Wernicke–Korsakoff syndrome is a neuropsychiatric disorder caused by thiamine deficiency composed of two related disorders accounting for an acute presentation and chronic progression. Hyperemesis gravidarum presents a significant risk factor for Wernicke–Korsakoff syndrome as symptoms may rapidly progress in the setting of pregnancy. We present the first-reported case of hyperemesis-gravidarum-associated Wernicke encephalopathy in a patient in the first half of pregnancy in which a missed diagnosis led to septic shock, fetal demise, and eventual profound Korsakoff syndrome.
Case presentation
We present the case of a 33-year-old primigravid African American woman at 15 weeks gestational age who initially presented at a community emergency department with nausea and vomiting that ultimately progressed to severe hyperemesis-gravidarum-associated Wernicke–Korsakoff syndrome, fetal demise, and septic shock. The patient received a total of 6 weeks of high-dose parenteral thiamine. Magnetic resonance imaging of the head and formal neuropsychological assessment following treatment plateau confirmed the diagnosis of Wernicke–Korsakoff syndrome.
Conclusions
The multisystem complications seen in severe thiamine deficiency can delay timely administration of high-dose thiamine, particularly in pregnancy, in which the classic triad of Wernicke–Korsakoff syndrome may not raise clinical suspicion due to rapid progression of neurological sequelae in this population. We advise a low threshold for parenteral thiamine repletion in pregnant women with persistent vomiting as hyperemesis gravidarum-induced severe thiamine deficiency can result in Wernicke–Korsakoff syndrome, sepsis, and fetal demise.
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Abkürzungen
WE
Wernicke encephalopathy
KS
Korsakoff syndrome
WKS
Wernicke–Korsakoff syndrome
HD
Hospital day
Introduction
Wernicke–Korsakoff syndrome (WKS) is a neuropsychiatric disorder composed of two related disorders caused by thiamine deficiency. Wernicke encephalopathy (WE) is characterized by the classic triad of symptoms with acuteonset encephalopathy, ophthalmoplegia, and ataxia. WE may progress to Korsakoff syndrome (KS), which is characterized by marked irreversible deficits in anterograde and retrograde memory, as well as apathy and confabulation. Around 85% of patients with WE progress to KS without treatment [1]. While commonly associated with alcohol use, WKS can occur with deficiencies in thiamine intake, absorption, storage, and metabolism from any etiology and has been associated with bariatric surgery, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and hyperemesis gravidarum (HG).
HG presents a significant risk factor for WKS due to nutritional deficiency caused by persistent vomiting. Nausea and vomiting affect up to 80% of all pregnancies, and persistent vomiting is the most common indication for hospitalization during the first half of pregnancy. Symptoms become severe in up to 3% of these cases, resulting in weight loss, dehydration, and electrolyte imbalance [2, 3]. A recent systematic review of WE in pregnancy revealed a maternal mortality rate of 5% and 50% fetal mortality, some despite diagnosis and treatment [4]. In the general population, fetal demise after 20 weeks gestation occurs in about 1 in 175 pregnancies [5]. This increased mortality to the fetus is a unique and defining feature of HG-induced WKS.
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While preventable, HG-associated WKS is considered rare and can be missed. We present the first-reported case of HG-associated WE in a patient in the first half of pregnancy in which a missed diagnosis led to septic shock, fetal demise, and eventual profound KS.
Case report
A 33-year-old primigravid African American woman at 15 weeks gestation presented obtunded to the hospital for acute-onset altered mental status. Her medical history was significant for asthma, hypothyroidism, and β-thalassemia trait. She had no past psychiatric or substance use history. Her pregnancy had been complicated by ketonuria, nausea, vomiting, and poor oral intake noted at her initial prenatal visit with emergency department presentations for intractable vomiting and poor oral intake requiring intravenous fluid repletion (Fig. 1).
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On examination, the patient was disoriented, agitated, and persistently tachycardic to 150 beats per minute. Labs were notable for multiple electrolyte abnormalities, microcytic anemia, transaminitis, hypothyroidism, lactic acidosis, and rhabdomyolysis (Tables 1, 2, 3, 4, 5). Urine drug screen and blood alcohol level were negative. Urinalysis showed protein, ketones, and large amounts of bilirubin. Initial blood cultures showed one set positive for methicillin-sensitive Staphylococcus aureus (MSSA). Computerized tomography (CT) of the head was unremarkable. Electrocardiogram (EKG) showed sinus tachycardia with a heart rate of 151 beats per minute. Obstetric ultrasound confirmed a single, live, intrauterine pregnancy at appropriate gestational age. Altered mental status was attributed to dehydration and sepsis, and she was started on intravenous nafcillin, hypotonic fluids, and high-dose parenteral thiamine. A plasma thiamine level did not demonstrate deficiency (Table 6).
