Wernicke-Korsakoff Syndrome in Hyperemesis Gravidarum: A Case Report and Literature Review

Abstract

Background:

Wernicke-Korsakoff syndrome (WKS) is a triad of ophthalmoplegia, ataxia and memory deficits due to thiamine insufficiency resulting from under- or untreated Wernicke’s encephalopathy (WE), which may be associated with hyperemesis gravidarum (HEG).

Case presentation:

We present a case of a 36-year-old Filipino woman in her first trimester with HEG, along with the WKS triad and abnormal hyperintense signals in the bilateral thalami and midbrain, left occipital lobe, periaqueductal gray matter and pontine periventricular areas. Neurologic deficits partially improved but persisted despite intravenous thiamine administration.

Evidence review:

A review of current treatments for WE, and the prevention and neurocognitive recovery of WKS was done. The beneficial effects of thiamine for acute WKS are supported by several case reports and clinical experience. Evidence from one randomized controlled trial wherein thiamine was given in various doses for treating WE or preventing WKS in an alcohol-dependent population is limited by methodological issues. Rehabilitation and pharmacotherapy for neurocognitive recovery seems promising, but they have inadequate evidentiary support. More robust studies on multi-modal strategies are warranted to facilitate the neurocognitive recovery of patients with WKS.

Introduction

Wernicke’s encephalopathy (WE) is caused by thiamine deficiency and is clinically diagnosed by the presence of two of the four following signs: dietary deficiency, eye signs, cerebellar signs, and either an altered mental state or memory impairment.^1,2 The persistence of memory impairment, as often observed, will reclassify it as Wernicke-Korsakoff syndrome (WKS), which immediately follows WE.^1,3 This condition is due to depletion of thiamine-dependent enzymes, such as transketolase, alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase, causing demyelination, apoptosis and edema in specific areas of the brain.^3-8 Conditions like pregnancy, alcohol consumption, chronic disability, diabetes, dysentery and increased energy expenditure may result in thiamine deficiency.⁹ Furthermore, hyperemesis gravidarum (HEG), which is characterized by severe vomiting during pregnancy, may further cause extreme thiamine deficiency leading to WKS.^10,11

We present a case of a pregnant woman diagnosed with WKS associated with HEG with the persistence of manifestations despite thiamine treatment and resolution of radiographic findings. Improvement was noted after rehabilitation that was initiated one year after the symptom onset. We also reviewed the current evidence regarding the treatment of WE, and the prevention and neurocognitive recovery of patients with WKS.

Case Presentation

A 36-year-old, Filipino, pregnant at sixth week of gestation with unremarkable past medical and family history was admitted for intractable vomiting, anorexia and generalized weakness. Metoclopramide, intravenous histamine 2 receptor antagonist and hydration were instituted. No phenothiazine was given throughout the duration of symptoms. She was discharged after improvement of symptoms. On her 13th week of gestation, the patient experienced double vision and worsening of vomiting, prompting readmission. The patient eventually went into coma. Her vital signs and serum sodium levels were consistently normal. Cranial magnetic resonance imaging (MRI) revealed abnormal hyperintense signals in the bilateral thalami and midbrain, left occipital lobe, periaqueductal gray matter and periventricular area at the pontine level (Figure 1A-C).

Figure 1.

Pertinent cranial magnetic resonance imaging findings (fluid-attenuated inversion recovery sequence) of our case. Figure. A to C: Imaging at 1 week after the initial clinical presentation displayed abnormal hyperintense signals (arrowheads) in the bilateral thalami and left occipital lobe (A), bilateral midbrain and periaqueductal gray matter (B), and periventricular area at the level of the pons (C). Figure. D to F: Imaging after 6 months showed partial resolution of hyperintense signals in the specified regions (arrowheads).

