CONTENTS

• Rapid Reference 🚀
• Pathophysiology
• Signs & Symptoms
• Risk factors
• Epidemiology
• Laboratory studies
• Imaging
• Differential diagnosis & securing the diagnosis
• Prevention
• Treatment
• Prognosis
• Related topics
  • Metronidazole induced encephalopathy (MIE)
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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pathophysiology

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biochemistry

• Thiamine is a co-factor in numerous enzymatic reactions involved in energy metabolism, as shown below. Thiamine deficiency has consequences including the following:
  • (1) Accumulation of lactate
  • (2) Excess production of glutamate, which may lead to excessive excitatory neurotransmission in the brain
• This can cause vasogenic and cytotoxic edema.

pharmacology of thiamine

• The daily requirement of thiamine is ~1-2 mg. Thiamine is absorbed in the jejunum and stored in the liver. Absorption is relatively inefficient; for example, one study of healthy volunteers found that only 5% of a 50-mg oral dose was absorbed.(30146080) However, a recent study suggests that this might be overcome with the use of very high doses of oral thiamine, as shown in the figure below.(22305197)
• Total body stores of thiamine are ~30 mg (but potentially lower in liver disease).
• Inadequate thiamine intake can cause a previously healthy person to become deficient within ~2-4 weeks. (32551830) In the context of acute or chronic illness, deficiency can occur more rapidly.

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signs & symptoms

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Signs and symptoms are generally unreliable in the diagnosis. The classic triad of encephalopathy, ophthalmoplegia, and ataxia is present in only ~15% of cases. Among non-alcoholic patients with Wernicke encephalopathy, the triad is even less common.(31171116)

#1 = encephalopathy

• Delirium is the most consistent clinical characteristic.
• This may progress to coma.
• Isolated encephalopathy without ocular or cerebellar signs may be more common in nonalcoholic Wernicke encephalopathy.(32390125)

#2 = ophthalmoplegias

• Horizontal nystagmus is the most common finding (although both horizontal and vertical nystagmus may occur).
• Cranial nerve palsies may include:
  • Abducens nerve (CN6) – usually bilateral.
  • Conjugate gaze palsies.
  • These may progress to complete ophthalmoplegia.

#3 = ataxia

• Legs are affected more than arms (because the ataxia is due to vestibular dysfunction combined with cerebellar dysfunction).
• This affects gait primarily (arms and speech are usually unaffected).

other potential clues to Wernicke encephalopathy

• Hypothermia (due to hypothalamic involvement).
• Hypotension.

other clinical features of thiamine deficiency

• Peripheral neuropathy (“dry beriberi”)
  • May cause pain, paresthesias, weakness, and/or sensory loss.
• High-output heart failure (“wet beriberi”)
• Abdominal pain, emesis, and lactic acidosis (“gastrointestinal beriberi”)

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risk factors

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🔑 Alcoholism is the cause of only ~50% of Wernicke encephalopathy. Other cases may occur due to a variety of factors, frequently in a multi-factorial fashion. Factors predisposing to Wernicke encephalopathy may be divided into roughly four groups:

#1/4: decreased thiamine intake

• Malnutrition, for example due to:
  • Substance use disorder, alcoholism.
  • Dementia, poverty.
  • Schizophrenia.
  • Anorexia nervosa.
  • Cachexia (e.g., associated with AIDS, malignancy).
  • Fad diets.
• Hyperemesis:
  • Hyperemesis gravidarum.
  • Cannabinoid hyperemesis syndrome.
• Total parenteral nutrition lacking thiamine.

#2/4: decreased gastrointestinal absorption

• Crohn's disease.
• Peptic ulceration, chronic gastritis.
• Chronic diarrhea.
• Gastrointestinal surgery (especially bariatric surgery).

#3/4: decreased hepatic storage capacity for thiamine

• Cirrhosis of any etiology.
• Alcoholism.

