures. All these symptoms are indications for a prompt delivery of the fetus. The mode of delivery is usually determined according to the obstetric indications. Induction of labor is not contraindicated. Evaluation of the maternal and fetal status is mandatory before the induction of labor.
Over half a million women worldwide, particularly in low- and middle-income countries, die each year because of pregnancy-related causes, of which approximately 10–15% die because of preeclampsia and eclampsia. In developed countries, approximately 0.4–7.2% maternal deaths are ascribed to preeclampsia and eclampsia.,
Though posterior reversible encephalopathy syndrome is an integral component of eclamptic encephalopathy, it does not adversely affect the prognosis. In majority of the patients, posterior reversible encephalopathy syndrome resolves spontaneously and the patients show a remarkable clinical improvement. Kurdoglu et al., noted a slightly higher perinatal mortality in eclamptic women with posterior reversible encephalopathy syndrome (24.4% versus 13.9%) and the babies born had low Apgar scores. Majority of eclamptic women with posterior reversible encephalopathy syndrome showed neurological recovery with prompt treatment. Demir et al., noted that 89% (55/62) eclamptic women had full neurological recovery, and the remaining patients had partial recovery. Demir et al., advocate the use of magnesium sulfate over mannitol in patients with posterior reversible encephalopathy syndrome. A Chinese study also noted a similar rate of neurological recovery, and all eclamptic patients with posterior reversible encephalopathy syndrome recovered completely. Two patients who developed disseminated intravascular coagulation died. Death is likely in patients with severe posterior encephalopathy syndrome, particularly, if the syndrome is associated with a large intracerebral hemorrhage or multiple organ dysfunction.
In many patients, permanent neurological sequelae have been reported. Permanent vision loss is the most frequent sequelae., In addition, nonspecific asymptomatic white matter brain lesions on neuroimaging have been noted in women with eclamptic encephalopathy (with or without posterior reversible encephalopathy) years after the patient has recovered.,, Residual white matter changes are most frequently located in the frontal lobes, followed by the parietal, insular, and temporal lobes.
Posterior reversible encephalopathy is a serious complication of eclampsia. Early recognition helps in preventing some of its devastating sequelae such as permanent vision loss. Eclampsia and its associated complications can be prevented by good obstetric care, early detection of preeclampsia, and the judicious prophylactic/therapeutic use of magnesium sulfate.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]