Approach

The diagnosis of Wernicke encephalopathy is challenging and often missed, with the majority of cases identified on postmortem exam.[16][18][26]​​ The classic clinical triad of mental status changes, ophthalmoplegia, and gait dysfunction may only be present in up to 16% of patients with Wernicke encephalopathy; around 19% of patients may present without any classical signs.[16] Given the clinical variability of the condition, a high index of suspicion is required when assessing patients. Treatment should not be delayed pending the results of investigations, owing to the risk of permanent neurologic injury and death.[1]

History

A history of alcohol-use disorder, poor/unbalanced dietary intake, vomiting, diarrhea, fever, coexisting medical conditions (e.g., cancer or kidney disease), immunodeficiency, or gastrointestinal surgery should be elicited. Thiamine deficiency presenting as Wernicke encephalopathy is often linked with alcohol-use disorders, particularly in developing countries, however other potential causes of the condition should be thoroughly explored.[1][69]​​​ In one series of 53 case reports, 81% of Wernicke encephalopathy cases were not alcohol-related.[70]

Exam

The classic clinical triad of mental status changes, ophthalmoplegia, and gait dysfunction is only present in up to 16% of cases; therefore, a thorough exam is required in patients with suspected Wernicke encephalopathy.[16] Exam should be focused and cover assessment of mental status, cranial nerve function (especially the optic and oculomotor nerves), vestibular and gait function, strength, reflexes, and fundoscopy.

It is important to note that while the classic triad describes ophthalmoplegia, nystagmus is a more common finding.[71]​ Other oculomotor findings include gaze palsies, sixth nerve palsies, and impaired horizontal vestibulo-ocular reflexes. Patients may also have miosis, anisocoria, light/near dissociation, papilledema, and retinal hemorrhages.

Mental status changes that may be evident include inattentiveness, apathy, a decreased level of consciousness, and memory impairment.[71]​ Ataxia presents mainly as gait dysfunction due to loss of equilibrium. Patients can develop a wide-based gait and struggle to walk, or be unable to stand.[71]

Retrospective data suggest that patients with alcohol-use disorder and Wernicke encephalopathy are more likely to present with cerebellar signs, and less likely to present with oculomotor signs than patients with nonalcohol-related Wernicke encephalopathy. In this study, diagnosis was delayed in patients without alcohol-use disorder compared with patients who had the disorder (median time to diagnosis: 4 vs. 1 day/s).[72]

More uncommonly, patients may develop hearing loss, epileptic seizures, hypothermia or hyperthermia, spastic paraparesis, and tachycardia or hypotension related to the cardiovascular manifestations of thiamine deficiency.​[23][73]

Investigations

The diagnostic challenge in Wernicke encephalopathy generally lies in the lack of sufficiently sensitive and specific diagnostic tests. Wernicke encephalopathy remains a clinical diagnosis; therefore, treatment should not be delayed pending the results of investigations. A positive diagnosis is often considered established if there is a manifest reversal of clinical signs with parenteral administration of thiamine.[26]

Laboratory

A comprehensive blood panel should be ordered to include serum thiamine, blood alcohol level, blood glucose, serum magnesium, a complete blood count, serum electrolytes, renal and liver function tests, and serum ammonia. Urine and blood toxicology screens should also be ordered in all patients presenting with suspected of Wernicke encephalopathy. A lumbar puncture may be performed if there is a clinical suspicion of encephalitis, meningitis, or subarachnoid hemorrhage.

Where possible, serum thiamine should be measured prior to treatment with parenteral administration of thiamine, however this should not delay its administration.[1]​ A normal thiamine level does not always exclude the condition as up to 8% of patients with Wernicke encephalopathy may have a normal or high thiamine level.[70]​ In rare cases, this may be explained by mutations in thiamine metabolism and transport genes.

Imaging

Magnetic resonance imaging (MRI) is the preferred imaging modality in the workup of Wernicke encephalopathy and has been shown to have a sensitivity of 53% and a specificity of 93%.[1][74][75][76]​​​​​​​​ Although both MRI and computed tomography (CT) have low sensitivity in this context, MRI is seen as more advantageous when compared to CT given it can visualize and quantify edematous lesions rather than only detecting them as low-density abnormalities.[75]​ With MRI, on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences, such abnormalities appear as signal hyperintensities in affected regions.[76]​ Typical MRI findings in patients with Wernicke encephalopathy include symmetrical signal abnormalities in the periventricular thalamic region, hypothalamus, mammillary bodies, periaqueductal region, and floor of the fourth ventricle.[76]

The imaging characteristics of Wernicke encephalopathy may differ in patients without concurrent alcohol-use disorder. Selective involvement of cranial nerve nuclei, cerebellum, red nuclei, dentate nuclei, fornix, splenium, cerebral cortex, and basal ganglia typically characterize imagining in patients with nonalcoholic-related Wernicke encephalopathy. In patients with a history of alcohol-use disorder, lesions may more commonly demonstrate contrast enhancement in the mamillary bodies and thalamus.[77][Figure caption and citation for the preceding image starts]: Fluid attenuated inversion recovery (FLAIR) MRI brain of patient with Wernicke encephalopathyRamulu P, Moghekar A, Chaudhry V, et al, Wernicke's encephalopathy, Neurology 2002;59:846; used with permission [Citation ends].com.bmj.content.model.Caption@3d70db52

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