Neglected woman with hyperemesis gravidarum leading to Wernicke encephalopathy

Abstract

A teenage primigravida at 13 weeks of gestation presented with hyperemesis gravidarum of 45 days and a history of giddiness and inability to walk due to involuntary movements of limbs and eyes since 2 days. She was treated with intravenous fluids, thiamine and antiemetics. MRI brain showed hyperintensities in bilateral dorsomedial thalami, periaqueductal grey matter in T2-weighted and FLAIR images. A diagnosis of Wernicke encephalopathy was made and she was managed in intensive care unit and received injection thiamine as per the guidelines and her weakness and ataxia improved over 3 weeks and she was discharged at 17 weeks of pregnancy in good state of health.

Background

Wernicke encephalopathy is a serious neurologic manifestation of thiamine (vitamin B₁) deficiency, and is most common in alcoholics. The classical triad of Wernicke encephalopathy is ataxia, confusion and ophthalmoplaegia. Wernicke encephalopathy in obstetric patients with persistent nausea and vomiting remains an under-recognised condition, and hyperemesis gravidarum has been identified as a predisposing factor. The diagnosis of Wernicke encephalopathy in the setting of hyperemesis gravidarum can be confirmed by MRI, the treatment of which is simple and effective. If not recognised and treated, it can result in maternal mortality, which accounts to 10%–20%.¹ Prompt supplementation of thiamine in a woman with prolonged vomiting in pregnancy is essential to prevent the morbidity and mortality associated with Wernicke encephalopathy.

Case presentation

A teenage primigravida at 13 weeks of gestation presented with complaints of prolonged vomiting of 45 days duration and with a history of inability to walk associated with involuntary movements of limbs and eyes since 2 days. On examination, she was found to be confused and disoriented but conscious. Her pulse was 124 beats/min regular and good volume, blood pressure was 120/70 mm Hg and her oxygen saturation was 98% on pulse oximetry. Her random blood sugar was 125 mg/dL and urine ketones were negative.

Central Nervous System (CNS) examination showed bilateral pupils to be equal and reactive to light, extraocular movements were normal with the presence of vertical nystagmus. Motor examination revealed power of 3/5 in all four limbs, and gait could not be assessed as she was unable to stand up and walk and there was presence of action tremor. Finger–nose test and dysdiadokokinesia were found to be positive and no other neurological deficits noted. Abdominal examination revealed 14 weeks size uterus and there was no organomegaly. An obstetrical abdominal ultrasound showed single live intrauterine gestation of 13⁺⁴ weeks. A clinical diagnosis of Wernicke encephalopathy was made and she was admitted in intensive care unit (ICU) and was managed with intravenous fluids and injection thiamine 100 mg every 8th hourly along with antiemetics and intravenous multivitamins supplementation.

Laboratory investigations showed normal electrolyte levels with Na⁺ −135 meq/L and K⁺ −3.35 meq/L renal function tests were found to be normal and her liver function tests revealed elevated Alanine aminotransferase (ALT) and other parameters were found to be normal (table 1). Neurology opinion was obtained and MRI of the brain was performed.

Table 1.

Serum electrolytes along with renal and liver function tests were monitored

Date	20 January 2020	21 January 2020	24 January 2020	28 January 2020
Random blood sugar	78 mg/dL	68 mg/dL	72 mg/dL	75 mg/dL
Urea	6 mg/dL	6 mg/dL	12 mg/dL	9 mg/dL
Creatinine	0.20 mg/dL	0.17 mg/dL	0.32 mg/dL	0.28 mg/dL
Na+/K+/Ca+2	135/3.35	138/3.29	136/3.97	134/3.92/8.3
Total bilirubin	0.89	0.84
Albumin	3.5 g/dL	2.5 g/dL		2.5 g/dL
Serum total protein	6.5 g/dL	4.8 g/dL		5.2 g/dL
AST/ALT	39/111	38/91		43/59

ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase.

