Wernicke encephalopathy

Wernicke encephalopathy (WE), also Wernicke's encephalopathy,<ref name="MeSH">Template:Cite web</ref> or wet brain is the presence of neurological symptoms caused by biochemical lesions of the central nervous system after exhaustion of B-vitamin reserves, in particular thiamine (vitamin B₁).<ref name = "Oudman_2022">Template:Cite journal</ref> The condition is part of a larger group of thiamine deficiency disorders that includes beriberi, in all its forms, and alcoholic Korsakoff syndrome. When it occurs simultaneously with alcoholic Korsakoff syndrome it is known as Wernicke–Korsakoff syndrome.<ref name=SULLIVAN2012>Template:MEDRSTemplate:Cite journal</ref><ref name="ropper">Ropper A, Brown R. Princ. of Neurology, Adams & Victor. 8º ed. McGraw Hill 2007.</ref>

Classically, Wernicke encephalopathy is characterised by a triad of symptoms: ophthalmoplegia, ataxia, and confusion. Around 10% of patients exhibit all three features, and other symptoms may also be present.<ref name=pmid11304070>Template:Cite journal</ref> While it is commonly regarded as a condition particular to malnourished people with alcohol misuse, it can be caused by a variety of diseases.<ref name=SULLIVAN2012 /><ref name=EFNS/> It is treated with thiamine supplementation, which can lead to improvement of the symptoms and often complete resolution, particularly in those where alcohol misuse is not the underlying cause.<ref>Template:Cite journal</ref> Often other nutrients also need to be replaced, depending on the cause. Medical literature notes how managing the condition in a timely fashion can avoid worsening symptoms.<ref name="EFNS">Template:Cite journal</ref><ref>Template:Citation</ref><ref name="Wernicke-Korsakoff syndrome despite">Template:Cite journal</ref>

Wernicke encephalopathy may be present in the general population with a prevalence of around 2%, and is considered underdiagnosed; probably, many cases are in patients who do not have commonly-associated symptoms.<ref>Template:Cite journal</ref>

Signs and symptoms

The classic triad of symptoms found in Wernicke encephalopathy is:<ref name="LOUGH2012">Template:Cite journal</ref>

• Ophthalmoplegia: later expanded to include other eye movement disorders; typically affecting the lateral rectus muscle.<ref name="LOUGH2012" /> Lateral nystagmus is the most commonly seen disorder, but lateral rectus palsy—usually bilateral—is common, as well.
• Ataxia: later expanded to include imbalance or any cerebellar dysfunction.
• Confusion: later expanded to include any neuropsychological disturbances. Prevalent in roughly eight in 10 diagnosed cases.Template:Medical citation needed

Other possible symptoms include:

• Pupillary changes, Retinal haemorrhage, papilledema,<ref>Template:Cite journal</ref> and impaired vision and hearing.<ref name="Chitra 53–6">Template:Cite journal</ref><ref name=TRUSWELL2000 /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Fatiguability, apathy, irritability, drowsiness, psychological slowing and/or motor slowing.<ref name="Harper1986" />
• Dysphagia,<ref name="Puiggros_1994">Template:Cite book</ref> blushing, sleep apnea, epilepsy<ref>Template:Cite journal</ref> and stupor.
• Lactic acidosis.<ref>Template:Cite journal</ref>
• Memory impairment,<ref name="LOUGH2012" /> amnesia,<ref>Template:Cite journal</ref> depression,<ref>Template:Cite journal</ref> and psychosis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Hypothermia,<ref name=TRUSWELL2000>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> polyneuropathy,<ref name=Rohkamm2004>Template:Cite bookTemplate:Page needed</ref>Template:Failed verification and hyperhidrosis.<ref name="Puiggros_1994"/><ref>Template:Cite book</ref>

Although hypothermia is usually diagnosed with a body temperature of 35 °C (95 °F) or less, incipient cooling caused by deregulation in the central nervous system (CNS) needs to be monitored because it can promote the development of an infection.<ref name="Puiggros_1994"/> The patient may report feeling cold, followed by mild chills, cold skin, moderate pallor, tachycardia, hypertension, tremor, or piloerection. External warming techniques are advised to prevent hypothermia.Template:Citation needed

