Atypical eclampsia in a normotensive patient with altered mental status and severely elevated transaminases: Case report and review

Classically, pre‐eclampsia and eclampsia are considered hypertensive disorders of pregnancy, and current diagnostic criteria include hypertension with proteinuria or other laboratory abnormalities or symptoms suggestive of end‐organ damage. However, atypical presentations can occur in the absence of elevated blood pressures. We present the case of a pregnant patient who developed status epilepticus at 24 weeks and 4 days of gestation, followed by altered mental status and severely elevated transaminases. She had no elevated blood pressures during her prenatal care or hospital course. Following delivery, she experienced normalization of transaminase levels and a return to her baseline mental status. Pre‐eclampsia and eclampsia can occur in the absence of elevated blood pressures, which highlights the limitations of using standard diagnostic criteria in normotensive patients with end‐organ damage. In such cases, it is important to include pre‐eclampsia and eclampsia in the differential diagnosis, as the diagnosis usually warrants preterm delivery to minimize maternal morbidity and mortality.


| INTRODUC TI ON
[6] Furthermore, other obstetric and non-obstetric conditions, such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acute fatty liver of pregnancy, and systemic lupus erythematosus, can present with abnormal symptoms, vital signs, and laboratory values that mimic the presentation of pre-eclampsia and eclampsia. 1,2tients with signs of end-organ damage in the absence of elevated blood pressures pose a unique diagnostic challenge in which atypical pre-eclampsia and eclampsia must be distinguished from other diagnoses as the main contributor to end-organ damage.We present the case of a pregnant patient without major risk factors for hypertensive disease who suddenly developed status epilepticus with tonic-clonic seizures at 24 weeks and 4 days, followed by persistent altered mental status and development of new-onset transaminitis, with improvement after delivery.Her blood pressures remained within normal limits throughout her hospital course.

| C A S E PR E S E NTATI O N
Our patient is a 40-year-old gravida 4, para 3 with no past medical history, who was initially brought to the emergency department with sudden onset of severe headache followed by status epilepticus with generalized tonic-clonic seizures at 24 weeks and 4 days' gestational age.At the time of presentation, the patient was noted to be unresponsive to verbal questions or commands; she also had non-purposeful jerky movements of her entire body, mydriasis, and tachycardia.Her seizures were initially treated with lorazepam; however, she had additional episodes of tonic-clonic seizures which did not resolve until she received levetiracetam with a 24-h course of intravenous (IV) magnesium sulfate.She was intubated due to acute hypoxic respiratory failure in the setting of seizures.
Laboratory tests on admission showed anemia with a hemoglobin of 10.3 g/dL but were otherwise unremarkable, including normal platelet count of 152 K/cumm, serum creatinine of 0.62 mg/dL, aspartate transaminase (AST) of 31 U/L, alanine transaminase (ALT) of 24 U/L, and urine protein-creatinine ratio of 0.24.She also had negative computed tomography (CT) and magnetic resonance imaging (MRI) imaging of the brain, urine toxicology, and cultures of blood, urine, and cerebrospinal fluid (Table 1).She was extubated on hospital day 4. Following extubation, the patient was conversant but notably not oriented to place or situation and unable to recognize her family.On the same day, she had an acute rise in her transaminases, which continued to trend upwards to AST of 460 U/L and ALT of 885 by 26 weeks' gestation (Figure 1).Throughout her admission, the patient was afebrile with low to normal blood pressures ranging between 70-120/50-60 mm Hg (mean arterial pressures in the range 67-82 mm Hg), and she received albumin boluses for intermittent hypotension.Due to worsening transaminitis and ongoing altered mental status, she was transferred to another hospital for higher level of care at 26 weeks and 1 day.
Upon being transferred, the patient continued to have normal blood pressures with upward-trending platelet count and normal serum creatinine, urine protein-creatinine ratio, coagulation studies, peripheral blood smear, ammonia level of 14 umol/L, lactate dehydrogenase (LDH) of 289 U/L, and haptoglobin of 116 mg/dL, all of which argued against a diagnosis of eclampsia.Despite continued treatment with levetiracetam, she remained unresponsive to verbal stimuli.Further neurologic workup demonstrated a lack of seizure activity on EEG and a lack of acute infarction, mass effect, and midline shift on brain MRI with magnetic resonance angiography (MRA) and magnetic resonance venogram (MRV).Furthermore, an extensive workup for alternative causes of transaminitis was negative, including abdominal ultrasound imaging to evaluate for hepatobiliary obstruction and Budd-Chiari syndrome, antithrombin-III level to evaluate for acute fatty liver of pregnancy, and various labs to evaluate for infectious hepatitis (i.e., antibodies for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and hepatitis B and C), autoimmune hepatitis (i.e., antinuclear antibodies, anti-smooth muscle antibody, anti-liver kidney microsomal antibodies), and primary biliary cirrhosis (i.e.anti-mitochondrial antibodies).She had an elevated serum ceruloplasmin level of 65 mg/dL with a normal 24-h urine copper excretion postpartum, excluding Wilson's disease.
Enoxaparin, which the patient was receiving for thromboembolism prophylaxis, was discontinued to eliminate the potential for druginduced hepatotoxicity.
Atypical eclampsia became the leading diagnosis after extensive workup systematically excluded other etiologies for the worsening transaminase elevations, persistently altered mental status, and new-onset hyperreflexia.Therefore, IV magnesium sulfate was restarted for seizure prophylaxis and two doses of betamethasone were administered.The patient then underwent cesarean delivery at 26 weeks and 3 days, with consent from her surrogate decision-maker.
On postoperative day 1, the patient's transaminases peaked with AST 1150 U/L and ALT 1739 U/L; her LDH increased to 918 U/L and her 24-hour urine protein was 420 mg.On postoperative day 2, the patient's transaminases began to trend downwards and her mental status improved.She was now alert and oriented to date, place, person, and setting and conversed appropriately in both English and Spanish.At the time of discharge on postoperative day 6, her AST was 55 U/L and her ALT was 477 U/L.Her blood pressures remained normal during her entire hospital course.
After discharge, the patient's transaminases were found to have normalized, and no further seizures occurred.

