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CONCISE REVIEW FOR CLINICIANS

Wernicke EncephalopathydClinical Pearls


Shirshendu Sinha, MBBS; Archish Kataria, MBBS; Bhanu Prakash Kolla, MD;
Nuria Thusius, MD; and Larissa L. Loukianova, MD, PhD

CME Activity
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jointly accredited by the Accreditation Council and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. San-
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Credit Statements: AMA: Mayo Clinic College of Medicine and Science des- plete the following:
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gory 1 Credit(s). Physicians should claim only the credit commensurate with 2. Complete the online CME Test and Evaluation. Participants must achieve
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MOC Credit Statement: Successful completion of this CME activity, which mayoclinicproceedings.org, select CME, and then select CME articles to
includes participation in the evaluation component, enables the participant locate this article online to access the online process. On successful
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Learning Objectives: On completion of this article, you should be able Date of Release: 6/3/2019
to (1) recognize the historical background, epidemiology, and pathogen- Expiration Date: 5/31/2021 (Credit can no longer be offered after it has
esis of Wernicke encephalopathy (WE), (2) recognize the signs and symptoms passed the expiration date.)
of WE, and (3) demonstrate knowledge of practice parameters for the use of Privacy Policy: http://www.mayoclinic.org/global/privacy.html
thiamine in WE. Questions? Contact dletcsupport@mayo.edu.

Abstract

Wernicke encephalopathy (WE) was first described by Carl Wernicke in 1881. WE is caused by thiamine
deficiency. Alcoholism is the most common etiologic factor associated with WE in the United States, but
it can occur in any patient with a nutritional deficiency state such as hyperemesis gravidarum, intestinal
obstruction, and malignancy. WE is a clinical diagnosis. The common findings include mental status
changes, ocular dysfunction, and a gait apraxia, present in only 10% of cases. Only a few cases of WE are
diagnosed before death. Approximately 80% of patients with untreated WE have development of Kor-
sakoff syndrome, which is characterized by memory impairment associated with confabulation. The
initial clinical diagnosis of WE is critical, keeping in mind that the classic triad of symptoms is often
absent. Recognition of nutritional deficiency and any portion of the classic triad should prompt treat-
ment. Additionally, hypothermia, hypotension, and coma should raise clinical suspicion for the disease.
Primary treatment includes timely administration of thiamine, for which the route and dosage remain
controversial. Clinical judgment should be exercised in diagnosis and treatment (dosage, frequency,
route of administration and duration) in all cases of WE. Overdiagnosis and overtreatment may be
preferred to prevent prolonged or persistent neurocognitive impairments given the excellent safety

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MAYO CLINIC PROCEEDINGS

profile of thiamine. Further prospective research is warranted to better understand the disease
biology, risk factors, and treatment recommendations.
ª 2019 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(6):1065-1072