Among the frequently altered functions is the cardio-circulatory. There may be tachycardia, dyspnea, chest pain, orthostatic hypotension, changes in heart rate and blood pressure.<ref name="Rohkamm2004p148">Template:Cite book</ref> The lack of thiamine sometimes affects other major energy consumers, the myocardium, and also patients may have developed cardiomegaly.<ref>Template:Cite journal</ref> Heart failure with lactic acidosis syndrome has been observed.<ref>Template:Cite journal</ref> Cardiac abnormalities are an aspect of the WE, which was not included in the traditional approach,<ref name="ropper" /><ref name = "Zarranz_2007" /> and are not classified as a separate disease. Infections have been pointed out as one of the most frequent triggers of death in WE.<ref name="Brown_2007" /><ref name="Zarranz_2007" /> Furthermore, infections are usually present in pediatric cases.<ref name="Vasconcelos_1999">Template:Cite journal</ref><ref name="Fattal-Valevski_2005">Template:Cite journal</ref>

In the last stage, other symptoms may occur: hyperthermia, increased muscle tone, spastic paralysis, choreic dyskinesias, and coma.Template:Citation needed

Because of the frequent involvement of the heart, eyes, and peripheral nervous system, several authors prefer to call it Wernicke disease rather than simply encephalopathy.<ref name="ropper" /><ref name="Hauser_2010" />

Early symptoms are nonspecific,<ref name="Phee_2009"/><ref name="Johnson_2022">Template:Cite web</ref> and it has been stated that WE may present nonspecific findings.<ref name=pmid17434099>Template:Cite journal</ref> In Wernicke Korsakoff's syndrome some single symptoms are present in about one-third.<ref>Template:Cite book</ref>

Location of the lesion

Depending on the location of the brain lesion, different symptoms are more frequent:Template:Citation needed

• Brainstem tegmentum. – Ocular: pupillary changes. Extraocular muscle palsy; gaze palsy: nystagmus.
• Hypothalamus. Medulla: dorsal nuc. of vagus. – Autonomic dysfunction: temperature, cardiocirculatory, respiratory.
• Medulla: vestibular region. Cerebellum. – Ataxia.
• Dorsomedial nuc. of the thalamus. Mammillary bodies. – Amnestic syndrome for recent memory.

Mamillary lesions are characteristic-small petechial hemorrhages.

• Diffuse cerebral dysfunction.- Altered cognition: global confusional state.
• Brainstem: periaqueductal gray.- Reduction of consciousness<ref>Template:Cite book</ref>
• Hypothalamic lesions may also affect the immune system, which is known in people who consume excessive amounts of alcohol, causing dysplasias and infections.

Korsakoff syndrome

Korsakoff syndrome, characterised by memory impairment, confabulation, confusion, and personality changes, has a strong and recognised link with WE.<ref name=SULLIVAN2012 /><ref name="Thompson_2012">Template:Cite journal</ref> A very high percentage of patients with Wernicke–Korsakoff syndrome also have peripheral neuropathy, and many people who consume excess alcohol have this neuropathy without other neurologic signs or symptoms.<ref name = "Cecil_2007">Template:Cite book</ref> Korsakoff's occurs much more frequently in WE due to chronic alcoholism.<ref name="Thompson_2012" /> It is uncommon among those who do not consume excessive amounts of alcohol. Up to 80% of WE patients who misuse alcohol develop Korsakoff's syndrome.<ref name=pmid17434099/> In Korsakoff's, atrophy of the thalamus and the mammillary bodies and frontal lobe involvement is usually observed.<ref name=pmid17434099/> In a study, half of Wernicke–Korsakoff cases had good recovery from the amnesic state, which may take from 2 months to 10 years.<ref name = "Oudman_2022" />

Risk factors

Wernicke encephalopathy has classically been thought of as a disease solely of people who drink excessive amounts of alcohol, but it is also found in the chronically undernourished, and in recent years has been discovered post bariatric surgery.<ref name="LOUGH2012" /><ref name=pmid17434099/> Without being exhaustive, the documented causes of Wernicke encephalopathy have included:

