When time is brain: a systematic review about Wernicke encephalopathy as a dramatic consequence of thiamin deficiency in hyperemesis gravidarum

Abstract Introduction and objective Nausea and vomiting affect up to 80% of all pregnancies, sometimes so severely that the condition of hyperemesis gravidarum (HG) is established. HG may in addition be a predisposing factor for Wernicke encephalopathy (WE), a severe and life-threatening condition due to vitamin B1 (thiamin) deficiency. If untreated, WE may progress to Korsakoff’s syndrome, an irreversible cognitive disorder. We reported a case that recently occurred at our clinic and performed a systematic review of the literature to investigate the clinical presentation, maternal and perinatal outcomes and treatment of WE in women with HG. Methods We performed a systematic review of case series and case reports searching the Medline database on Pubmed from inception until December 2021. We used as search terms (Wernicke encephalopathy) OR (Wernicke-Korsakoff syndrome) AND (hyperemesis gravidarum) AND (pregnancy) AND (thiamin deficiency). Articles were considered eligible for inclusion in our review if they described at least one case of WE due to thiamin deficiency in relation to HG. An overall of 82 cases of WE due to HG in pregnancy from 66 manuscripts, including our own, were selected. Results The maternal mean age was 26.38 ± 5.23 years, while mean gestational week at hospitalization was 14.57 ± 4.12 after a mean of 6.6 ± 3.14 weeks of vomiting duration. WE manifestation occurred at a mean gestational age of 16.54 ± 3.06 weeks. Regarding clinical presentation, ocular signs and symptoms were reported by 77/82 (93.9%) women, 61/82 (74.4%) presented with ataxia and 63/82 (76.8%) with confusion. Dysarthria affected 15/82 women (18,3%), while muscular weakness was present in 36/82 (43.9%) and impaired reflexes in 42/82 (51.2%). Memory impairment involved 25/82 (30.5%) of the study population. Almost all cases reported a thiamin administration treatment, however data regarding the clinical course of the neurological condition and the perinatal outcomes were often missing and showed a great heterogeneity when reported. Conclusion WE is a challenging diagnosis, as its clinical presentation is nonspecific. A high clinical suspicion and the awareness of its possible predisposing conditions such as HG may help clinicians to get a prompt diagnosis and starting treatment, which are vital to prevent possible life-impairing neurological sequelae.


Introduction
Up to 80% of all pregnancies are affected by nausea and vomiting, particularly during the first trimester of pregnancy.In up to 3% of pregnancies, these disorders are severe, establishing the condition of hyperemesis gravidarum (HG) [1].Women with HG are often dehydrated and suffer from important weight loss, malnutrition, electrolyte imbalance and vitamin deficiency [1].
Primary thiamin deficiency may be caused by inadequate intake and typically affects populations whose diet is primarily based on polished rice [2,3].However, it may arise as well from conditions associated with increased thiamin requirements, such as pregnancy, malnutrition, alcoholism, gastrointestinal surgical procedures, cancer, and thyrotoxicosis [4][5][6][7][8][9].In particular, HG is associated with inadequate intake and malabsorption caused by nausea and vomiting, in addition to increased fetal demand and the hypermetabolic state of pregnancy [10].
Wernicke encephalopathy (WE) is a severe and life-threatening condition arising from vitamin B1 (thiamin) deficiency, as thiamin is a coenzyme involved in various biochemical pathways in the nervous system [3].A depletion of thiamin stores occurs within 2 to 3 weeks without supplementation [5,8].WE may initially manifest with a wide range of nonspecific symptoms, such as asthenia, memory loss, sleep disorders and emotional lability [3].Ataxia, oculomotor deficiencies and mental status alterations represent the classical triad of clinical symptoms, however only 16-20% of patients affected manifest them at initial evaluation [11].Cases of thiamin deficiency in patients who did not develop typical signs of WE have also been reported [7,12].
The use of MRI may improve diagnostic accuracy, as it typically shows with high specificity T2w and FLAIR (Fluid Attenuation Inversion Recovery) symmetrical hyperintensity in the paraventricular regions of the thalamus, hypothalamus, mammillary bodies, floor of the fourth ventricle and periaqueductal region [13][14][15][16].These are the areas where thiamin levels most affect the maintenance of cellular osmotic gradients [17].
If untreated, WE can progress to Korsakoff's syndrome, an irreversible cognitive disorder characterized by anterograde amnesia, confabulations and executive impairment [11].
In this case report and systematic review of case reports and case series of the literature, we aimed to investigate the clinical presentation, maternal and perinatal outcomes and treatment of WE due to thiamin deficit in women with hyperemesis gravidarum.