#4/4: increased use or removal of thiamine

• Large dietary carbohydrate load (especially refeeding syndrome).
• Hypermetabolic states (e.g., sepsis, systemic inflammation, hyperthyroidism).
• Certain rapidly-growing malignancies.
• Hemodialysis or peritoneal dialysis.
• Diuresis (especially heart failure patients on chronic diuretics).
• Metronidazole can function as a thiamine antagonist (but this shouldn't be confused with metronidazole-induced encephalopathy 📖).(32390125)

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epidemiology

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Wernicke encephalopathy may be more common than generally perceived

• ~1% prevalence in the general population.
• ~12.5% prevalence among people with alcoholism.
• ~8% prevalence among patients status post bariatric surgery.(30364782)

thiamine deficiency as an iatrogenic complication of hospitalization

• Causative factors:
  • Pre-existing inadequacy of thiamine stores.
  • Inadequate nutrition (e.g., prolonged periods of time with NPO).
  • Hypermetabolic states (e.g., infection, inflammation).
  • Increased urinary excretion (e.g., diuresis or dialysis).
• The prevalence of thiamine deficiency among critically ill patients may be high, with some articles reporting ~20%.(30146080)
• Wernicke encephalopathy may manifest initially within the hospital, following admission for another illness. This will be extremely difficult to diagnose, as it will tend to be attributed to multi-factorial delirium (previously termed “ICU psychosis”).
• Thiamine deficiency might also contribute to critical care neuropathy or gastrointestinal dysfunction in some patients.(30146080) One RCT investigating the utility of thiamine in septic shock found no benefit overall, but a reduced mortality among the subgroup of patients with thiamine deficiency.(26771781)

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laboratory studies

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whole blood thiamine diphosphate level

• Whole blood thiamine diphosphate level is largely a reflection of thiamine levels within erythrocytes. This may be more accurate than serum or plasma thiamine measurement, since whole blood thiamine is a more accurate reflection of intracellular thiamine stores.
• The normal value is generally taken to be 70-180 nM/L, although there is no universally defined cutoff.(30151974)
• Whole blood thiamine diphosphate levels seem to be superior to other tests of thiamine levels.(25564426) However, its sensitivity and specificity remain unclear.

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imaging

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CT scan

• CT scan usually won't reveal Wernicke encephalopathy. The primary role is to exclude alternative etiologies.
• CT could show reduced attenuation at the periaqueductal gray matter and medial portion of the thalami.(32390125) There may also be contrast-enhancement.

MRI scan

• MRI has a sensitivity of ~50% with a specificity of ~90%.(32390125) However, MRI may normalize within days of thiamine initiation.
• Distribution of abnormalities:
  • Symmetric.
  • Typical location is surrounding the third ventricle:(32390125)
    • Mammillary bodies (involvement is a distinctive feature, with strong contrast enhancement considered pathognomonic).(Runge 2020; 31589567)
    • Medial thalami and hypothalamus.
    • Periaqueductal region, tectal plate.
    • Floor of the fourth ventricle.
  • (Additional abnormalities can be seen in the putamen, caudate, splenium of the corpus callosum, dorsal medulla, pons, red nucleus, substantia nigra of the midbrain, cranial nerve nuclei, dentate nucleus, vermis and paravermal region of the cerebellum, fornix, and the precentral and postcentral gyri).(32390125)
• Findings:
  • Hyperintensity on T2/FLAIR sequences with diffusion restriction.
  • Decreased T1 signal.
  • Contrast enhancement may be seen in about half of patients, due to blood-brain barrier disruption.(31589567)
• Note: abnormalities in the corpus callosum should raise concern for Marchiafava-Bignami disease (due to alcoholism plus vitamin deficiencies).

radiological differential diagnosis may include: (Tang 2015)

• Certain viral infections (e.g., West Nile Virus).
• Metronidazole-induced encephalopathy.
• Artery of Percheron infarction.
• CVT (cerebral venous thrombosis).
• Osmotic demyelination.
• Wilson's disease.

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differential diagnosis & securing the diagnosis

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clinical differential diagnosis will vary based on presentation, but may include:

• Alcohol withdrawal.
• Refeeding syndrome (which may involve Wernicke encephalopathy plus superimposed electrolyte abnormalities)
• Hepatic encephalopathy.
• Normal pressure hydrocephalus.
• Posterior circulation ischemic stroke.
• Septic shock (thiamine deficiency causing Wernicke encephalopathy plus high-output heart failure and lactic acidosis).

securing the diagnosis of Wernicke encephalopathy

• No diagnostic criteria exist which are both sensitive and specific. Therefore, clinical judgement is required.
• Empiric thiamine supplementation should be started while the diagnostic process is underway (prior to definitive diagnosis).
• Consideration should be given to the following components:
  • (1) Risk factors for thiamine deficiency.
  • (2) Exclusion of alternative diagnostic possibilities.
  • (3) Neuroimaging (especially MRI) may sometimes be strongly supportive.
  • (4) Clinical response to IV thiamine (in some cases, opthalmoplegia can resolve within hours of starting therapy).
  • (5) Whole blood thiamine levels (this may be useful to adjudicate the diagnosis retrospectively).
• Attempts should be made to reach diagnostic certainty, since Wernicke's Encephalopathy requires a protracted course of IV thiamine.