| DISCUSS ION
The classic diagnosis of pre-eclampsia requires elevated blood pressures and proteinuria, or elevated blood pressures with another severe feature such as thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, new-onset headache, or visual disturbances. 1However, this case highlights the importance of recognizing atypical presentations of pre-eclampsia and eclampsia, which can develop in the absence of hypertension and lead to severe maternal morbidity.
In our patient's case, the diagnosis of eclampsia was initially uncertain as the presentation was not fully consistent with classic criteria.She had low-to-normal blood pressures rather than elevated blood pressures, along with normal measurements in coagulation parameters, platelet count, serum creatinine, and urine protein-tocreatinine ratio.
The differential diagnosis for the patient's seizures and transaminitis was broad, and an extensive workup was pursued to rule out other causes, given that a misdiagnosis of eclampsia would result in unnecessary preterm delivery and its associated neonatal complications.Acute fatty liver of pregnancy was less likely given that the patient did not have a fever, leukocytosis, hypoglycemia, or abnormal coagulation factors. 8,9Other thrombotic microangiopathies of pregnancy, such as atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP), were considered in the differential diagnosis for altered mental status; however, the normal serum creatinine argued against aHUS and the upward-trending platelet count also argued against TTP and aHUS.Infectious hepatitis and autoimmune hepatitis were ruled out based on negative laboratory testing, as described earlier. 10Drug-induced liver injury following levetiracetam administration is possible but extremely uncommon, with occurrence estimated to be from 1/100 000 to 1/1 000 000. 11,12 Enoxaparin can cause liver injury in 4%-13% of patients; however, transaminases usually stay elevated during drug use and normalize within 1 week of discontinuation of the drug. 13In our patient, the transaminases continued to rise after discontinuation of enoxaparin but then trended downward in the postpartum period even when anticoagulation was restarted, making a drug etiology for transaminitis less likely. 13Wilson's disease is a rare, autosomal recessive disorder caused by abnormal copper accumulation primarily in the liver and brain and can cause behavioral changes and transaminase elevations.Classically in Wilson's disease, serum ceruloplasmin is decreased (<20 mg/dL) and urine copper excretion is elevated (>100 μg/dL), although ceruloplasmin levels can be physiologically elevated in pregnancy. 14Our patient had a slightly elevated serum ceruloplasmin and a normal 24-h urine copper level postpartum, eliminating the need for an invasive liver biopsy, which is the gold standard for diagnosing Wilson's disease. 15though multiple aspects of the patient's clinical presentation, including normal blood pressures, were not consistent with eclampsia, we ultimately decided to proceed with delivery for suspected atypical eclampsia due to several concerning features: severe headache prior to seizure onset, worsening altered mental status, hyperreflexia on physical examination, worsening transaminitis, and negative workup for alternative causes.Postpartum laboratory results, including LDH >600 U/L and 24-h urine protein >300 mg, were also consistent with eclampsia.The patient's improvement in mental status and transaminases after delivery provided the most compelling support for the diagnosis of atypical eclampsia. 1,2e diagnostic features for atypical pre-eclampsia and eclampsia, as established by Sibai and Stella, 2 include gestational hypertension or gestational proteinuria that presents in association with symptoms of pre-eclampsia, hemolysis, thrombocytopenia, and elevated liver enzymes.Other diagnostic features of atypical preeclampsia and eclampsia include early signs and symptoms (at less than 20 weeks' gestation) and late manifestations (>48 h after delivery). 2This is clinically significant as patients with pre-eclampsia and eclampsia do not always present with blood pressure elevations, as was the case for our patient, and a high index of suspicion should be applied to avoid missed diagnoses.

