Case of hypoactive delirium precipitated by thiamine deficiency

Abstract

Thiamine is an essential cofactor in the process of nucleic acid synthesis. Neuronal tissues are especially sensitive to thiamine deficiency, manifesting as Wernicke’s encephalopathy (WE). The typical triad of WE, encephalopathy, oculomotor dysfunction and gait ataxia, is only present in less than one-third of the cases. We present the case of a middle-aged man with hypoactive delirium due to presumed thiamine deficiency, who had a prolonged hospital course and a delayed diagnosis of the cause of altered mental status. The presentation of this disorder solely as a decreased level of consciousness is uncommon but has been reported in the literature. It is essential to recognise WE as a treatable condition that may manifest only as a hypoactive delirium. The delay in the diagnosis and treatment may lead to coma and death.

Background

Thiamine (vitamin B1) is an essential cofactor for numerous enzymes involved in carbohydrate metabolism, nucleic acid synthesis and fatty acid synthesis.¹ Neuronal tissue is especially sensitive to thiamine deficiency (TD), manifesting as Wernicke’s encephalopathy (WE), an acute neurological disease first described by Carl Wernicke in 1881 as the classic triad of confusion, gait ataxia and oculomotor disease.² In reality, less than 20% of patients with WE present with this classic triad.^{3 4} Patients usually present with only one symptom, acute encephalopathy,⁴ making WE a challenge to diagnose. Delirium can present as either hyperactive, hypoactive or mixed (hypoactive and hyperactive delirium). Hypoactive delirium tends to go unrecognised, leading to worse outcomes compared with hyperactive delirium.⁵ We present a case report of a patient with a prolonged hospital course complicated by hypoactive delirium with a delayed diagnosis of WE, and prompt reversal of symptoms with high dose intravenous thiamine supplementation.

Case presentation

A 59-year-old man with a history of type 2 diabetes mellitus was admitted from acute rehabilitation for an episode of fever, garbled speech and mild persistent tachycardia. He had altered mental status and was found to be only oriented to the person. There were no focal neurological deficits. He was discharged to inpatient rehabilitation 1 day prior to this admission after a prolonged hospitalisation of 3 weeks for multiple epidural abscesses causing thoracic and lumbar back pain. He also had methicillin-sensitive Staphylococcus aureus bacteremia. He required thoracic and lumbar laminectomies with epidural abscesses' evacuation, chest tube drainage for a right-sided empyema, and prolonged intravenous antibiotics. The recent hospitalisation was also complicated by hypernatraemia with a peak sodium level of 156 mmol/L (normal 135–148 mmol/L), which resolved with 5% dextrose. Patient’s oral intake remained poor. He was seen by nutrition and his diet was supplemented with Boost, but never requiring a nasogastric tube feeding or total parenteral nutrition. The main reason for inadequate oral intake was a fluctuating level of consciousness. Patient had prolonged hypoactive delirium without any additional apparent reversible cause. Social history was notable for the incarceration of over two decades with recent release. Before incarceration, the patient was drinking six alcoholic drinks per day for 9 years. Since incarceration, he reportedly abstained from alcohol.

During current admission, his course of intravenous cefazolin was continued. His fever did not recur. There was no clinical evidence of worsening of recent infection or a new focus of infection. However, his mental status continued to wax and wane, with persistent psychomotor retardation. Intermittently, he was oriented to person and place. He remained slow to respond with a depressed level of consciousness and disorganised speech. He was arousable to verbal commands. He fulfilled the criteria for delirium (hypoactive) based on the Confusion Assessment Method. The highest 4AT score was 11, which was consistent with possible delirium. His daughter stated that this was far from his baseline. He was an active and independent individual without dementia before this hospitalisation.