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prevention

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conventional approaches to preventing Wernicke encephalopathy

• Thiamine supplementation is a sensible intervention for at-risk patients (e.g., patients with alcoholism or malnutrition). More on the risk factors for thiamine deficiency above.
• 100 mg IV/IM thiamine daily is often used for this purpose (in the absence of any high-level evidence).
• Oral thiamine is probably adequate for this purpose as well (with advantages regarding reduced cost and ease of administration). One small study found that in a population of patients with alcoholism, 250 mg thiamine IM daily generated similar thiamine levels after three days when compared to a regimen of 50 mg PO five times daily.(3358822) This suggests that an oral regimen of ~200 mg twice daily might be adequate to prevent deficiency in at-risk patients.
  • In clinical practice, at-risk patients are often treated with IV thiamine for a few days and then thiamine supplementation is stopped entirely. Rather than discontinuing thiamine supplementation altogether, it might be more sensible to transition from intravenous thiamine supplementation to high-dose oral supplementation, which could be continued for the duration of the patient's hospital course.
  • However, oral thiamine may not be a viable strategy for patients with impaired gastrointestinal absorption of thiamine.

could more aggressive prevention be useful among critically ill patients?

• Nearly all critically ill patients will have at least one risk factor for thiamine deficiency (e.g., reduced nutritional intake, diuresis, systemic inflammation, dialysis). Consequently, thiamine deficiency is very common among critically ill patients (as explored above).
• Oral thiamine administration is probably effective, safe, and cheap (costing roughly ~$10 per patient for an entire ICU stay).
• ICU delirium is very expensive, with estimates that a single episode of ICU delirium may cost ~$17,000.(30179988)
• This suggests that if the incidence of Wernicke encephalopathy is higher than one in ~1,700 patients (0.05%), then routine thiamine administration could be both clinically beneficial and cost-saving. Available data shows that the incidence of Wernicke encephalopathy is well above 0.05%, which could make prophylaxis a logical intervention.(24666443)

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treatment

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thiamine

• When in doubt about the diagnosis, empiric treatment should be initiated.
  • IV thiamine is entirely safe.
  • Failure to provide therapy may promulgate chronic neurologic injury.
  • Thiamine should ideally be given simultaneously or before administration of carbohydrates (e.g., food or IV dextrose).
• Parenteral high-dose thiamine is generally required, for two reasons:
  • (1) Oral absorption is inefficient.(28680171)
  • (2) Because there are no active transporters of thiamine into the CNS, thiamine must passively move into the CNS. This process is aided by creating high gradients, and thus the impetus to suggest high doses of repletion initially.
  • (If intravenous thiamine is unavailable, then using very high-dose oral thiamine may be attempted to overcome low bioavailability, for example perhaps 500-1,500 mg PO q8hr).(22305197)
• There is no well-defined dosing regimen, nor high-quality evidence. Articles often recommend the following:(32551830)
  • i) 500 mg IV TID for 2-3 days, followed by
  • ii) 200-500 mg IV daily for ~5 days or until clinical improvement ceases, followed by
  • iii) oral thiamine (e.g., 100-500 mg PO TID)
• Ophthalmoparesis may improve within hours of receiving IV thiamine.

magnesium

• Rationale for ensuring adequate magnesium levels:
  • Magnesium is a cofactor for thiamine activity and promotes cellular uptake of thiamine.
  • Disorders which lead to thiamine deficiency often also cause magnesium deficiency (especially alcoholism).
• Check and aggressively replete magnesium (more on that here).

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prognosis

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• Ocular abnormalities usually begin to improve within about one day.
• Ataxia and confusion usually begin to improve within a week. Confusion will generally resolve over a month.
• Chronic Korsakoff's psychosis (marked by confabulation) may occur in patients with delayed treatment.