W
ernicke encephalopathy (WE) Patients with alcoholism and malnutrition
is an often underrecognized are also often deficient in magnesium, a
condition with estimates sug- cofactor for normal functioning of
gesting that only about 15% of cases of WE thiamine-dependent enzymes and neuro-
are diagnosed before death.1 The primary chemical transmission.5 The brain lesions
etiology of WE is thiamine deficiency. of WE follow a symmetric distribution
Although alcoholism is the most common among structures that surround the third
predisposing factor in the United States, and fourth ventricles and the aqueduct.
WE can also occur in patients with nutri- The most commonly affected structures are
tional deficiency states such as hyperemesis mammillary bodies, involved in up to 80%
gravidarum, intestinal obstruction, bariatric of cases of WE.6 Lesions in the dorsomedial
surgery, cancer chemotherapy, hemodialysis, thalamus have been associated with reported
and malignant diseases.2 One of the index memory loss in WE. Atypical lesions, usually
cases that Carl Wernicke described in 1881 associated with nonealcohol-related cases of
was a 20-year-old nonalcoholic seamstress WE, can be located in the cerebellum, ver-
who attempted suicide by ingesting sulfuric mis, cranial nerve nuclei, red nuclei, dentate
acid and subsequently had development of nuclei, caudate nuclei, splenium, and cere-
pyloric stenosis leading to a nutritional defi- bral cortex.2
ciency of thiamine.2 WE can occur in pediat-
ric patients, with most of the cases secondary Clinical Features
to malignancy.3 In some individuals, thia- The classic clinical triad of the syndrome
mine deficiency may not be apparent. In consists of mental status changes, ophthal-
such subclinical cases, WE can be unmasked moplegia, and gait ataxia (Table 1). Clini-
by administration of a carbohydrate load cians are taught to expect a very distinct,
(iatrogenic) and diagnosis of conditions unique, and striking presentation, which
such as hypomagnesemia, thyrotoxicosis, may in fact be present in only 10% of cases.7
and refeeding syndrome among others. Absence of such a stereotypical presentation
reinforces the misconception that WE is
THIAMINE DEFICIENCY AND RESULTANT rare. Clinicians, particularly those working
BRAIN DAMAGE in the emergency setting, need to be aware
WE is the most important encephalopathy of the clinical variability of WE because
occurring because of a single vitamin defi- most patients will present to the emergency
ciency. Thiamine is an important cofactor department and the disorder will remain un-
for several key enzymes responsible for the diagnosed.2 Consequently, the syndrome is
maintenance of cerebral energy homeostasis. most often recognized only at autopsy. The
These include a-ketoglutarate dehydroge- most consistent characteristic of the syn-
nase and pyruvate dehydrogenase of the drome is a change in mental status.7 The
Krebs cycle and transketolase of the pentose cognitive changes range from apathy and
phosphate pathway4 (Figure). Toxic inter- mild neurocognitive symptoms to severe
mediates accumulate due to a decrease in symptoms including, in rare situations,
enzyme activity. Thiamine deficiency also coma.8 The second most common character-
impairs the conversion of pyruvate to acetyl istic is ophthalmoplegia, but other ocular
coenzyme A. This, in turn, increases lactic findings may be present. Complete ophthal-
acid production. All of these intermediates moplegia occurs rarely, whereas horizontal
induce tissue injury by inhibiting meta- nystagmus is the most common ocular ab-
bolism in areas of the brain with high meta- normality.8 The other ocular findings
bolic requirement and thiamine turnover. include sixth nerve palsy, ptosis, retinal
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THIAMINE DEFICIENCY AND WERNICKE ENCEPHALOPATHY

Pentose phosphate pathway


Glucose
Oxidative Ribulose-5- Nonoxidative
phase phase Ribulose-5-
phosphate
Glucose-6-phosphate phosphate
+ Transketolase other sugars
NADPH and other enzymes

Glycolysis
Pyruvate Lactate
Pyruvate
dehydrogenase
Fatty acids Lipids
Acetyl-CoA
Amino acids Proteins

Acetylcholine Oxaloacetate
myelin
Citric acid
Citric acid
cycle

α-Ketoglutarate Thiamine-dependent enzymes


dehydrogenase
α-Ketoglutarate

Neurotransmitter
(e.g. glutamate)

FIGURE. Role of thiamine in various enzymatic pathways. CoA ¼ coenzyme A; NADPH ¼ nicotinamide
adenine dinucleotide phosphate.

hemorrhage, papilledema, anisocoria, or Korsakoff syndrome can present without ev-


miosis.2 It is suggested that the term idence of acute signs and symptoms of WE.2
“ocular” should replace ophthalmoplegia in
the clinical triad.2 The third and final charac- Other Clinical Manifestations Associated
teristic is gait ataxia, the presentation of With Thiamine Deficiency
which can range from mild gait abnormality Thiamine deficiency can also present as
to a complete inability to stand.2 Addition- other syndromes such as dry beriberi (neu-
ally, the presence of hypothermia, hypoten- ropathy), wet beriberi (neuropathy with
sion, and coma should increase the index high-output congestive heart failure), gastro-
of suspicion for the disease.2 All the afore- intestinal beriberi (abdominal pain, vomit-
mentioned clinical findings are derived ing, and lactic acidosis), and coma with
from retrospective studies. Thus, in the Marchiafava-Bignami disease.9,10 High-
absence of large prospective data, the precise output congestive heart failure, although
prevalence of symptoms/signs of WE cannot far less common than neuropathy, can pre-
be determined. Approximately 80% of pa- sent with tachycardia, dyspnea on exertion,
tients with untreated WE have development electrocardiographic abnormalities, and
of Korsakoff syndrome.8 Korsakoff syn- other symptoms. Peripheral edema may or
drome consists of permanent memory may not be a clinical feature in wet beriberi.2
impairment associated with confabulation.8 Favorable outcome has been noted in such
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MAYO CLINIC PROCEEDINGS

