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A 56-year-old woman presents to the hospital complaining of generalized weakness that has been progressing for the past month. Her initial symptoms involved numbness and weakness in her legs and lower body. She explains that over the course of the next few days, the loss of strength and sensation progressed to involve her hands and neck.

The patient's medical history includes type 2 diabetes mellitus and high blood pressure. Regarding her past medical history, she notes that about a year ago, she had gallstones that provoked an episode of necrotizing pancreatitis. At that time, she says, she was also suffering from severe protein calorie malnutrition. This was treated with total parenteral nutrition (TPN) until about 6 months ago, she notes, when she was able to return to a normal diet.

The patient is admitted to the hospital, where a lumbar puncture identifies albuminocytologic dissociation in the cerebrospinal fluid (CSF), consistent with a presumptive diagnosis of Guillain-Barré syndrome (GBS), or acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Clinicians also perform a brain magnetic resonance imaging scan that shows small vessel ischemic changes. She is empirically treated for five days with intravenous immunoglobulin, but has no clinical response. Shortly thereafter, the patient develops worsening pancytopenia and encephalopathy, and is transferred to a specialist center.

At the specialist center

The patient arrives in a hypotensive state (blood pressure 64/48 mm Hg). She does not respond to verbal questioning, and has a minimal response to painful stimuli; her Glasgow Coma Scale score is 6. Examination reveals pronounced generalized edema and flaccid paralysis of all four extremities.

Lab tests show that the patient is malnourished and in a septic state.

Findings include:

• Calcium: 6.7 mg/dL
• Hemoglobin: 9.4 g/dL
• White cell count: 2.1 X 109/L
• Phosphorus: 1.1 mg/dL
• Creatinine: <0.2 mg/dL
• Albumin: <1.5 gm/dL
• Lactate: 4 mmol/L

Another provisional diagnosis

She is noted to be suffering from malnutrition, based on a nutritional risk screening (NRS-2002) score of 5 points and a malnutrition universal screening score of 5. She is intubated to protect her airway and resuscitated with intravenous fluids, and several hours later, requires an intravenous infusion of norepinephrine. To prevent sepsis, she is also started on meropenem, vancomycin, and anidulafungin.

The patient is provisionally diagnosed with AIDP complicated by septic shock, and is started on empirical treatment with high-dose intravenous thiamine (500 mg every 8 hours).

There is no evidence of seizure activity on the electroencephalogram, but it does show diffuse slow waves consistent with severe metabolic encephalopathy.

Day 3

The patient has received four doses of high-dose thiamine therapy which has restored her serum thiamine level to normal (104 nmol/L; reference range, 70-180 nmol/L).

An magnetic resonance imaging scan of the brain finds hyperintensity of the bilateral medial thalamus on T2-weighted and fluid-attenuated inversion recovery axial images. Clinicians consider that the findings suggest Wernicke's encephalopathy.

Day 4

The patient's mental status is significantly improved and she can respond correctly to simple commands. Based on her restored hemodynamic stability and negative blood and urine cultures, clinicians discontinue norepinephrine and antimicrobial treatment.

Days 5-7

The patient is successfully extubated.

Electromyography (EMG) shows severe sensorimotor polyneuropathy, and her cognition and weakness are gradually improving.

Day 14

The patient is transferred out of the intensive care unit. Thiamine supplementation is continued throughout her hospital stay.

Discussion

Clinicians reporting this of thiamine deficiency resulting in beriberi¹ note that the patient's initial symptoms of encephalopathy, ascending lower extremity weakness, and cerebrospinal fluid (CSF) findings led to an initial provisional diagnosis of Guillain-Barré syndrome (GBS).

This resulted in the patient's receiving initial treatment with intravenous immunoglobulin rather than thiamine supplementation, which ultimately resolved the symptoms rapidly, authors noted. This rapid clinical improvement following thiamine supplementation in thiamine deficiency-associated neuropathy^2,3 is an important contrast to IVIG therapy in the treatment of GBS, which may take 2-4 weeks to show an effect.

Thiamine (vitamin B1) is a water-soluble vitamin that has a vital role in cell metabolism, specifically in the tricarboxylic acid cycle (Krebs's cycle),⁴ case authors write. While recommended daily thiamine intake for an average adult is 1–1.5 mg⁵, the human body can only store an average amount of 25–30 mg at any one time.⁶ This means that thiamine depletion can occur within 14 days of inadequate thiamine intake or malabsorption.⁷

In addition to the four causes of thiamine deficiency listed in Case Challenge 2, other contributing factors⁸ include:

• Anorexia nervosa
• Dieting
• Bariatric surgery-related malabsorption
• Diarrhea
• Celiac disease
• Dysentery
• Pregnancy
• Dialysis

Case authors suggest that the peripheral and ascending neuropathy seen in both GBS and thiamine deficiency can make clinical differentiation quite difficult.⁹ In addition to causing sensorimotor polyneuropathy, they write, both GBS and dry beriberi can lead to albuminocytologic dissociation -- an increase in CSF protein (>0.55 g/L) without an increase in white blood cells -- within the CSF. They explain that axonal injury in severe dry beriberi is what causes symptoms mimicking the ascending motor paralysis usually seen in GBS.^10,11

Thiamine deficiency leads to beriberi, which has both dry and wet manifestations. Dry beriberi is characterized by varying degrees of neuropathy; it can be associated with Wernicke's encephalopathy (which can also result from chronic alcohol abuse¹² and Korsakoff syndrome).

