MRI-Negative Neuropathy-Predominant Wernicke Encephalopathy: A Diagnostic Challenge — Case Report and Literature Review

Diana Fernanda Aguayo (MD student),
Universidad de Monterrey.

José David Santiago Luna (MD student).
Universidad Anáhuac Oaxaca

Amin H. Karim MD
Baylor College of Medicine, Houston, Texas

Abstract

Wernicke encephalopathy (WE) is an acute neurological emergency caused by thiamine (vitamin B1) deficiency. Although classically characterized by confusion, ophthalmoplegia, and gait ataxia, the complete clinical triad is present in a minority of patients. Normal neuroimaging findings and atypical manifestations, such as severe peripheral neuropathy or optic atrophy, present significant diagnostic challenges. We report the case of a 48-year-old male with alcohol use disorder who presented with MRI-negative, neuropathy-predominant WE complicated by persistent lower extremity polyneuropathy, gait dysfunction, and bilateral optic atrophy despite thiamine supplementation. Initial diagnostic complexity was heightened by elevated cerebrospinal fluid protein levels, leading to suspicion of autoimmune encephalitis. This paper highlights the clinical spectrum of thiamine deficiency, discusses key differential diagnoses, and emphasizes the necessity of prompt empiric treatment regardless of neuroimaging findings.

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Introduction

Wernicke–Korsakoff syndrome (WKS) is a neurologic disorder resulting from thiamine (vitamin B1) deficiency. It encompasses two distinct clinical entities representing different stages of disease progression. Wernicke encephalopathy (WE) is the acute, life-threatening manifestation characterized by confusion, ophthalmoplegia, nystagmus, and gait ataxia. In contrast, Korsakoff syndrome (KS) is a chronic neuropsychiatric condition resulting from uncorrected or recurrent thiamine deficiency, defined by severe anterograde and retrograde amnesia, executive dysfunction, and confabulation [1].

While WKS is most frequently encountered in individuals with alcohol use disorder, non-alcoholic etiologies are increasingly recognized. These include bariatric surgery, hyperemesis gravidarum, severe anorexia nervosa, chronic parenteral nutrition, and inflammatory bowel disease [2].

WE remains primarily a clinical diagnosis. The classic triad occurs in only 16% of confirmed cases. Consequently, the European Federation of Neurological Societies (EFNS) guidelines recommend diagnosing WE if at least two of the following criteria are met: (1) dietary deficiency state, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) altered mental status or mild memory impairment [2,3].

Diagnostic imaging, particularly magnetic resonance imaging (MRI) of the brain, serves as a supportive tool. Characteristic MRI findings include symmetric hyperintensities in the mammillary bodies, medial thalami, tectal plate, and periaqueductal gray. However, brain MRI sensitivity remains suboptimal, and normal neuroimaging does not rule out the condition [3]. Because delay in therapy risks permanent neurocognitive injury or mortality, empiric intravenous thiamine must be initiated immediately upon clinical suspicion.

Here, we present the case of a 48-year-old male with alcohol use disorder who developed neuropathy-predominant WE with persistent polyneuropathy, gait instability, and severe bilateral visual loss despite thiamine therapy. Normal acute brain MRI findings and elevated cerebrospinal fluid (CSF) protein initially complicated the diagnostic workup. A comprehensive literature review accompanies the case to outline key differential considerations and rare manifestations of thiamine depletion.

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Case Description

Patient History & Initial Hospitalization

A 48-year-old male with a history of chronic pain presented for continuous neurological evaluation following a diagnosis of Wernicke–Korsakoff syndrome.

The acute illness began in 2024 following a 1-week episode of heavy alcohol intake. The patient sustained a fall down a flight of stairs and was found immobilized on the floor by his family and local police. Shortly thereafter, he experienced progressive confusion, short-term memory impairment, visual hallucinations, severe lower back pain, and bilateral lower extremity neuropathic pain.

During his initial emergency hospitalization, his clinical course was complicated by sepsis, delirium, and convulsive seizures. Suspecting WE, clinicians ordered a brain MRI, which revealed no classic signal abnormalities in the mammillary bodies or periventricular structures. Given the presence of seizures, altered mental status, and negative neuroimaging, an autoimmune etiology was investigated. Cerebrospinal fluid (CSF) analysis demonstrated albumino-cytological dissociation with an elevated protein level of 172 mg/dL without pleocytosis. Empiric therapy with intravenous immunoglobulin (IVIG) produced no measurable clinical improvement. Subsequently, high-dose (HD) intravenous (IV) thiamine was administered for 5 days, followed by oral thiamine (100 mg daily).