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metronidazole induced encephalopathy (MIE)

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basics

• Metronidazole-induced encephalopathy (MIE) is typically a subacute side effect, but this can occur relatively rapidly.
• MIE should be considered within the differential diagnosis of hospital-acquired delirium, cerebellar dysfunction, or seizure. Among patients who are already critically ill, inability to detect/report cerebellar symptoms can render diagnosis challenging.

epidemiology

• MIE is usually caused by subacute/chronic exposure. However, toxicity has been reported following as little as 5 grams cumulative exposure, or as soon as within two days of initiation.(33824746, 30536109)
• Risk factors are poorly delineated, but might include:
  • Hepatic dysfunction (metronidazole is mostly metabolized in the liver).(30536109)
  • High-dose administration (>2 grams/day). (31622182)
  • High cumulative exposure (e.g., >~20 grams total). (31622182)

clinical findings (30536109)

• Cerebellar dysfunction is most common:
  • Dysarthria (63%).
  • Gait instability (55%).
  • Limb discoordination (53%).
• Altered mental status (40%).
• Polyneuropathy (30%).
• Oculomotor disturbance (20%).
• Dizziness/vertigo (20%).
• Seizures (~15%).(31622182)
• Lateralized paresis (7%).

neuroimaging

• MRI is the most sensitive imaging modality. The most common sites of involvement:
  • 🦷 Cerebellar dentate nuclei are most often involved, with abnormalities in ~90% of patients.(30536109)
  • Splenium of the corpus callosum (~40%).(30536109) Lesions involving the corpus callosum almost always involve the splenium exclusively.(31622182)
  • Dorsal brainstem:
    • Midbrain (40%), pons (25%), and/or medulla (18%).(30536109)
    • May include the vestibular nuclei, abducens nucleus, and superior olivary nucleus.
  • Periaqueductal grey matter.
• MRI abnormalities usually consist of T2/FLAIR hyperintensity without contrast enhancement or diffusion restriction (suggestive of vasogenic edema).
  • However, lesions in the corpus callosum may show diffusion restriction. Diffusion restriction in this white matter structure may relate to axonal edema, rather than demyelination or cellular necrosis (given the reversibility of MRI findings in most patients).(31622182)
• Radiological differentiation of MIE vs. Wernicke encephalopathy:
  • Wernicke encephalopathy is favored by involvement of the mammillary bodies, medial thalamus, and cerebellar vermis.
  • MIE is favored by dentate nucleus involvement.
• ⚠️ Ascertainment bias will cause patients with dramatic imaging abnormalities to be more likely to be diagnosed with MIE (whereas patients without imaging findings are less likely to be diagnosed with MIE). This bias will artificially inflate the sensitivity of neuroimaging for the diagnosis of MIE.

differential diagnostic considerations include:

• Wernicke encephalopathy.
• Marchiafava-Bignami disease (cystic degeneration of the corpus callosum, usually related to alcoholism).
• Hepatic encephalopathy.
• Viral encephalomyelitis (e.g., enterovirus).
• Methyl bromide poisoning (used as a pesticide gas).
• Related differential diagnoses: Abnormalities of the splenium of the corpus callosum: 📖

management

• Metronidazole must be discontinued (with substitution of an alternative antibiotic if needed).
• Thiamine administration should be considered:(28716273)
  • One of the pathophysiological mechanisms of MIE may be inhibition of thiamine pyrophosphorylation. It is possible that metronidazole might impair cellular utilization of thiamine.(30536109)
  • MIE may overlap clinically with Wernicke encephalopathy, making this distinction difficult or impossible (the two processes may occur together).(32599426)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to consider Wernicke encephalopathy in patients with atypical risk factors (e.g., ICU patients, hyperemesis gravidarum, chronic diuretic use for heart failure).
• Inadequate dose and duration of thiamine used for patients with Wernicke encephalopathy. One or two days of IV thiamine isn't sufficient!
• Incorrectly excluding the diagnosis of Wernicke encephalopathy because patients lack the classic triad of symptoms (confusion, ataxia, ophthalmoplegia). In fact, very rarely will patients with Wernicke encephalopathy display all of these components.
• Inadequate use of thiamine prophylaxis against Wernicke encephalopathy among at-risk critically ill patients. Oral thiamine is probably adequate for this purpose, making the expense of prophylaxis negligible.

Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.

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