Since pure intravenous (IV) thiamine was not immediately available, IV vitamin B complex (B1/B2/B3/B6) was started at 1000 mg/8 mg/320 mg/100 mg via slow infusion once daily for one week. It was then shifted to IV thiamine at 600 mg/day given for 2 weeks. She became more arousable after one week of IV thiamine, albeit with slow and incoherent responses, disorientation, anterograde and retrograde amnesia, bilateral horizontal nystagmus, dysphagia, limb rigidity and leg dystaxia on heel-to-shin test. Subsequent cranial MRI showed partial resolution of the previously noted hyperintense signals (Figure 1D and F). She had early preterm labor and delivered a live baby girl via cesarean section at 37th week of gestation. She had post-partum bleeding and received 2 units of packed red blood cells. She remained bedridden with persistent cognitive deficits, confabulation, nystagmus, ataxia and dependence in activities of daily living for 2 months. She was transferred to another hospital for further work-ups, including cerebrospinal fluid and anti-N-methyl-D-aspartate glutamate receptor (NMDA) receptor analyses, which showed unremarkable results. Twenty-one channel electroencephalogram done 8 months after symptom-onset showed diffuse low-voltage 5-7 Hz theta activity with posterior dominance, poor reactivity and absence of epileptiform discharge.

Differential diagnoses included posterior reversible encephalopathy, extra-pontine myelinolysis, central nervous system infection and nonconvulsive status epilepticus. However, these were less likely due to the presence of normal blood pressure, serum sodium levels, and reversibility of altered sensorium with administration of thiamine, along with the hyperintensities on the thalamus, and periventricular and brainstem structures. The clinical course and radiological presentation was consistent with a diagnosis of WKS.

She was eventually transferred in our tertiary hospital one year after symptom-onset. She had a score of 7 out of 30 on Montreal Cognitive Assessment for Filipino Patients (MOCA-P): 2 points each for abstraction and calculation, and 1 point each for visuospatial/executive, naming and attention.¹² She showed below-average scores on Fuld Object-Memory Evaluation (FOME) due to inability to recall objects despite verbal reminders.¹³ Motor and sensory nerve conduction studies were normal. For the first time, she was referred for rehabilitation, which included daily bedside therapy sessions consisting of cognitive training (i.e., memory drills, problem-solving, behavioral modification techniques), language exercises (i.e., vocabulary-building, conversational coaching), swallowing training (i.e., oromotor exercises, perioral thermo-tactile stimulation), and functional training (i.e., stretching and strengthening exercises, vertical mobility exercises). She was eventually discharged with noted functional improvements from being bedridden to being able to tolerate wheelchair rides, and from being completely dependent to being moderately assisted in activities of daily living. She also learned to follow commands, recognize familiar faces, assist in routine self-care tasks, and consistently engage in social interaction. She was advised to continue rehabilitation as outpatient upon discharge.

Discussion

Literature review shows that patients with WKS associated with HEG present typically during the third to fourth decade of life and as early as 18 years old (Table 1). Most cases occur during the first trimester of pregnancy and with accompanying weight loss ranging from 8 to 25 kg. Our patient initially presented with double vision, which is a typical prodrome of WE, followed by nystagmus, ataxia, memory deficits, and change in sensorium, which are consistent with the presentation of WKS.¹¹

Table 1.

Review of Cases With Wernicke-Korsakoff Syndrome and Hyperemesis Gravidarum.