Case report
We report the case of a 27-year-old nullipara who first came to medical attention at 8 weeks of gestational age reporting a 2-week history of persistent nausea and vomiting.She was given oral antiemetic therapy and was discharged.She presented again to our emergency room at 13 weeks with intense asthenia, nausea and general mental confusion and was thus immediately admitted to our ward.
Obstetrical examination was insignificant and fetal ultrasound demonstrated normal fetal growth and anatomy for gestational age.As her symptomatology appeared to be worsening, a neurological consultation was performed.The patient presented with intense asthenia, nystagmus, ataxia and altered mental state.These characteristics, together with the anamnestic data of hyperemesis gravidarum, were suggestive of a severe thiamin deficiency.Magnetic resonance imaging (MRI) scans showed FLAIR sequence hyperintensity in the anterior portion of the floor of the third ventricle, in dorsomedial portions of the thalami and in the periaqueductal area.Since these lesions were compatible with Wernicke's encephalopathy, B1 parenteral supplementation (500 mg/per day) together with physiotherapy were immediately started.
Hospitalization was complicated by the development of gestational hypertension and hypercalcemia due to hyperparathyroidism for which the patient underwent a right parathyroidectomy, with a diagnose of atypical parathyroid adenoma at the histopathological examination.As she presented with a persistent state of malnutrition, parenteral nutrition was started and the patient was transferred to a rehabilitation center to continue physiotherapy.
A few days later the patient was hospitalized again for hyperpyrexia at 23 weeks of gestational age.Blood culture resulted positive for Staphylococcus Aureus MRSA and intravenous antibiotics was started.A Doppler ultrasound performed at the level of the midline catheter used for parenteral nutrition revealed a complete occlusion of the basilic vein for a thrombus extending to axillary and subclavian veins.Thanks to antibiotics and anticoagulant therapy, the septic thrombophlebitis progressively improved.At 33 weeks of gestational age, the patient was hospitalized again in the Obstetric department for threatened preterm delivery.An elective cesarean section was finally performed at 37 weeks of gestational age and a healthy female baby weighing 3070 g was born.At one-month post-partum follow-up, the patient could walk unassisted and her neurological state appeared improved.Eighteen months after delivery, her walking abilities were normal, but she still presented with nystagmus, weak reflexes and long and short-term memory impairment.

Materials and methods
This is a systematic review including case series and case reports of the current literature, in addition to the above-reported case.Regarding the case report we presented, the woman gave informed consent and care has been taken in preserving her anonymity.As to the systematic review, we searched the Medline database on Pubmed from inception until December 2021.We used as search terms (Wernicke encephalopathy) OR (Wernicke-Korsakoff syndrome) AND (hyperemesis gravidarum) AND (pregnancy) AND (thiamin deficiency).We restricted our research to human cases and the English language.Articles were considered eligible for inclusion in our review if they described at least one case of Wernicke encephalopathy due to thiamin deficiency in relation to hyperemesis gravidarum.We excluded one article reporting a case of WE not related to hyperemesis gravidarum in pregnancy.The first author was involved in the selection process according to the aforementioned criteria.
For each case, we extracted the following data: year of publication, maternal age (years), gestational age at WE diagnosis (weeks), HG duration at WE diagnosis (weeks), vomiting duration (weeks), weight loss (kg), WE symptoms reported (ocular signs and symptoms, ataxia, confusion, presence of full triad, dysarthria, muscular weakness, impaired reflexes, impaired memory), fetal outcome, birthweight, treatment regimen applied, thiamin dose, timing and neurological condition at follow up (months).
We analyzed the extracted data with the statistical program SPSS (version 26.0).Means, standard deviations and percentages were calculated using reported data points.Any data points not reported in case reports are stated in the tables as NP (not present).There was no funding source involved in this project.

