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Summary Table

Domain	Detail
Risk Factors	Chronic alcohol use disorder, malnutrition, hyperemesis gravidarum, bariatric surgery (especially gastric bypass), prolonged total parenteral nutrition without supplementation, anorexia nervosa, refeeding syndrome, chronic dialysis
Etiology	Thiamine (vitamin B1) deficiency leading to failure of aerobic metabolism in vulnerable brain regions
Patient Presentation	Wernicke: acute onset of confusion, visual disturbances, unsteady gait. Korsakoff: chronic inability to form new memories with fabrication of false memories to fill gaps
Classic Physical Exam	Wernicke: the classic triad of encephalopathy (confusion/altered mental status), oculomotor dysfunction (nystagmus, lateral rectus palsy, conjugate gaze palsy), and cerebellar ataxia (wide-based gait). Korsakoff: anterograde amnesia and confabulation with relatively preserved long-term memory and alertness
Key Diagnostic Results	Clinical diagnosis; do not delay treatment. MRI brain showing T2/FLAIR hyperintensity in mammillary bodies, medial thalamus, and periaqueductal gray matter. Low erythrocyte transketolase activity (most accurate lab marker)
Management	IV thiamine BEFORE glucose administration. High-dose IV thiamine 500 mg three times daily for 2 to 3 days, then 250 mg IV once daily for 3 to 5 additional days. Replete magnesium concurrently. Korsakoff syndrome is largely irreversible
Keywords	"Classic triad," "give thiamine before glucose," "confabulation," "mammillary bodies," "chronic alcoholic found confused," "nystagmus and ataxia," "patient making up stories"

1. Pathophysiology

Thiamine (vitamin B1) serves as an essential cofactor for three critical enzymes in central energy metabolism: pyruvate dehydrogenase (which links glycolysis to the citric acid cycle), alpha-ketoglutarate dehydrogenase (which operates within the citric acid cycle itself), and transketolase (which functions in the pentose phosphate pathway). When thiamine is depleted, all three pathways stall. The result is a collapse of aerobic glucose metabolism, accumulation of lactate, failure of ATP production, and eventual cytotoxic edema and neuronal death.

The body stores only about 30 to 50 mg of thiamine, and the biological half-life is roughly 9 to 18 days. This means that a patient with poor nutritional intake can exhaust their thiamine reserves in as few as 2 to 3 weeks. Chronic alcohol use accelerates depletion through three mechanisms: reduced dietary intake, impaired gastrointestinal absorption of thiamine, and decreased hepatic storage and phosphorylation of thiamine into its active form, thiamine pyrophosphate (TPP).

The brain regions most vulnerable to thiamine deficiency are those with the highest metabolic demand and thiamine turnover. These include the mammillary bodies, the medial thalamus (particularly the dorsomedial and anterior nuclei), the periaqueductal gray matter, the tectal plate, and the superior cerebellar vermis. Each damaged region maps directly to the clinical findings:

Mammillary bodies and medial thalamus are integral components of the Papez circuit, which is central to memory encoding. Damage here produces the anterograde amnesia that defines Korsakoff syndrome.
Oculomotor nuclei, abducens nuclei, and vestibular nuclei in the brainstem are vulnerable, explaining the nystagmus, lateral rectus palsy, and conjugate gaze palsies seen in Wernicke encephalopathy.
Superior cerebellar vermis damage produces truncal and gait ataxia, typically a wide-based, unsteady gait.
Diffuse cortical and reticular formation involvement produces the global confusional state and altered sensorium.

The critical concept for the exam is this: Wernicke encephalopathy and Korsakoff syndrome exist on a single pathological continuum. Wernicke encephalopathy is the acute, potentially reversible phase. If untreated (or if treatment is delayed), irreversible structural damage to the mammillary bodies and thalamus converts the condition into Korsakoff syndrome, a chronic and largely permanent amnestic disorder. Approximately 80% of patients who survive untreated Wernicke encephalopathy go on to develop Korsakoff syndrome.

One final pathophysiological point that is heavily tested: glucose administration in a thiamine-depleted patient can precipitate or worsen Wernicke encephalopathy. Glucose metabolism through glycolysis and the citric acid cycle requires thiamine-dependent enzymes. Giving a glucose load without first repleting thiamine diverts the remaining thiamine stores toward glucose metabolism, critically depleting whatever small reserve the brain has left.