Investigations

A workup for infectious and metabolic abnormalities was initiated. Blood and urine cultures were negative. Basic metabolic panel and liver function tests were unremarkable, with blood glucose ranging from 126 to 344 mg/dL (normal range 68–110 mg/dL) controlled by insulin lispro and glargine during hospitalisation. Serum vitamin B12, folic acid, thyroid-stimulating hormone and ammonia were normal. Serum thiamine level, which came back after several days, was 117 nmol/L (normal range 78–185 nmol/L). CT head without contrast showed no acute intracranial abnormality. Chest X-ray and CT chest with contrast were negative for any significant effusion or septic emboli. Ejection fraction was normal, and there were no valvular vegetations on the transthoracic echocardiogram. MRI spine showed postsurgical improvement without any new abscesses or collections. MRI of the head with and without contrast did not show any abnormality. The lumbar puncture and electroencephalography were not performed due to the rapid resolution of symptoms after intravenous thiamine.

Differential diagnosis

At first, his delirium was attributed to infection and prolonged hospital stay. However, the infectious workup, as outlined above, was negative. His fever quickly resolved without any new intervention (his intravenous cefazolin was continued). There were no new infectious source and there was low suspicion for septic embolisation and stroke, given the normal CT head without contrast and MRI brain. There was also low suspicion for endocarditis, given the negative blood cultures and normal repeat echocardiogram results.

The patient initially had delirium following surgery, so hypoxic brain injury during the procedure was considered; however, peroperative report, the patient had never been hypoxic or hypotensive. Electrolyte abnormalities were an unlikely cause of his delirium as his mental status changes did not follow the onset of his hypernatraemia or improve with its resolution.

Folate deficiency, B12 deficiency, and thyroid disease were considered; however, serum folate, B12, and thyroid stimulating harmone (TSH) returned normal. Cefazolin neurotoxicity was also in the differential diagnosis, but unlikely as the patient’s altered mental status resolved without changing the antibiotic. The patient had poor nutrition during his hospitalisation, not eating sufficiently secondary to his delirium and thus received supplemental nutrition from Boost glucose control and monitoring feedings. It was not until day 29 of hospitalisation and all of the above causes for delirium were ruled out that TD was suspected. Serum thiamine level was normal, but unfortunately, this lab lacks sensitivity and specificity to diagnose WE.

Treatment

Due to the exclusion of other causes and clinical suspicion of TD, the patient was started on empiric intravenous thiamine 500 mg every 8 hours on day 29 of hospitalisation. Over the subsequent 2 days, he became progressively more awake, fully oriented to self and place, and started following all commands with appropriate responses. Clearly, he was more alert and interactive than he had been in weeks. His speech was fully intelligible for the first time since his surgery. Intravenous thiamine was continued for 5 days, and he was discharged on life-long oral thiamine 100 mg daily.

Outcome and follow-up

The patient was discharged to acute rehabilitation and remained alert and oriented to person, place and time. After a 7-week rehab stay and completion of intravenous antibiotics, he was discharged home with normal mental status. At 3 months, in the infectious disease clinic, he was without any cognitive abnormalities. Fortunately, even with the delay in diagnosis, he did not suffer any long-term mental status changes or memory impairment after receiving appropriate intravenous thiamine followed by lifelong oral replacement.

Discussion

Thiamine, also known as vitamin B1, is a water-soluble vitamin that plays multiple vital roles in the body, including energy metabolism, maintenance of and signal transduction in neural tissues, and biomolecules production and protection from oxidative damage.^{1 6} Because thiamine is a cofactor for pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase, enzymes involved in oxidative phosphorylation, TD leads to inadequate energy metabolism and lactic acid buildup, which can cause neuronal cell death.^{1 6} TD mostly affects the nervous and cardiovascular systems, manifesting as wet beriberi (high output heart failure), Wernicke-Korsakoff syndrome, and/or dry beriberi (polyneuritis).⁷ TD is most commonly seen in alcoholics; however, any sort of condition predisposing to poor diet, malabsorption or hypermetabolic state can cause TD. The most common risk factors for TD other than alcoholism include malignancy, gastrointestinal surgeries and diseases, hyperemesis gravidarum and starvation.^{3 6}