performed in patients dying from symptoms


TABLE 1. Clinical Triad of Wernicke
suggestive of WE for further clarification.12
Encephalopathy
The diagnosis of WE is primarily clinical,
1. Encephalopathy
yet the classic triad of memory impairments,
d Disorientation

d Indifference
ophthalmoplegia, and cerebellar signs such
d Inattentiveness
as gait ataxia are reported in only 10% of
d Decreased loss of consciousness the cases.7 In an attempt to reconsider diag-
d Memory impairment nostic criteria for WE, Caine et al13 studied
the clinical features of 28 alcoholic patients
2. Oculomotor abnormalities
d Nystagmus
with autopsy-proven WE who were exten-
d Lateral rectus palsy
sively evaluated during life. They concluded
d Conjugate gaze palsy that in a cohort of known alcoholics, any 2
d Internuclear ophthalmoplegia of the following 4 conditions should prompt
d Unequal pupils a presumptive diagnosis: (1) nutritional defi-
d Light-near dissociation
ciency, (2) ocular findings, (3) ataxia, and
d Retinal hemorrhage
(4) mental status changes. A case series
d Papilledema
based on the criteria proposed by Caine
3. Gait ataxia/cerebellar dysfunction et al found that clinical features of WE could
d Primarily stance and gait vary significantly between alcohol-related
d Unlike alcoholic cerebellar degeneration, Wernicke and nonealcohol-related etiologies. It was
encephalopathy has no upper limb ataxia noted that dietary deficiency and vomiting
Other: Peripheral neuropathy, hypothermia, were more frequent among nonalcoholics,
hypotension, cardiac failure, coma whereas eye and cerebellar signs were more
frequent among alcoholics.12 Also, the
classic triad was significantly more common
cases after thiamine replacement.11 Neuro- in alcoholics than in nonalcoholics. A
pathic beriberi is a sensorimotor peripheral consensus guideline from the European
neuropathy that often involves the lower ex- Federation of Neurological Societies recom-
tremities. It is painful and could result from mends that the clinical diagnosis of WE
deficiency of multiple B vitamins, especially should take into account the different pre-
pyridoxine and pantothenic acid.2,8 Notably, sentations of clinical signs between alco-
patients receiving total parenteral nutrition holics and nonalcoholics and the higher
can present with components of all forms prevalence of the disease in alcoholics.12
of deficiency syndromes. In some of these Thiamine levels can be measured using
cases, the predominant presenting symptom high-performance liquid chromatography.
had been abdominal pain and lactic acidosis, The most commonly used method measures
which can result in emergency exploratory free thiamine levels in plasma using high-
laparotomy with negative results.2 performance liquid chromatography; howev-
er, the result is not immediately available
Diagnostic Challenges and lacks sensitivity and specificity for diag-
WE often is undiagnosed until after death. nosing active disease. A less commonly used,
One autopsy study confirmed that WE was although more accurate, method involves
suspected in only about one-third of alco- detecting monophosphorylated and diphos-
holic and 6% of nonalcoholic patients during phorylated thiamine in whole red blood cells
their lifetime. This report could represent given that the majority of the blood’s thia-
extreme cases, and the number of patients mine is present in such cells.14 Even though
remaining undiagnosed before death is prob- laboratory assay is not diagnostic for WE, it
ably higher. These findings suggest that most can identify patients with very low circu-
cases of WE are likely to remain unrecog- lating levels of thiamine who are at risk of
nized and undiagnosed during life.12 It has development of WE. Thiamine assay is
also been suggested autopsy should be important in cases of ambiguous
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THIAMINE DEFICIENCY AND WERNICKE ENCEPHALOPATHY

presentation and can be measured before


TABLE 2. Diagnostic Mimics of Wernicke
administration of thiamine.2
Encephalopathy
In terms of imaging, computed tomogra-
1. Drugs and toxins
phy is not a reliable test for WE.12 Conven-
d Prescription medications (eg, opioids, sedative-
tional magnetic resonance imaging (MRI)
hypnotics, antipsychotics, lithium, skeletal muscle
performs better and can identify WE- relaxers, polypharmacy)
related lesions in two-thirds of patients.12 d Nonprescription medications (eg, antihistamines)