2. Classification and Clinical Manifestation

Stage	Syndrome	Core Features	Reversibility
Acute	Wernicke Encephalopathy	Classic triad: (1) Encephalopathy / confusion, (2) Oculomotor dysfunction, (3) Cerebellar ataxia	Potentially reversible with prompt IV thiamine
Chronic	Korsakoff Syndrome	(1) Anterograde amnesia (inability to form new memories), (2) Confabulation (fabrication of memories without intent to deceive), (3) Relatively preserved alertness and long-term memory	Largely irreversible; only ~20% show meaningful recovery
Combined	Wernicke-Korsakoff Syndrome	Features of both: residual amnestic syndrome persisting after treatment of the acute Wernicke phase	Wernicke features may resolve; Korsakoff features typically persist

Clinical Features of Wernicke Encephalopathy

Feature	Prevalence	Examination Findings
Encephalopathy	~82%	Disorientation, inattention, drowsiness, apathy. Can progress to stupor and coma if untreated
Oculomotor dysfunction	~29%	Horizontal nystagmus (most common), lateral rectus (CN VI) palsy, impaired conjugate gaze, rarely complete ophthalmoplegia
Cerebellar ataxia	~23%	Wide-based gait, truncal instability, inability to tandem walk. Limb ataxia is less prominent
Complete classic triad	Only 16 to 33%	The full triad is present in the minority of cases. This is a critical exam pearl

Clinical Features of Korsakoff Syndrome

Feature	Description
Anterograde amnesia	Inability to form new episodic memories. This is the hallmark finding. The patient cannot recall events from minutes or hours ago
Retrograde amnesia	Variable loss of past memories, with a temporal gradient (more recent memories lost preferentially)
Confabulation	The patient spontaneously produces fabricated, distorted, or misinterpreted memories without conscious intent to lie. They are not "making up stories" deliberately; they genuinely believe their confabulated narratives
Preserved other cognition	Alertness, attention, social behavior, and procedural memory are relatively intact. This distinguishes Korsakoff from dementia
Lack of insight	Patients are typically unaware of their memory deficit (anosognosia)

3. Diagnostic Workup

Test	Role	Key Findings
Clinical diagnosis	Best initial "test"	Any combination of confusion, oculomotor abnormalities, or ataxia in a patient at risk for thiamine deficiency. Do NOT wait for lab confirmation before treating
MRI brain	Best initial imaging	T2-weighted and FLAIR sequences show symmetric hyperintensity in the mammillary bodies, periaqueductal gray, medial thalamic nuclei, and tectal plate. Mammillary body involvement is the most characteristic finding
Erythrocyte transketolase activity	Most accurate lab marker	Decreased baseline activity with greater than 25% increase after in vitro addition of TPP (the "TPP effect"). This reflects functional thiamine deficiency at the cellular level
Serum thiamine level	Supportive but limited	May be low, but has poor sensitivity. A normal serum level does not rule out functional deficiency in the brain
Basic metabolic panel	Supportive	Check for concurrent electrolyte abnormalities, particularly hypomagnesemia (magnesium is a cofactor for thiamine-dependent enzymes)
Blood lactate	Supportive	May be elevated due to impaired aerobic metabolism
Liver function tests	Contextual	Evaluate for concurrent alcoholic liver disease

The single most important point about the diagnostic workup is that Wernicke encephalopathy is a clinical diagnosis, and treatment must begin immediately upon clinical suspicion. You do not wait for MRI results or thiamine levels before giving IV thiamine. The mortality rate of untreated Wernicke encephalopathy is approximately 17 to 20%, and delayed treatment dramatically increases the risk of progression to irreversible Korsakoff syndrome.

In practice, you should think of the diagnosis whenever an at-risk patient (chronic alcohol use, malnutrition, recent bariatric surgery, hyperemesis gravidarum) presents with any one or two components of the triad, not just the complete triad. Waiting for all three features is a common and dangerous error.