TD can lead to neurological manifestations, such as WE, a common disease in malnourished patients, with a prevalence of 12.5%.⁸ As common as it is, its diagnosis is missed in 75%–80% of cases.⁸ It can be challenging to diagnose for several reasons. The classic triad of symptoms (gait ataxia, nystagmus, and confusion) is present in only 10%–20% of patients, compared with mental status changes, which are seen in 82% of patients.^{3 4} It is incredibly difficult to diagnose TD in non-alcoholics, as it is much less common in this population and non-alcoholics more often have atypical presentations.³ Intravenous thiamine should be initiated as soon as WE is suspected because of the disease’s morbidity and because it is an inexpensive and well-tolerated treatment.³ For these reasons, we recommend clinicians maintain a high index of suspicion for this very treatable disease.

Our patient had the sole manifestation of hypoactive delirium with a history of incarceration, insufficient oral intake during prolonged hospitalisation, and a remote history of alcohol use disorder, which was not discovered until after the diagnosis. Before diagnosing hypoactive delirium precipitated by TD, the patient had been in a state of delirium for 3 weeks. Making a timely diagnosis of WE is essential, as it is a serious medical condition that, if left untreated, can progress to coma and death.^{3 8–10} After supplementation of high-dose intravenous thiamine for 2 days, our patient became fully oriented. He was able to speak and communicate clearly without any deficits. Typically, the global confusion resolves within a day, but there can be long-term memory impairment and learning.¹¹ Our patient, fortunately, did not have any known cognitive or neurological deficits on discharge. Due to absence of any other apparent immediately reversible cause of delirium and dramatic improvement after high dose thiamine, we made the presumptive diagnosis of WE manifesting as hypoactive delirium.

One of the important factors in the patient’s delayed diagnosis was his delirium manifesting with hypoactive symptoms of drowsiness, occasional slurred speech, and psychomotor retardation. Delirium can be divided into hyperactive delirium, hypoactive delirium and mixed hyperactive and hypoactive delirium. Hyperactive delirium manifests with agitation, increased motor activity and restlessness, while hypoactive delirium manifests with decreased activity, decreased quantity and slowing of speech, psychomotor retardation and listlessness.⁵ Hypoactive delirium is essential to identify and address because it is associated with more extended hospitalisation and increased mortality since these patients do not draw the attention of caregivers like patients with hyperactive delirium.⁵ A meta-analysis of adult Intensive care unit (ICU) patients found that hypoactive delirium has the highest incidence (11%) and prevalence (17%) of delirium subtypes.¹² As common as this disease is, the diagnosis is missed in over half of patients.¹³ Patients with TD may present with a depressed level of consciousness, but this presentation is uncommon.¹⁰ The blood thiamine level was normal in our patient. Similarly, WE has been reported in a patient with a normal blood thiamine level in a patient without a history of alcoholism.¹⁴ WE cannot be excluded based on a normal blood thiamine level, as it does not correlate with cerebral thiamine level.¹⁴ Moreover, it takes many days before the blood thiamine level results, as in our case, so it may not impact clinical decision-making.

WE manifesting solely as a hypoactive delirium is a unique presentation. There are other similar case reports of patients with WE with clinical descriptions concerning for hypoactive delirium, such as altered levels of consciousness, drowsiness or lethargy.^15–17 It is essential to recognise that WE can manifest as hypoactive delirium without cerebellar or ocular signs. WE presenting as hypoactive delirium may lead to a delay in diagnosis and treatment and poor patient outcomes. WE is a treatable cause of delirium; a high index of suspicion is needed to suspect the diagnosis and initiate early treatment.

Learning points.

• Wernicke’s encephalopathy (WE) can present as hypoactive delirium, which can be challenging to diagnose.

• The clinician should always keep thiamine deficiency in the differential diagnosis for acute encephalopathy in patients with risk factors for thiamine deficiency.

• Untreated, WE carries a bad prognosis. Patients should be promptly treated with high-dose intravenous thiamine whenever WE diagnosis is considered without relying on blood thiamine level.