Investigations

Her antenatal screening tests for HIV, HbsAg, Hepatitis 'C' Virus (HCV) and Venereal Disease Research Laboratory (test for Syphilis) (VDRL) were negative.

Complete haemogram and thyroid function tests were done and parameters were within normal limits.

Ophthalmic examination was done and found to have vertical pendular nystagmus and fundus examination was normal with no evidence of papilloedema.

MRI was done 2 days after ICU admission showed hyperintensities in dorsomedial thalami, medial thalamus, mammillary bodies and periaqueductal grey matter (figures 1–4).

Figure 1.

Axial FLAIR sequence of the brain at the level of basal ganglia reveals symmetrical hyperintensity in dorsomedial thalami.

Figure 2.

Coronal T2-weighted sequence of brain reveals symmetrical hyperintensity in medial thalami.

Figure 3.

Axial FLAIR sequence of the brain at the level of the midbrain also reveals symmetrical hyperintensity in mammillary bodies.

Figure 4.

Axial FLAIR sequence of the brain at the level of midbrain depicts hyperintensity in the periaqueductal grey matter.

Treatment

She received intravenous fluids along with antiemetics and initially she was started on injection thiamine 100 mg intravenously every 8th hourly for 2 days. As symptomatically no improvement was noted, the dose of thiamine was increased to 200 mg every 8th hourly along with intravenous multivitamin supplementation. With this treatment vomiting subsided in 3 days but ataxia persisted for 3 weeks and motor examination showed improvement in the power of both upper and lower limbs and she was able to walk with support after 3 weeks. Intravenous thiamine supplementation was continued until discharge from hospital and at discharge she was advised to continue oral thiamine supplementation along with tablet doxylamine hydrochloride. Nutritional advice was given to consume frequent small amounts with adequate water.

Outcome and follow-up

She improved after 3 weeks of intensive treatment and pregnancy continued and an obstetric Ultra Sono Gram (USG) repeated a day prior to discharge showed a live fetus corresponding to gestational age with no anamolies. Subsequent follow-up after a month showed normal weight gain and fetal growth and her general condition was normal. There was no history of ataxia or vomiting at home during this period and she was able to consume diet in small quantities and carryout her day today work.

She was admitted again on 23 July 2020 and underwent induction of labour for oligohydramnios and delivered normally 2.5 kg male baby with an APGAR (Score to describe baby status at birth: Appearence, Pulse, Grimace, Activity, Respiration) score of 8/10 at 1 min.

Discussion

Wernicke encephalopathy was first described in 1881 by a German neuropsychiatrist Carl Wernicke in an alcoholic with sulfuric acid poisoning with persistent vomiting who presented with sudden onset of mental confusion, weakness or paralysis of eye movements and ataxia. Imaging in these subjects showed the presence of punctate haemorrhages in tissue lining the third ventricle, in the mammillary bodies and in the retinae and it was termed as ‘encephalitis hemorrhagica superior’.² Vitamin deficiency as the causative factor for Wernicke encephalopathy was first suspected in 1935 by Strauss,³ and was confirmed when the clinicopathological findings were reproduced on consumption of diet deficient with thiamine which was administered in humans and animals in 1942.⁴ Thiamine, also known as vitamin B₁, is an important cofactor for enzymes pyruvate dehydrogenase, transketolase, 2-oxo-glutarate dehydrogenase and many other enzymes. It is crucial for the generation of glucose in the central nervous system as it acts as a cofactor for these enzymes. Thiamine requirement is increased in pregnancy due to the presence of rapidly growing fetus.⁵ The pathophysiology of Wernicke encephalopathy mainly revolves around a single-vitamin deficiency. Thiamine, as it is an important cofactor for enzymes involved in glycolysis, TCA cycle, pentose phosphate single-vitamin deficiency pathway, deficiency leads to depletion of ATP, Nicotinamide Adenine Dinucleotide (NADPH) and increase in lactic acid and generation of free radicals resulting in cell damage and intracellular and extracellular oedema in the central nervous system as it is necessary to maintain the osmotic gradient across the cell membrane.⁶ This leads to glial cell proliferation, neuronal demyelination and eventually cellular degeneration.