Areas of increased T2 and fluid-attenuated d Drugs of abuse (eg, ethanol, heroin, hallucinogens,

inversion recovery signals, decreased T1 nonmedicinal use of prescription medications)


d Withdrawal states (eg, ethanol, benzodiazepines)
signal, and diffusion abnormality surround-
ing the aqueduct and third ventricle and 2. Medication adverse effects (eg, hyperammonemia
within the medial thalamus, dorsal medulla, from valproic acid, confusion from quinolones,
tectal plate, and mammillary bodies can be serotonin syndrome)
typically identified on the MRI. Involvement 3. Sepsis/infection
of corpus callosum on MRI should raise sus- 4. Metabolic derangements
picion for Marchiafava-Bignami disease, a d Electrolyte disturbance (elevated or depressed): so-

rare disorder seen in people with chronic dium, calcium, magnesium, phosphate
d Endocrine disturbance (depressed or increased):
alcohol consumption and malnutrition due
to vitamin B complex deficiencies. It can pre- thyroid, parathyroid, pancreas, pituitary, adrenal
d Hyperglycemia and hypoglycemia
sent in a similar fashion as WE and should d Hyperosmolar and hypo-osmolar states
be considered in the differential diagnosis.15 d Hypercarbia and hypoxia
However, performing MRI on an emergent d Inborn errors of metabolism: porphyria, Wilson

basis for this indication is cumbersome. disease


Overall, thiamine administration, either in
5. Brain disorders
high or low dosage, is considered low risk
d Central nervous system infection
and untreated patients could have serious d Seizures, especially nonconvulsive status epilepticus
adverse consequences. Thus, any form of d Head trauma