MRI is the imaging modality of choice when confirmation is needed. CT of the head is insensitive for Wernicke encephalopathy and is primarily useful to rule out alternative diagnoses such as stroke or intracranial hemorrhage. On MRI, the hallmark is symmetric T2/FLAIR hyperintensity in the mammillary bodies (the most characteristic location), periaqueductal gray, and medial thalami. In chronic or severe cases, you may also see mammillary body atrophy on imaging, which correlates with Korsakoff syndrome.

Erythrocyte transketolase activity is the most accurate laboratory measure of thiamine status. It measures the functional activity of a thiamine-dependent enzyme in red blood cells. A decreased baseline activity that rises more than 25% after the addition of TPP in vitro confirms functional thiamine deficiency. However, this test is not widely available and results are not immediate, reinforcing why this is a clinical diagnosis first.

Serum thiamine levels can be measured but are an imperfect marker. They reflect recent intake rather than tissue stores, and a normal level does not exclude Wernicke encephalopathy.

Always check magnesium levels concurrently. Magnesium is a required cofactor for the conversion of thiamine to its active form (TPP). Thiamine repletion will be ineffective if magnesium is not corrected simultaneously.

4. Management and Treatment

Phase	Intervention	Details
Immediate	IV Thiamine	500 mg IV three times daily (dissolved in 100 mL normal saline, infused over 30 minutes) for 2 to 3 days
Subsequent	IV Thiamine (step-down)	250 mg IV once daily for an additional 3 to 5 days
Maintenance	Oral Thiamine	100 mg orally three times daily, continued indefinitely in patients with ongoing risk factors
Concurrent	Magnesium repletion	IV magnesium sulfate 2 g, then continued supplementation as needed to normalize serum levels
Critical rule	Thiamine BEFORE glucose	In any malnourished or alcohol-dependent patient, administer IV thiamine before or concurrently with any dextrose-containing IV fluid
Korsakoff management	Supportive	Continued oral thiamine, cognitive rehabilitation, structured environment. No pharmacological treatment has demonstrated reliable reversal of established Korsakoff syndrome

Step 1: Administer IV thiamine immediately. This is the single most important intervention. The moment you suspect Wernicke encephalopathy, give 500 mg of thiamine IV three times daily. The parenteral route is essential because gastrointestinal absorption of oral thiamine is unreliable, especially in alcoholic patients (absorption is limited to about 4.5 mg per oral dose due to saturation of intestinal transporters). Continue this high-dose regimen for 2 to 3 days, then step down to 250 mg IV once daily for 3 to 5 more days. Once the patient can tolerate oral intake and the acute phase has resolved, transition to 100 mg orally three times daily.

Step 2: Replete magnesium. Hypomagnesemia is common in alcoholic patients, and magnesium is a required cofactor for thiamine pyrophosphokinase, the enzyme that converts thiamine into its active form. If magnesium is not corrected, thiamine supplementation alone will be insufficient.

Step 3: Withhold or delay glucose-containing fluids until thiamine has been given. This is one of the most heavily tested management principles. If a confused, malnourished patient arrives and you immediately hang D5W or give an amp of D50, you risk precipitating fulminant Wernicke encephalopathy. The glucose load demands thiamine-dependent metabolism, exhausting the patient's last reserves. The correct sequence: thiamine first, then glucose.

Step 4: Address the underlying cause. For alcoholic patients, this means initiating alcohol cessation support and long-term nutritional rehabilitation. For non-alcoholic causes (hyperemesis gravidarum, bariatric surgery, prolonged TPN), address the nutritional deficiency and ensure thiamine supplementation is incorporated into the patient's ongoing care.

Step 5: Evaluate the response. Oculomotor abnormalities typically begin improving within hours to days of thiamine repletion. Ataxia improves over days to weeks. Confusion may take days to weeks to clear. If confusion and memory impairment persist beyond weeks despite adequate thiamine repletion, suspect progression to Korsakoff syndrome, which has a much poorer prognosis.