Though the clinical features are complex, Wernicke encephalopathy is associated with classical triad of ophthalmoplaegia, confusion and cerebellar dysfunction, which manifests as ataxia. Most common occular sign is the presence of horizontal nystagmus. Remission of ophthalmoplaegia occurs in 1–6 hours, however, residual horizontal nystagmus is noted in 60%, whereas recovery from ataxia and confusion occurs after a few days to weeks, sometimes is incomplete resulting in morbidity.⁷

Wernicke encephalopathy can lead to permanent neurological lesions and is fatal in 10%–20% cases.¹ A case series of five gravid women with Wernicke encephalopathy due to hyperemesis reported that following 14–40 days of vomiting, they developed neurological symptoms. With an average 1-week delay in diagnosis resulted in increased morbidity due to delay in initiation of treatment with thiamine supplementation.⁸ Miscarriage, preterm birth and intrauterine growth retardation and fetal loss rate (excluding termination of pregnancy) with Wernicke encephalopathy was reported to be 37%.⁹ Wernicke encephalopathy is catastrophic in onset though rare in incidence but it was associated with increased morbidity and mortality due to delay in diagnosis and initiation of treatment. Prevention of development of Wernicke encephalopathy in women with hyperemesis is crucial and women should be promptly treated with thiamine supplementation

Diagnosis of Wernicke encephalopathy is mainly clinical with high suspicion as biochemical tests to detect deficiency of vitamin B₁ are time consuming and also not available in most of the healthcare settings. Instead a presumptive diagnosis can be made if the patient responds on thiamine supplementation after excluding the other causes. Thiamine is said to be non-toxic in high levels and this approach carries less risk, timely supplementation reduces mortality and morbidity. However, the biochemical criteria for detection of thiamine deficiency consist of low levels of erythrocyte transketolase activity and high thiamine pyrophosphate effect.¹⁰ MRI can be done to confirm Wernicke encephalopathy with sensitivity and specificity of 53% and 93%, respectively.⁷ MRI changes are predominantly noted in the paraventricular region of thalamus, hypothalamus, mammillary bodies, periaqeductal region, floor of fourth ventricle and the cerebellum which shows increase in the T2 signals bilaterally. The cells are dependent on oxidative metabolism and are sensitive to thiamine levels.⁷ Changes occur in imaging following 2–3 weeks after depletion,¹¹ which emphasises the need to treat hyperemesis gravidarum patient with prompt thiamine supplementation.

There is insufficient evidence from the randomised controlled trials regarding the optimum dose, frequency, route of administration and duration of thiamine administration in the treatment of Wernicke encephalopathy. According to case report in 2007 by Sechi et al,⁷ it was noted that in suspected case of Wernicke encephalopathy, administration of thiamine in doses of 500 mg three times per day for 2–3 days was given. If patient improved symptomatically, the dose was changed to 250 mg three times a day for 3–5 days followed by oral thiamine supplementation which was continued for several months. It is also reported that dose of less than 250 mg/day was found to be ineffective and the dose of thiamine as recommended by the European Federation of Neurological Societies is 200 mg three times per day to be given intravenously.¹² This woman could show improvement only after increasing the dose to 200 mg intravenous 8th hourly. Though the effectiveness of thiamine supplementation in treating Wernicke encephalopathy has been proved in many case reports and case series, there is no meta-analysis or randomised trails available regarding the ideal dose for treating Wernicke encephalopathy. Hence, it is generally accepted that high clinical suspicion in setting of hyperemesis gravidarum with initiation of prompt thiamine supplementation at the earliest is the key to eventual neurological recovery, reducing the morbidity and mortality associated with it.

Learning points.

• Hyperemesis gravidarum if neglected leads to Wernicke encephalopathy.

• The dose of thiamine has to be appropriate to obtain neurological recovery and reduce morbidity and mortality associated with Wernicke encephalopathy.

• Prolonged hospitalisation is necessary to manage a woman with Wernicke encephalopathy.