diagnostic testing (either laboratory or diag- d Hypertensive encephalopathy

nostic imaging) should not delay treatment d Psychiatric conditions

in individuals suspected of having WE.16


6. System organ failure
d Cardiac, kidney, and liver failure
Caveats
Other medical conditions (Table 2) such as
stroke, drug overdose, other encephalopa-
thies, and infections such as meningitis is considerable comorbidity between eating
could mimic WE. These disorders should disorders and substance use disorders. The
be thoroughly evaluated, particularly in pa- subgroup of patients with AN and alcohol
tients at low risk for WE.2 Conversely, WE use disorders is at higher risk of develop-
can be precipitated in high-risk patients ment of WE.19 Patients who have undergone
such as those with critical illness or sepsis bariatric surgery are another group at risk of
due to increased metabolic demand causing development of WE due to thiamine malab-
relative thiamine deficiency. In patients sorption and greater incidence of alcohol
with cancer, absolute thiamine deficiency abuse among such patients.20 Patients with
can occur because of malabsorption, malnu- AN and alcohol use disorders should be
trition, or vomiting, triggering WE.6-8,17 referred to specialty care for evidence-based
In patients with eating disorders such as evaluation and treatment recommendation.
anorexia nervosa (AN), self-imposed long-
term nutritional deprivation can lead to thia- Treatment
mine deficiency. Individuals who have rapid The mainstay of treatment is administration
weight loss are particularly vulnerable to of thiamine in a timely fashion. Diagnostic
development of WE.18 Additionally, there confirmation is often difficult and delayed,
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and therefore a high degree of clinical suspi- will require parenteral administration of
cion and recognition of disease should thiamine.2 Patients with nonacute WE will
prompt the clinician to initiate treatment at receive prophylactic oral thiamine in the
the earliest opportunity. This practice is outpatient setting.2 Education on the adverse
based on opinion that thiamine is relatively consequences of thiamine deficiency should
inexpensive and safe, and its quick adminis- be incorporated into the treatment plan.
tration has been reported to prevent progres-
sion of WE to irreversible deficits of Prevention
Korsakoff syndrome.21 Oral administration of thiamine at 100 mg 3
However, there is no consensus on the times daily may be reserved for patients with
effective dose of thiamine, route of adminis- low suspicion of deficiency for prophylaxis
tration, daily dose frequency, or the duration or after correction through parenteral
of the treatment. The traditional recommen- administration. This treatment is based on
dation is a parenteral thiamine dosage of 100 standard clinical practice because insuffi-
mg/d.8 This recommendation is not based on cient evidence exists in the literature to sup-
controlled trials. Some reports argue that port this recommendation. Another mode of
dosages higher than 100 mg are required WE prevention has been studied in
for the treatment of WE, especially in alco- Australia, where the incorporation of thia-
holics.7,8,22 Chronic alcohol users are mine to bread flour was found to decrease
susceptible to poor nutritional intake, the prevalence of WE in a prospective au-
gastrointestinal malabsorption, and reduced topsy study.25 This practice has been adop-
hepatic reserve. It is logical that alcoholics ted by many other Western countries
will require a higher daily dosage of thia- where food is fortified with thiamine and
mine. High-dose parenteral administration other essential vitamins.
will also facilitate better passive diffusion of
thiamine across the blood-brain barrier.23 Does Treatment Work?
In terms of parenteral administration, the Thiamine administration can improve symp-
intravenous route is preferred over intra- toms to a certain extent, especially if admin-
muscular.2 Pharmacokinetic studies have istered promptly. Ocular findings respond
documented that the plasma half-life of thia- well to treatment. The response to thiamine
mine is only 96 minutes.24 Thus, adminis- administration on ocular findings is quite
tering thiamine 2 to 3 times daily might predictable and constant. Failure of recovery
achieve better bioavailability than a single should alert the physician to consider alter-
dose. Adverse reactions to thiamine are native diagnoses. In most cases, horizontal
rare. As such, thiamine is very well tolerated and vertical gaze palsies and ptosis recover
regardless of the route of administration or completely within days to weeks. Although
dosage form.2 The European Federation of horizontal nystagmus shows dramatic recov-
Neurological Societies guideline recom- ery soon after treatment with thiamine, it
mends intravenous infusion of thiamine, can persist in a subtle manner for months
200 mg diluted with 100 mL of normal sa- in up to 60% of the patients.21
line or 5% dextrose, given over 30 minutes Delayed recovery is seen in gait ataxia in
3 times daily in cases of WE.12 In nutrition- contrast to ocular signs and symptoms. Some
ally deficient patients, thiamine should be patients experience complete improvement,
administered before glucose to avoid iatro- although most are left with residual gait dis-
genic occurrence of WE. Because magne- turbances. In patients with chronic dementia
sium serves as a cofactor for thiamine of unclear reason, fine horizontal nystagmus
activity, its level should also be checked and gait abnormalities can be clues to
and be supplemented via oral or parenteral alcohol-related etiology.21
administration in cases of hypomagnese- Mental status changes and acute enceph-
mia.5 Hospital admission is recommended alopathy often gradually recede, but residual
for the management of acute WE, which neurologic deficits are common and
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THIAMINE DEFICIENCY AND WERNICKE ENCEPHALOPATHY

persistent.2 Mild neurocognitive symptoms intellectual content; Archish Katariad


such as apathy, drowsiness, and confusion design, drafting of work, revising for impor-
respond well to treatment. Memory and tant intellectual content; Bhanu Prakash
learning deficits, on the other hand, show Kolladrevising for important intellectual
poor recovery, and unfortunately, many content; Nuria Thusiusdrevising for
patients are left with permanent residual important intellectual content; Larissa
Korsakoff amnesia. Loukianovadapproval of the version to be
published.
CONCLUSION
Abbreviations and Acronyms: AN = anorexia nervosa;
Wernicke encephalopathy is a medical emer- MRI = magnetic resonance imaging; WE = Wernicke
gency that is poorly understood and underre- encephalopathy
cognized. Although most prevalent in
patients with alcohol use disorders, anyone
Potential Competing Interests: Dr Sinha has received
who has a nutritional deficiency of thiamine grant funding from UCare. The other authors report no
is at high risk for development of WE. A competing interests.
high index of suspicion should be maintained
Correspondence: Address to Shirshendu Sinha, MBBS,
in specific patient cohorts such those with ma-
Department of Psychiatry and Psychology, Mayo Clinic
lignant diseases or eating disorders and those Health SystemeSouthwest Minnesota Region, 101 Martin
who have undergone bariatric surgery. The Luther King Jr Dr, Mankato, MN 56001 (sinha.shirshendu@
classic clinical triad of the syndrome consist- mayo.edu).
ing of altered mental status, eye movement
disorders, and gait ataxia may be present in REFERENCES
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MAYO CLINIC PROCEEDINGS

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