While not seen in this patient's case, classic presentation of Wernicke's encephalopathy involves a triad of altered mental status (confusion and mild memory impairment), ataxia, and ocular symptoms (ophthalmoplegia or nystagmus). Without treatment, Wernicke's encephalopathy can lead to irreversible cognitive impairment and can be fatal.

Although Wernicke's encephalopathy is a clinical diagnosis, magnetic resonance imaging and serum thiamine levels (not assessed on presentation in this case) may assist with confirmation of diagnosis in some cases, clinicians note.

Wet beriberi is marked by cardiomyopathy and cardiomegaly, with presenting symptoms of heart failure, such as dyspnea and peripheral edema. In a fulminant form of wet beriberi known as Shoshin beriberi, patients develop cardiogenic shock, lactic acidosis, and if left untreated, multi-organ failure.

Chronic inflammatory demyelinating polyneuropathy:

• Includes a spectrum of acquired inflammatory sensory and motor polyneuropathies with relapsing and remitting clinical features ^13,14
• Typically involves more motor than sensory deficits
• Can involve cranial and bulbar nerves in 10–20% of cases
• Usually includes evidence of a viral or bacterial pathogen to explain an inflammatory response [as with AIDP]

Due to the underlying severe protein-calorie malnutrition and duration of critical illness in this patient, clinicians also considered critical illness myopathy and critical illness polyneuropathy in the differential diagnosis. Both disorders share the risk factor of sepsis, and can be complicated by encephalopathy and delirium¹⁵, although their EMG findings differ.^16,17

Citing the many factors that can lead to thiamine deficiency, case authors opine that prevalence of beriberi is likely to be greater than previously reported. It is important that physicians consider the possibility of thiamine deficiency in patients with a history of alcohol abuse, severe protein-calorie malnutrition, bariatric surgery, dependence on total parenteral nutrition, or any disease state complicated by malabsorption and increased caloric requirements.^18-20

They conclude that ²¹ resulting in beriberi should be considered in the differential for any patient presenting with neuropathy, weakness, cardiomyopathy, or autonomic instability when in the appropriate clinical context.

References

1. Shible AA, et al: Dry Beriberi Due to Thiamine Deficiency Associated with Peripheral Neuropathy and Wernicke's Encephalopathy Mimicking Guillain-Barré syndrome: A Case Report and Review of the Literature. Am J Case Rep, 2019; 20: 330-334

2. Hughes RA, et al: Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev, 2014; 19(9): CD002063

3. Meurin P: [Shoshin beriberi. A rapidly curable hemodynamic disaster]. Presse Med, 1996; 25(24): 1115–18

4. Ba A: Metabolic and structural role of thiamine in nervous tissues. Cell Mol Neurobiol, 2008; 28(7): 923–31

5. Sriram K, et al: Thiamine in nutrition therapy. Nutr Clin Pract, 2012; 27(1): 41–50

6. van Snippenburg W, et al: Thiamine levels during intensive insulin therapy in critically ill patients. J Intensive Care Med, 2017; 32(9): 559–64

7. Baynes JW, Dominiczak MH: Medical biochemistry. 2nd ed. Philadelphia, Elsevier Mosby, 2005

8. World Health Organization. Office of the United Nations High Commissioner for Refugees. Thiamine deficiency and its prevention and control in major emergencies. Geneva: World Health Organization, 1999 (Micronutrient series)

9. Hamel J, Logigian EL: Acute nutritional axonal neuropathy. Muscle Nerve, 2018; 57(1): 33–39

10. Nardone R, et al: Thiamine deficiency induced neurochemical, neuroanatomical, and neuropsychological alterations: A reappraisal. Scientific World Journal, 2013; 2013: 309143

11. Daroff RB, et al: Bradley's neurology in clinical practice. Seventh edition. London, New York, Elsevier, 2016

12. Hughes RA, et al: Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev, 2014; 19(9): CD002063

13. Meurin P: [Shoshin beriberi. A rapidly curable hemodynamic disaster]. Presse Med, 1996; 25(24): 1115–18

14. Khan J, et al: Early development of critical illness myopathy and neuropathy in patients with severe sepsis. Neurology, 2006 67(8): 1421–25

15. Lacomis D: Electrophysiology of neuromuscular disorders in critical illness. Muscle Nerve, 2013; 47(3): 452–63

16. Bolton CF: Neuromuscular manifestations of critical illness. Muscle Nerve, 2005; 32(2): 140–63

17. Koike H, et al: Postgastrectomy polyneuropathy with thiamine deficiency. J Neurol Neurosurg Psychiatry, 2001; 71(3): 357–62

18. Hahn JS, et al: Wernicke encephalopathy and beriberi during total parenteral nutrition attributable to multivitamin infusion shortage. Pediatrics, 1998; 101(1): E10

19. Zak J 3rd, et al: Dry beriberi: An unusual complication of prolonged parenteral nutrition. J Parenter Enteral Nutr, 1991; 15(2):200–1

20. Logue J, et al Vitamin B1 deficiency. BMJ Best Practice. Last updated Sept 2017

21. Thiamin Fact Sheet for Health Professionals National Institutes of Health Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Thiamin-HealthProfessional/

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