Table 1
Serial metabolic panels showed early electrolyte abnormalities in support of dehydration and malnutrition due to vomiting
Normal ranges
HD0
HD2
HD10
HD18
Glucose
70–140 mg/dL
122
77
78
Sodium
129–148 mmol/L
147
145
139
140
Potassium
3.3–5.0 mmol/L
2.8
3.5
3.6
4.1
Chloride
97–109 mmol/L
114
118
109
111
Bicarbonate
18–26 mmol/L
23.0
20
20
18
BUN
3–13 mg/dL
7
3
7
6
Creatinine
0.4–0.8 mg/dL
0.7
0.5
0.4
0.5
Phosphate
2.5–4.6 mg/dL
3.6
3.0
Calcium
8.2–9.0 mg/dL
10.4
9.1
9.6
Magnesium
1.5–2.2 mg/dL
1.4
1.6
2.0
Abnormal findings are in bold
Ketonuria also supported a picture of minimal oral intake
There was concern for possible early presentation of hemolytic anemia given drop in hemoglobin
Normal ranges
HD0
HD2
HD10
HD18
PTT
24.2–38.1 seconds
23
28
31
PT
9.5–13.4 seconds
13.6
13.3
18.1
INR
0.85–0.97
1.19
1.59
d-Dimer
320–1290 ng/mL
1610
27,324
Fibrinogen
291–538 mg/dL
890
502
LDH
80–447 IU/L
347
Abnormal findings are in bold
Direct Coombs was negative, and peripheral smear was nonspecific. Hemolysis was later ruled out on HD10
PTT, partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; LDH, lactate dehydrogenase; ng, nanograms; mg, milligrams; mL, milliliter; dL, deciliter; L, liter; IU, international units; HD, hospital day
Table 6
Nutritional studies were unremarkable and misleading as plasma thiamine level was obtained following initiation of repletion
Normal ranges
HD0
HD2
HD10
HD18
B12
130–656 pg/mL
1568
1708
B9
2.7–17.0 ng/mL
13.6
B1 (plasma)
8–30 nmol/L
896
Iron
44–178 µg/dL
73
68
TIBC
302–519 µg/dL
221.6
288
Transferrin
220–441 mg/dL
155
Ferritin
2–230 ng/mL
197.4
Abnormal findings are in bold
Elevated free thiamine did confirm adherence to repletion while inpatient
B12, Cobalamin; B9, folic acid; B1, thiamine; TIBC, total iron binding capacity; pg, picograms; ng, nanograms;
The patient developed paranoid delusions and auditory hallucinations prompting an encephalopathy workup. Rhabdomyolysis and transaminitis continued prompting concern for early hemolysis or rheumatological etiology (Tables 3 and 4). Sinus tachycardia persisted. Lumbar puncture showed elevated protein [glucose 58 mg/dL, protein 315 mg/dL, 2 white blood cells (WBC) per mm3, 32 red blood cells (RBC) per mm3]. Viral hepatitis titers, paraneoplastic panel, copper level, and ceruloplasmin were unremarkable. Magnetic resonance imaging (MRI) of the head showed findings consistent with a diagnosis of WKS (Fig. 2). A new pituitary mass was noted (Fig. 3). Prolactin level was normal (234 ng/mL, normal range 110–330 ng/mL). Repeat blood cultures were negative.
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She was transferred to a larger academic center on hospital day (HD) 10 for further evaluation. On examination, she was disoriented, confabulatory, paranoid, and surprised to hear she was pregnant. Transfer workup showed ongoing transaminitis, rhabdomyolysis, and hypothyroidism (Tables 3 and 4). Labs demonstrated new elevated fibrinogen and d-dimer (Table 5). Coagulopathy was ruled out by hematology consultants. Repeat blood cultures were negative. Transthoracic echocardiogram was unremarkable. She was seen by multiple consulting services, including infectious disease. MRI imaging of head, spine, and lower extremities failed to reveal a source as leukocytosis steadily worsened.
At HD18 and 18 weeks gestation, she developed septic shock with fetal demise and underwent dilatation and evacuation. She was intubated, started on pressors, and moved to the intensive care unit (Fig. 1). Blood cultures grew Klebsiella and Candida, and she was switched to piperacillin–tazobactam and anidulafungin. Repeat cardiac imaging showed new high-output cardiomyopathy with reduced ejection fraction of 15%. Heparin was infused due to concern for pulmonary embolism, which was ruled out by vascular medicine, and she was transitioned to enoxaparin. Transesophageal echocardiography did not demonstrate vegetation. Blood cultures cleared, and she was extubated and transitioned back to the general floors by HD28. On HD40 she spiked an isolated fever of 102 °F after completing intravenous antibiotics and her husband asked to take the patient home. In accordance with hospital risk management, the patient and family were counseled on the risks of her current medical condition and the patient was discharged with return precautions.
Three weeks later, the patient returned to the emergency department with her husband (Fig. 1). On physical examination, she demonstrated new horizontal nystagmus, ataxia, and encephalopathy. Urinalysis was notable for 3+ leukocyte esterase, positive nitrites, and > 182 WBCs per high-power field. Psychiatry consultants noted ongoing paranoia and cognitive impairment. Her husband as the surrogate decision maker agreed to continue treatment with ceftriaxone for a urinary tract infection and high-dose parenteral thiamine for presumed WKS. A central line was placed for long-term thiamine administration. The patient was transferred to acute physical rehabilitation and was incrementally able to participate in physical and occupational therapy. She received inpatient formal neuropsychological testing where she demonstrated profound anterograde amnesia, abulia, disorientation, impaired processing speed, and anosognosia highly consistent with a diagnosis of WKS. After 6 weeks of parenteral thiamine since her initial presentation until treatment plateau and 18 days of physical rehab, she was discharged back home with her husband.