Regarding Korsakoff syndrome: Once established, there is no proven pharmacological therapy to reverse the anterograde amnesia and confabulation. Approximately 20% of patients show some degree of recovery over months to years with continued thiamine supplementation and a structured, supportive environment. The remaining 80% have a permanent amnestic disorder.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Delirium tremens (alcohol withdrawal)	Also presents in an alcoholic patient with confusion and agitation. Both can feature altered mental status and autonomic instability	Delirium tremens occurs 48 to 96 hours after cessation of alcohol, features prominent tremor, tachycardia, hypertension, fever, and visual hallucinations (classically "seeing bugs"). Wernicke lacks the hyperadrenergic features and typically has oculomotor findings and ataxia rather than tremor and autonomic storms
Hepatic encephalopathy	Also presents in a chronic alcoholic with confusion and altered mental status	Hepatic encephalopathy features asterixis (flapping tremor), elevated ammonia, and evidence of liver dysfunction (jaundice, ascites, coagulopathy). It lacks the oculomotor and ataxic features of Wernicke
Cerebellar stroke (posterior circulation)	Presents with acute ataxia and may include nystagmus, mimicking two of the three Wernicke triad components	Cerebellar stroke has a sudden, maximal-at-onset presentation, often with prominent vertigo, headache, and focal neurological deficits on one side. CT/MRI shows an acute infarct or hemorrhage. Wernicke is subacute and typically bilateral/symmetric
Normal pressure hydrocephalus	Classic triad of gait disturbance, urinary incontinence, and dementia overlaps with ataxia and confusion	NPH features the triad of "wet, wacky, and wobbly" (urinary incontinence, dementia, magnetic gait). It lacks oculomotor findings, and CT/MRI shows ventriculomegaly out of proportion to sulcal atrophy
Alzheimer disease (confused with Korsakoff)	Both feature prominent memory loss	Alzheimer involves progressive decline in multiple cognitive domains (language, visuospatial, executive function) with gradual onset. Korsakoff has a disproportionate anterograde amnesia with relatively preserved alertness and other cognition, plus confabulation, which is not a feature of typical Alzheimer
Psychogenic / malingering (confused with confabulation)	A student might misinterpret confabulation as deliberate lying or psychiatric fabrication	Confabulation in Korsakoff is involuntary and without intent to deceive. The patient genuinely believes their fabricated memories. Malingering or factitious disorder involves conscious, purposeful deception with a clear external incentive

6. Traps and High-Yield Pearls

The single most common way students miss questions on this topic is by not recognizing Wernicke encephalopathy when the complete triad is absent. The full triad of confusion, oculomotor dysfunction, and ataxia is present in only about one-third of cases. Exam vignettes often present only one or two features in a patient with clear risk factors, and the student who waits for all three before considering the diagnosis will miss it. The correct approach: in any at-risk patient with even one component of the triad, treat empirically with IV thiamine.

The second classic trap is the glucose-before-thiamine error. A vignette may describe a confused, malnourished patient brought to the emergency department, and the question asks for the next best step. The temptation is to give dextrose-containing IV fluids to an apparently hypoglycemic patient. The correct answer is to give IV thiamine first (or at minimum, simultaneously). Giving glucose without thiamine is not just wrong on the exam; it can be fatal in real practice.

A third pitfall involves confusing Wernicke encephalopathy with delirium tremens. Both occur in alcoholic patients with altered mental status, but the management is fundamentally different (benzodiazepines for delirium tremens, thiamine for Wernicke). Look for the temporal relationship to alcohol cessation: delirium tremens appears 2 to 4 days after the last drink and features hyperadrenergic symptoms (tremor, tachycardia, diaphoresis, visual hallucinations). Wernicke can occur at any time and features the oculomotor-ataxia-confusion triad without prominent autonomic hyperactivity.

Finally, remember that Korsakoff syndrome is distinguished from other dementias by its pattern. The patient with Korsakoff has a severe and disproportionate anterograde amnesia with confabulation, but remains alert and socially appropriate with relatively preserved procedural and remote memory. If the vignette describes a patient who cannot remember what happened five minutes ago but can carry on a pleasant conversation and appears cognitively intact in other respects, think Korsakoff, not Alzheimer.

The core competency being tested across all Wernicke-Korsakoff questions is the ability to recognize a nutritional emergency in an at-risk population, initiate treatment before confirmation, and sequence your interventions correctly (thiamine before glucose, magnesium alongside thiamine). The exam is testing clinical reasoning under time pressure, not pattern completion of a perfect triad.

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