Niroomanesh and Mirzaie 16
Seizures refractory to standard medical management No proteinuria 26-year-old G1P1 who developed tonic-clonic seizures at 4 h postpartum.Seizures were resistant to initial treatment with diazepam and magnesium sulfate.After 30 min, the seizures were controlled with thiopentone.AST and ALT values not listed.
Albayrak et al. 17 Normotensive prior to seizures (cases 1-3) Seizures refractory to standard medical management (case 4) Case 1: 20-year-old G1P0 at 37 weeks gestation who presented with normal BPs (between 100/60 and 130/80 mm Hg) in labor.At 4 h postpartum, she developed generalized convulsion lasting 23 min, followed by 2 additional seizures.She was given magnesium sulfate.She had 330 mg of proteinuria in addition to slightly increased ALT 35 U/L and AST 66 U/L post-seizure.Cranial MRI and CT scan were normal.Case 2: 20-year-old at 37 weeks gestation who presented with normal BPs, no prodrome of hypertensive disease, and no lab abnormalities (including liver enzymes).After delivery, she had generalized seizure lasting 5-10 s, blindness, and occipital headache.BP was 150/100 mm Hg.Magnesium sulfate was given.Urine protein was 930 mg/dL on postpartum day 3. Case 3: 31-year-old multipara at 33 weeks gestation who presented with normal BPs.At 2 h after emergent cesarean section, she had BP 160/100 mm Hg, severe headache, and blurry vision.Case 4: 24-year-old G1P0 at 30 weeks gestation with borderline elevated BP (140/90 mm Hg) and 440 mg/dL of proteinuria, but no other lab abnormalities.She was discharged 2 days later for outpatient management of pre-eclampsia, then readmitted 4 days later with fetal demise and eclamptic seizures.Despite magnesium sulfate, she had nine convulsions prior to delivery and continued to convulse until postpartum day 2.
Nasare et al. 18 Seizures refractory to standard medical management 23-year-old G1P0 at 40 weeks and 3 days with sudden BP rise from 150/90 to 170/110 mm of Hg and generalized tonic-clonic convulsions.She received magnesium sulfate.Within 30 min she seized again and required additional anticonvulsants: levetiracetam, phenytoin sodium, and a benzodiazepine.She developed a third seizure at 10 h postpartum and received phenytoin.After the fourth convulsion she received midazolam and the seizures subsided.Liver function tests were normal.
Ibrahim et al. 20 Onset <20 weeks' gestational age 24-year-old G1P0 at 19 weeks gestation with 10 h of tonic-clonic seizures.BP was 110/80 mm Hg.Subsequently at 30 and 31 weeks, her BPs were 130/90 mm Hg and 110/90 mm Hg, respectively.Serial liver function tests were normal, and daily urinalysis was negative for protein.

Singh and Agarwal 21
Onset in late postpartum period Normotensive 22-year-old G1P1 at 4 days postpartum with normal BPs, mild headache, and nausea just prior to an episode of generalized tonic-clonic seizure.At 2 h post-seizure her BP was 100/60 mm Hg.Urine protein was 330 mg/dL.AST and ALT values not listed.

Graves and
Vandergriff 24 Onset in the late postpartum period No proteinturia Normotensive 33-year-old G5P4A1 at 10 days postpartum with eclampsia.The patient had no hypertension, edema, or proteinuria during her prenatal visits or hospitalization, and had no history of pre-eclampsia or eclampsia in prior pregnancies.
Maturu et al. 26 Normotensive 24-year-old G1P0 at 30 weeks gestation who presented with new-onset generalized tonic-clonic seizures without prior hypertension or proteinuria in her antenatal records.Seizures stopped with midazolam.During the entire hospital stay, her liver function tests and BPs were never high. (Continues) Odeh et al. 27 Normotensive 28-year-old at 34 weeks and 3 days who presented with two episodes of tonic-clonic seizure (tongue biting, up-rolling eyes) which lasted 1 min each and were associated with loss of consciousness.She was also COVID-19-positive.She was treated with diazepam and magnesium sulfate.BP was 110/65 mm Hg and remained less than 120/80 mm Hg.ALT and AST values not listed, but "liver function for total protein was low 5 g/dL (normal range is 6.6-8.7 g/dL)." Aggarwal 28 Normotensive 30-year-old at 35 weeks and 5 days with BP was 110/60 mm Hg when she suddenly had a generalized tonic-clonic seizure.After diazepam and magnesium sulfate her BP was 90/60 mm Hg.There was trace proteinuria, but CT head, CSF analysis, and "blood investigations" were normal.
Note: Similarities between prior cases and the current case are emphasized in bold.
TA B L E 2 (Continued)

F I G U R E 1 2
,21,22,24-28  Eclampsia infrequently occurs without Transaminase trend in relation to gestational age.ALT, alanine aminotransferase; AST, aspartate aminotransferase.Summary of published cases of atypical eclampsia.
Studies on cerebrospinal fluid obtained from lumbar puncture on admission.