Discharge documentation from October 2024 noted recurrent urinary tract infections and persistent confabulation. Following medical stabilization, he was transferred to an inpatient rehabilitation facility. Despite physical and occupational therapy, his recovery was complicated by recurrent falls and severe spatial disorientation. Neuropsychological evaluation confirmed profound cognitive deficits, leading to formal diagnoses of Wernicke encephalopathy and Korsakoff syndrome.

Follow-up testing in November 2024 demonstrated significant ongoing cognitive dysfunction affecting attention, memory encoding, abstract reasoning, and problem-solving. A Saint Louis University Mental Status (SLUMS) evaluation yielded a score of 18/30, indicating severe cognitive impairment with prominent anosognosia.

Follow-Up Physical & Neurological Evaluation

By early 2026, the patient continued to report progressive bilateral visual impairment, severe neuropathic pain in both lower extremities, and progressive immobility requiring a cane for ambulation. He remained dependent on family support for activities of daily living.

• Past Medical History: Chronic pain syndrome, severe visual impairment, Wernicke encephalopathy, Korsakoff syndrome.
• Family History: Essential hypertension (father), premature myocardial infarction (paternal line), age-related macular degeneration.
• Social History: Former finance professional; 10-pack-year tobacco history (quit ~10 years prior); past heavy alcohol use, currently reporting minimal social intake.

Physical & Diagnostic Examination Findings

• Ophthalmologic Assessment (March 2026): Visual acuity measured 20/150 in both eyes (Snellen equivalent 20/200 bilaterally during uncorrected screening). Slit-lamp exam demonstrated bilateral temporal optic disc pallor. Optical coherence tomography (OCT) confirmed bilateral temporal retinal nerve fiber layer (RNFL) thinning and asymmetric optic nerve head cupping, consistent with optic atrophy. Pupillary light reflexes, extraocular movements, and intraocular pressures were normal.
• Neurological Examination: The patient was alert and oriented to self but exhibited subtle ongoing memory retrieval deficits. Cranial nerves II–XII were grossly intact except for visual field constriction. Motor examination revealed preserved muscle tone and bulk (5/5 strength throughout). Sensory testing revealed marked hypesthesia to light touch and pinprick in a stocking distribution over the lower extremities, left greater than right. Deep tendon reflexes were intact and symmetric. No appendicular dysmetria or dysdiadochokinesia was noted.
• Gait & Stance: Wide-based, ataxic gait. Tandem gait was severely impaired. The patient required a single-point cane and assistance for turn stability.

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Literature Review & Pathophysiology

Pathophysiology of Thiamine Deficiency

Thiamine (vitamin B1) is a water-soluble coenzyme critical for cellular energy metabolism. Its biologically active form, thiamine pyrophosphate (TPP), serves as an essential cofactor for key enzymes in the tricarboxylic acid (TCA) cycle and pentose phosphate pathway, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase [4].

Because human tissue thiamine storage capacity is limited (approximately 30 mg), biological depletion can occur within 2 to 3 weeks of inadequate intake. Thiamine is actively absorbed in the proximal small intestine via $Na^+$-dependent active transport mechanisms. Depletion disrupts neuronal oxidative oxidative phosphorylation, leading to cell membrane depolarization, intracellular glutamate accumulation, focal lactic acidosis, oxidative stress, and eventual microvascular disruption [4].

Acute histopathological lesions demonstrate severe vascular congestion, endothelial swelling, microglial activation, and petechial hemorrhages. Chronic lesions progress to demyelination, dense gliosis, and parenchymal tissue loss. The most specific pathological hallmark of WKS is bilateral atrophy of the mammillary bodies, dorsomedial thalami, tectal plate, and periaqueductal gray [5].

Clinical Manifestations & Atypical Features

The classic triad (encephalopathy, oculomotor dysfunction, and gait ataxia) is present in less than twenty percent of acute cases. Encephalopathy typically manifests as profound spatial disorientation, inattentiveness, and apathy. Oculomotor abnormalities include horizontal nystagmus, lateral rectus palsies, and conjugate gaze palsies [3,6]. Gait ataxia stems from combined cerebellar damage and severe sensory peripheral neuropathy [6].