Results
Initially, 67 manuscripts were identified, including our own.After excluding one paper as it was not related to hyperemesis gravidarum in pregnancy, an overall 82 cases of WE due to HG in pregnancy from 66 manuscripts were included.Three manuscripts described 2 cases [18][19][20], three described 3 cases [21][22][23], one described 4 cases [24] and one described 5 cases [25].One manuscript described a case of WE occurring after a termination of pregnancy [26] and one reported a case taking place after a spontaneous abortion [27].
Patients' demographic is presented in Table 1.The maternal mean age was 26.38 ± 5.23 years.Mean gestational week at hospitalization was 14.57 ± 4.12 and women reported a mean of 6.6 ± 3.14 weeks of vomiting duration.Women had lost a mean of 12.2 ± 5. 64  As listed in Table 3, there were 42 deliveries, 22 spontaneous abortions and 2 intrauterine fetal deaths (in the case presented by Hillbom [42], the baby had Down Syndrome).Five women opted for termination of pregnancy, 23 women had term deliveries, while 7 deliveries were preterm.The mean birthweight was 2812 g ± 562g.
All cases but two [29,67] reported vitamin administration and the mean daily thiamin dose was 680 g/per day (±609 g).The clinical course of the neurological condition was not always described and showed great heterogeneity when reported.The description of follow-up after discharge varied greatly and the timing of follow-up was extremely heterogeneous as well.Women presented for follow-up after a mean of 7.35 ± 5.22 months.In many cases resolution or improvement of the previous neurological condition was reported, but sometimes women suffered from residual impairment.In particular, 45/82 (54.9%) women did not manifest a complete resolution.Two cases of maternal death have been reported as well [29,67]; interestingly, in those cases thiamin had not been administered (see Table 3 for further details).