Discussion
Although WKS is classically found in patients with chronic alcohol use, this syndrome may be found in any patient with depleted intracellular thiamine such as from prolonged parenteral nutrition, gastrointestinal carcinoma, HIV/AIDS, eating disorders, chronic diarrhea, or persistent vomiting [6]. WKS is a clinical diagnosis, and identification depends on the clinical suspicion of those who may be looking for the classic constellation of ophthalmoplegia, confusion, and gait ataxia [7]. While these criteria were originally conceived to prevent underdiagnosis of WKS in alcoholics in which the syndrome frequently overlapped with hepatic encephalopathy, it continues to be utilized for diagnosis of WKS in a variety of patient populations [8]. Autopsy studies reveal, however, that up to 80% of cases of WKS are undiagnosed using these criteria; nearly 20% of patients present with none of these classical signs, and up to 37% may present with only one [9‐11].
There are no reliable and accessible measures for thiamine deficiency despite biochemical changes often preceding overt physical signs. Tests of nutritional status including 24-h urine excretion of thiamine, and specialty blood tests have been developed but are of limited clinical use given necessary processing time. Free thiamine in plasma or serum is representative of recent intake rather than storage and can be useful in assessing adherence. If available, thiamine in whole blood is less sensitive to recent intake and will provide a more accurate assessment of thiamine deficiency. MRI findings are only 53% sensitive but are 93% specific [12]. In this case, the patient’s free thiamine was appropriately elevated following initiation of replenishment and the lack of supporting evidence for WKS further confused the initial diagnostic impression. After transfer to a larger institution, diagnosis was confirmed with MRI and neuropsychological assessment. WKS remains a clinical diagnosis and requires the synthesis of history, physical examination, and objective findings.
HG is a preventable risk factor for nonalcoholic WKS. Although it generally takes months to years for an alcoholic to develop overt signs of WKS, the same syndrome in a pregnant woman may present as early as 6 weeks gestation and progress rapidly due to increased thiamine requirement during pregnancy [4]. Thiamine requirement increases by as much as 45% for fetal growth and development [13]. Measures of free thiamine have been shown to be higher in cord blood than in maternal blood, suggesting that the fetus is able to sequester thiamine at the expense of the mother [14]. While there is no direct evidence that thiamine deficiency of the mother can cause fetal complications, WKS is associated with fetal demise and spontaneous abortion [15].
Diagnosis of WKS should not rely upon the presence of the classical triad without consideration of the pregnancy and nutritional status of the patient. The patient did not exhibit oculomotor or cerebellar abnormalities early in her presentation. She presented at 12 weeks gestational age with HG, which is inconsistent with the typical prolonged nutritional deficiency seen in alcoholics. She went on to demonstrate several characteristics consistent with a diagnosis of WKS including profound anterograde amnesia, abulia, disorientation, impaired processing speed, and anosognosia along with peripheral neuropathy and high-output cardiomyopathy, also known as beriberi [16, 17]. It is unclear if the fetal demise was directly caused by her thiamine deficiency, though the resultant sepsis greatly accelerated her course as metabolic demand increased. Additional evidence supports that severe infection may be common in thiamine deficiency and repletion may be therapeutic [18‐21].
The outcome may have been different if thiamine supplementation was initiated as soon as nutritional deficiency was suspected. In total, there were 3 weeks from initial presentation at 12 weeks gestational age until the patient arrived obtunded at 15 weeks gestational age and was admitted. There are no standardized national guidelines for thiamine administration, though the European Federation of Neurological Societies and Royal College of Physician both advocate for thiamine 500 mg intravenously, three times a day until acute WE has resolved and benefits plateau, which may take several months [22]. These guidelines may need to be adapted in pregnancy, with earlier and more aggressive treatment.
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Conclusions
This patient’s initial presentation was medically complex and severe, and presented numerous diagnostic challenges. The multisystem complications seen in severe thiamine deficiency can delay timely administration of high-dose thiamine, particularly in pregnancy, in which the classic triad of symptoms may not be sensitive enough due to the rapid progression of neuropsychiatric symptoms in this population. We advise a low threshold for high-dose parenteral thiamine repletion in pregnant women with persistent vomiting as HG-induced severe thiamine deficiency may result in WKS, sepsis, and fetal demise.
Acknowledgements
We would like to acknowledge Garrett H.C. Colmorgen, MD, Director, Obstetrics and Maternal-Fetal Medicine, Bayhealth Medical Center, Dover, DE for reviewing this paper. We would like to thank all the residents, fellows, and faculty who contributed to the care of this patient. Thank you to Abby Adamcyzk for providing significant support in her role as graduate medical education librarian. Publication made possible in part by support from the Thomas Jefferson University Open Access Fund.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient and her guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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Competing interests
The authors declare they have no competing interests.
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