Atypical manifestations reported in the literature include:

• Neuro-Ophthalmic: Progressive vision loss, optic disc edema, retinal hemorrhages, and permanent optic atrophy [7].
• Neuromuscular & Peripheral: Severe flaccid quadriparesis, prominent distal sensory polyneuropathy, dysarthria, and dysphagia [7].
• Autonomic & Systemic: Hypothermia, severe hypotension, hypovolemic shock, and refractory hyponatremia [7].

Diagnostic Workup

WE remains a clinical diagnosis supported by laboratory and imaging studies:

1. Biochemical Testing: Serum thiamine levels or red blood cell transketolase activity assays can confirm deficiency. However, because processing often requires days, normal or pending values must never delay treatment [6].
2. Neuroimaging: Brain MRI sensitivity is estimated between 53% and 70%, though specificity approaches 93%. Characteristic changes include $T_2$/FLAIR hyperintensities surrounding the third ventricle, mammillary bodies, and medial thalami [3]. A completely normal MRI does not rule out acute or subacute WE.

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Differential Diagnosis

When patients present with acute delirium, ataxia, or unexplained encephalopathy—particularly alongside heavy alcohol use—several differential diagnoses must be systematically evaluated:

Condition	Overlapping Features	Distinguishing Clinical / Diagnostic Features
Autoimmune Encephalitis	Altered mental status, memory loss, seizures, elevated CSF protein.	Absence of clinical response to IVIG/plasmapheresis; positive neuronal cell-surface or intracellular autoantibodies [10].
Delirium Tremens (DT)	Confusion, hallucinations, psychomotor agitation, autonomic instability.	Resolves typically within 3 to 7 days post-cessation; lacks classic ocular palsies; responds to benzodiazepine protocols [11].
Hepatic Encephalopathy	Delirium, asterixis, fluctuating consciousness, sleep-wake inversion.	Elevated serum ammonia, presence of stigmata of chronic liver disease (ascites, jaundice, spider angiomas); clear response to lactulose/rifaximin [12].
Vitamin B12 Deficiency	Sensory ataxia, subacute combined degeneration, optic neuropathy, cognitive decline.	Low serum cobalamin, elevated methylmalonic acid (MMA) and homocysteine; characteristic megaloblastic anemia on CBC [13].
Hyponatremia	Acute confusion, unsteady gait, muscular lethargy, convulsive seizures.	Serum sodium level $<135\text{ mEq/L}$; clinical response following controlled sodium correction [14].

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Management Guidelines

WE is a neuro-medical emergency. Parenteral thiamine administration must be initiated immediately upon suspicion.

Therapeutic Regimens

• United States Standard Guidelines: Parenteral thiamine 100 mg IV/IM daily for 3 to 7 days, followed by maintenance oral therapy (100 mg daily) [3,6].
• EFNS / Royal College Guidelines: High-dose protocols are strongly favored to cross an impaired blood-brain barrier:
  • EFNS Criteria: Thiamine 200 mg IV every 8 hours until clinical improvement plateaus [3].
  • Royal College Criteria: Thiamine 500 mg IV every 8 hours for 3 consecutive days, followed by 250 mg IV daily for an additional 3 to 5 days, transitioning thereafter to oral maintenance (100–300 mg daily) [3,6,7].

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Discussion

This case highlights critical challenges in identifying and managing atypical presentations of Wernicke encephalopathy. Despite presenting with acute delirium, ataxia, and memory failure, the patient’s diagnostic trajectory was prolonged by a negative brain MRI and elevated CSF protein levels.

The absence of classic periventricular MRI signal alterations occurs in up to 47% of WE patients [3,17]. Relying solely on neuroimaging for diagnostic confirmation risks delaying definitive treatment. In this patient, albumino-cytological dissociation in the CSF initially directed therapeutic efforts toward autoimmune encephalitis. However, elevated CSF protein without cellular reaction can occasionally reflect concurrent severe peripheral nerve demyelination or non-specific central tissue disruption [10,18]. The complete lack of response to IVIG alongside rapid stabilization post-thiamine confirmed nutritional deficiency as the underlying etiology.

Furthermore, this patient’s long-term disease course demonstrates the rare and severe sequelae of thiamine deficiency. While ocular motor palsies often improve quickly post-treatment, optic neuropathy with permanent optic atrophy is a devastating, irreversible manifestation [7]. Additionally, while gait disturbances in WE are frequently attributed to central cerebellar loss, severe peripheral axonal polyneuropathy can dominate the presentation and lead to persistent, long-term disability [15,18].

Early empiric administration of high-dose parenteral thiamine remains the single most critical factor in preventing permanent neurocognitive transition to Korsakoff syndrome or irreversible sensory-motor deficits.

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