Study	Age, years	Age of gestation, weeks	Weight loss, kg	Manifestations	Imaging	Vitamin B1 treatment	Neurologic improvement	Residuals
Accetta (2002)14	21	20	25	Confabulation, anterograde amnesia, nystagmus, ataxia	CT: Normal MRI: Pons	Yes	Yes	Anterograde amnesia, ataxia
Bergin (1992)15	24	NR	NR	Ophthalmoplegia, anterograde amnesia, nystagmus, ataxia	CT: Not done MRI: Pons	Yes	Yes	Anterograde amnesia, ataxia
Chang-Kyoon (2005)16	27	12	14	Memory deficits, nystagmus, ophthalmoplegia, ataxia	CT: Normal MRI: Medial thalami, periaqueductal gray matter	No	Yes	Memory deficits, ataxia,
Di Gangi (2012)17	21	15	NR	Confabulation, nystagmus	CT: Not done MRI: Inferomedial thalamus, quadrigeminal plate, restiform bodies	Yes	No	Confabulation, nystagmus
Gardian (1999)18	25	11	NR	Anterograde amnesia, nystagmus, ataxia	CT: Normal MRI: Mediodorsal thalami, hypothalamus, periaqueductal gray matter	Yes	Yes	Nystagmus, ataxia
Kinkel (1991)19	26	17	15	Anterograde amnesia, nystagmus, ophthalmoplegia, ataxia	CT: Not done MRI: Thalamus, hypothalamus, periaqueductal gray matter, quadrigeminal plate	Yes	Yes	Amnesia, confabulation, nystagmus, ataxia
Lavin (1983)20	29	7	16	Nystagmus, ophthalmoplegia, ataxia	CT: Normal MRI: Not done	No	No	Nystagmus, ophthalmoplegia, ataxia
Nhari (2018)21	27	16	NR	Confabulation, nystagmus	CT: Moderate atrophy MRI: Normal	No	Yes	Anterograde and retrograde amnesia
	21	NR	NR	Nystagmus, ophthalmoplegia	CT: Not done MRI: Not done	No	Yes	Nystagmus, ophthalmoplegia
Nightingale (1982)22	20	8	18	Confabulation, anterograde amnesia, nystagmus, ataxia	CT: Normal MRI: Not done	No	Yes	Nystagmus, ataxia
Ohkoshi (1993)23	18	8	8	Amnesia, nystagmus, ataxia	CT: Caudate nuclei, quadrigeminal plate MRI: Caudate nuclei, hypothalamus, thalamus, periaqueductal gray matter	Yes	Yes	Retrograde amnesia
Peeters (1993)24	21	12	15	Nystagmus, ophthalmoplegia, ataxia	CT: Normal MRI: Thalamus, hypothalamus, mamillary body, midbrain, pons, periaqueductal gray matter	Yes	Yes	Nystagmus
Mishra (2019)25	30	10	NR	Memory deficits, nystagmus, ataxia	CT: Not done MRI: Not done	Yes	Yes	Memory deficits
Pagaling and Espiritu (2020)	36	13	NR	Anterograde and retrograde amnesia, nystagmus, ophthalmoplegia, ataxia, memory deficits, confabulation	CT: Not done MRI: Bilateral thalami and midbrain, left occipital lobe, periaqueductal gray matter, pontine periventricular area	Yes	No	Anterograde and retrograde amnesia, nystagmus, ophthalmoplegia, ataxia, memory deficits, confabulation

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; NR, not reported.

The memory impairment of our patient involved both episodic and semantic memory. Anterograde memory loss was greater than in retrograde memory. The pattern of memory loss could be explained by Ribot’s law, wherein the most recently acquired memories were more vulnerable to disruption from brain damage.^3,4,26 Memory impairment could be due to disruption of mammillothalamic tracts and frontal lobe dysfunction, while confabulation could be due to failure in the temporal reconstruction of memories.^3,4 Ataxia could result from damage of cerebellar vermian Purkinje cells or demyelination of large, sensory, peripheral nerves.^4,27 With our patient’s unremarkable electrodiagnostic studies, peripheral neuropathy was considered less likely. The hyperintensities on bilateral thalami, periaqueductal gray matter, mamillary body and brainstem were consistent with the literature. Mamillary body lesions were found to be usually associated with WKS and alcoholism.^1,3,11,28

To prevent thiamine deficiency, the daily requirement in pregnancy is 1.4 mg/day.^10,29 On average, body thiamine stores are less than 30 mg, which is adequate for 9-18 days.⁹ Thiamine is classified as Food and Drug Administration (FDA) Category A for recommended dietary allowance, and Category C for more than the recommended dietary allowance.