Discussion
Wernicke Encephalopathy (WE) is a neurological disorder caused by thiamin (vitamin B1) deficiency, commonly associated with alcoholism.However, it has been described in other medical conditions as well, such as hyperemesis gravidarum, cancer, bariatric surgery, hunger strike, soft drink diet in children, depression, Crohn's disease, schizophrenia, anorexia nervosa, ulcerative colitis and accidental thiamin deficient infant formula [82].Thiamin deficiency can be either caused by a diminished intake or by an increased demand and the condition determined by hyperemesis gravidarum in pregnancy involves them both.
Our findings showed that the maternal mean age was 26 years.Women were hospitalized at 14 weeks of mean gestational age after a mean of 6 weeks of vomiting.At the onset of WE women had lost a mean of 12 kg and were at 16 weeks of mean gestational age.
The classical triad of WE presentation is composed of altered mental status, ocular signs and ataxia, but it is described as significantly more frequent in alcoholics rather than in non-alcoholics [83].Altered mental status varies greatly, presenting as confusion, delirium, problems in alertness and sometimes even coma.Ocular signs mainly consist in nystagmus, ophthalmoplegia and gaze palsy.Blurred sight, diplopia and visual loss are often reported as well.The patient's history and physical examination are central, as WE diagnosis is mainly clinical.MRI is a valid tool to confirm the diagnosis as some typical lesions are characteristic of WE, however the absence of abnormalities at MRI imaging does not exclude this diagnosis due to its relatively low sensitivity [84].MRI typically shows T2, FLAIR and DWI hyperintensity in the paraventricular region of the thalamus bilaterally, hypothalamus, periaqueductal region, mammillary bodies and floor of the fourth ventricle.Other locations less typically involved at MRI include putamen, caudate, splenium of the corpus callosum, dorsal medulla, pons, cranial nerve nucleus, substantia nigra, red nucleus and cerebellar vermis among others [13].Biochemical diagnosis is often unavailable even in hospital settings, making thiamin administration the best diagnostic test [14].
Promptly administration of thiamin can prevent a rapid exacerbation of neurological symptoms and can reduce the risk of residual neurologic deficit, as the risk of irreversible progression to Korsakoff syndrome (KS) is consistent [3].
KS is a disproportionate impairment of memory consequent to a thiamin deficit which usually follows WE [85].It is characterized by a typical loss of working memory with relative preservation of reference memory.As a consequence, patients with KS suffer from severe anterograde amnesia and disorientation over time.Confabulation typically accompanies the syndrome, as well as emotional changes [57,85].Thiamin administration may prevent the progression of WE to KS, but its impact on KS when established is little [3,57].
A high level of suspicion for WE must be maintained in all clinical conditions that could lead to thiamin deficiency [83], therefore thiamin supplementation should be given to all pregnant women admitted with prolonged vomiting [86].Oral therapy is not sufficient in patients at risk of developing WE and prompt parenteral thiamin administration is necessary [87].As glucose infusion precipitates WE, thiamin administration before glucose is essential in case of thiamin deficiency [3,83,86].Therefore, the Royal College of Obstetricians and Gynecologists suggests that, for each day of intravenous dextrose administration, high doses (e.g. 100 mg) of parenteral thiamin should be given to prevent WE [86].
Concerning WE treatment, however, at present there is insufficient evidence to support conclusions about dosage, duration of treatment and number of daily doses.The European Federation of Neurological Societies recommends a dosage of 200 mg of parenteral thiamin 3 times daily until resolution of symptoms [83], while the Royal College of Physicians suggests a dosage of 500 mg of parenteral thiamin 3 times daily [87].Intravenous administration is preferred to the intramuscular route [83].
In the cases we analyzed, the mean thiamin starting dose was 680 g/per day, in agreement with the before-mentioned guidelines.However, cases reported in our review showed great heterogeneity in the administered dosage, which may have had an impact on the maternal outcomes.
Interestingly, despite the fact that long-lasting impairment may deeply affect the mothers, only a little is reported about WE impact on fetal development.Masselli et al. [88] described the clinical impact of

Limitations
We acknowledge some limitations regarding data extraction.Several case reports were lacking in clinical details about certain variables (e.g.thiamin dosage), while other variables (such as for example gestational age at HG presentation and vomiting duration) had often had to be inferred from the case description.Another limitation is the great heterogeneity in maternal outcomes and timing at follow-up, in addition these data were not always reported.Finally, pregnancy outcome was not always described and only a few manuscripts reported gestational age at birth, birthweight and newborn general conditions.

Conclusions
Because of its nonspecific clinical presentation and infrequent occurrence, WE diagnosis is challenging and relatively easily missed.Being aware of its possible predisposing conditions and maintaining a high clinical suspicion are the best tools for an early diagnosis, which is vital to prevent neurological sequelae.As its bond with hyperemesis gravidarum has been well established, clinicians must consider and promptly treat WE whenever facing a woman reporting severe vomiting and inability to alimentation, as two to three weeks of unbalanced nutrition can lead to thiamin depletion and to the onset of its life-threatening consequences.

Table 2 .
Signs, symptoms, treatment chosen and starting thiamin daily dosage used.

Table 3 .
Maternal and pregnancy outcomes.maternalWE on the fetus.Initially, the fetal brain MRI performed to confirm maternal WE diagnosis showed a signal alteration in periventricular areas.Thiamin administration, however, led to the resolution of MRI anomalies both in the mother and in the fetus.Post-natal development 6 months after birth was normal.In order to better understand maternal WE consequences, it would be relevant to follow up children who suffered from thiamin deficiency during fetal life to early detect any neurological and developmental impairment.