The presence of HEG alone or the administration of IV glucose without thiamine supplementation in patients with HEG is a known risk factor for thiamine deficiency in pregnant women.¹ For patients with HEG, daily administration of 100 mg of IV thiamine before administration of glucose may prevent WE.^30,31 However, there is currently no RCT supporting that supplementation with 100 mg of IV thiamine can prevent WE or WKS in pregnant women. The optimal prophylactic regimen for pregnant women with HEG needs further studies.^{4,32 -34}

The current practice for the treatment of WE has been largely based on several case reports, empiric clinical experience and one RCT.^32,34-41 According to a Cochrane review, the weight of evidences from case reports and clinical experience do not justify the performance of a placebo-controlled trial.⁴¹ The single RCT by Ambrose et al. presents head-on comparisons among the various doses of thiamine, resulting in the best outcomes for participants who received 200 mg/day for two days.³⁵ However, the study conclusions were limited due to the following methodological issues: enrollment of chronic alcoholics who did not exhibit manifestations of WE, non-disclosure of randomization method, large drop-out rate (n = 43) followed by undisclosed method of exclusion of participants (n = 19), failure to mention measures to minimize detection bias, and questionable instrument for outcome measurement.^35,41 The authors of this RCT qualified their findings as preliminary and recommended further RCTs to establish the optimal dosing strategies for the treatment of WE. Further search for other RCTs on thiamine yielded two unpublished studies of Nichols et al. and Dingwal et al.; however, the data are not available for full analysis.⁴¹ Administration of 200 mg of thiamine via slow intravenous infusion three times a day or initial dose of 500 mg intravenously given three times a day for three days, followed by 250 mg intravenously given once a day for 5 days or until the resolution of symptoms, was recommended for patients with WE.^33,34 A case series showed that longer duration of high-dose thiamine administration led to better improvement of symptoms.⁴² In the WKS-HEG cases reviewed in Table 1, several patients were given thiamine at various doses (median 300 mg/day, ranging from 200 to 1,500 mg/day) for 15 days to 21 weeks with no reported adverse event. Many of these patients had some clinical improvements, especially with nystagmus, while majority had residual deficits like memory impairment and ataxia. In our case, despite treatment with thiamine, its administration could be past the period of irreversible cellular injury; hence, there was persistence of deficits.⁴

Currently, there is no approved treatment for neurocognitive recovery for WKS among pregnant patients because studies are only limited to alcohol-related cases of WKS. Administration of memantine at a dose of 10 mg/day showed positive outcomes in cognitive and functional assessments; however, these studies are limited to case reports and one placebo-controlled clinical trial with a small sample size (n = 16).^43-45 Treatment with clonidine, donepezil, fluvoxamine, high dose thiamine or rivastigmine warrants further evaluation as previous evidences are limited to case reports, case series and RCTs with small sample size.^42,46-51 Clinical trials with behavioral rehabilitation programs for neurocognitive recovery showed favorable outcomes with improvement of recall in recent memory via the concept of errorless learning that emphasizes semantic and procedural memory.^3,52,53

Conclusion

Our case is a 36-year-old woman in her first trimester of pregnancy with HEG presenting with the triad of symptoms and hyperintense lesions in the thalami, midbrain, periaqueductal gray matter, left occipital lobe and and pontine periventricular areas. The clinical and radiologic presentation was consistent with the diagnosis of WKS associated with HEG. Intravenous thiamine resulted in partial improvement of sensorium and radiologic findings. However, neurologic and functional deficits persisted. Gradual improvement in activities of daily living was noted with comprehensive rehabilitation. Current evidence shows that the benefits of giving thiamine for the treatment of WE and prevention of WKS are established by empiric clinical experience and various case reports. The limited evidence from the single RCT on the comparisons of various thiamine doses necessitates further validation and exploration in future clinical trials with more robust methodological designs. Rehabilitation and other pharmacotherapies for neurocognitive recovery of patients with established WKS are promising and warrant further studies.