• pancreatitis, liver dysfunction, chronic diarrhea, celiac disease, Crohn's disease, uremia,<ref name=pmid17434099/> thyrotoxicosis<ref name="MedlinePlus">Template:MedlinePlusEncyclopedia</ref>
• vomiting,<ref name=EFNS/> hyperemesis gravidarum,<ref name="MedlinePlus" /> malabsorption, gastrointestinal surgery or diseases<ref name=EFNS/>
• incomplete parenteral nutrition,<ref name="MedlinePlus" /> starvation/fasting<ref name=EFNS/>
• chemotherapy,<ref name=pmid17434099/> renal dialysis,<ref name="MedlinePlus" /> diuretic therapy,<ref name="MedlinePlus" /> stem cell/marrow transplantation<ref name=EFNS/>
• cancer, AIDS,<ref>Template:Cite journal</ref> Creutzfeldt–Jakob disease,<ref name="LOUGH2012" /><ref>Template:Cite journal</ref> febrile infections<ref name=EFNS />
• this disease may even occur in some people with normal, or even high blood thiamine levels, or people with deficiencies in intracellular transport of this vitamin.<ref name="LOUGH2012" /> Selected genetic mutations, including presence of the X-linked transketolase-like 1 gene, SLC19A2 thiamine transporter protein mutations, and the aldehyde dehydrogenase-2 gene, which may predispose to alcohol use disorder.<ref name=pmid17434099/> The APOE epsilon-4 allele, involved in Alzheimer's disease, may increase the chance of developing neurological symptoms.<ref name=pmid17434099/>

Pathophysiology

Thiamine deficiency and errors of thiamine metabolism are believed to be the primary cause of Wernicke encephalopathy. Thiamine, also called B₁, helps to break down glucose. Specifically, it acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt. Thiamine is first metabolised to its more active form, thiamine diphosphate (TDP), before it is used. The body only has 2–3 weeks of thiamine reserves, which are readily exhausted without intake, or if depletion occurs rapidly, such as in chronic inflammatory states or in diabetes.<ref name="LOUGH2012" /><ref name=pmid17434099/> Thiamine is involved in:<ref name=pmid17434099/><ref>Template:Cite journal</ref>

1. Metabolism of carbohydrates, releasing energy.
2. Production of neurotransmitters including glutamic acid and GABA.
3. Lipid metabolism, necessary for myelin production.
4. Amino acid modification. Probably linked to the production of taurine, of great cardiac importance.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Neuropathology

The primary neurological-related injury caused by thiamine deficiency in WE is three-fold: oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway.<ref name=HIRSCH2012>Template:Cite journal</ref> Thiamine deficiency affects both neurons and astrocytes, glial cells of the brain. Thiamine deficiency alters the glutamate uptake of astrocytes, through changes in the expression of astrocytic glutamate transporters EAAT1 and EAAT2, leading to excitotoxicity. Other changes include those to the GABA transporter subtype GAT-3, GFAP, glutamine synthetase, and the Aquaporin 4 channel.<ref>Template:Cite journal</ref> Focal lactic acidosis also causes secondary oedema, oxidative stress, inflammation and white matter damage.<ref>Template:Cite journal</ref>

Pathological anatomy

File:Cerebellum small.gif

Cerebellum

Despite its name, WE is not related to Wernicke's area, a region of the brain associated with speech and language interpretation.

Brain lesions in WE are usually credited to focal lactic acidosis. An absence of thiamine can lead to too much pyruvate within the cells since it is not available to help convert pyruvate through the TCA cycle. An increase in pyruvate causes an increase in lactate concentration leading to focal lactic acidosis.<ref name=":02">Template:Cite journal</ref>

Lesions can be reversed in most cases with immediate supplementation of thiamine.Template:Citation needed

Lesions are usually symmetrical in the periventricular region, diencephalon, the midbrain, hypothalamus, and cerebellar vermis. Brainstem lesions may include cranial nerve III, IV, VI and VIII nuclei, the medial thalamic nuclei, and the dorsal nucleus of the vagus nerve. Oedema may be found in the regions surrounding the third ventricle, and fourth ventricle, also appearing petechiae and small hemorrhages.<ref name="Powell_2003" /> Chronic cases can present the atrophy of the mammillary bodies.<ref name="Zuccoli_2009">Template:Cite journal</ref>

In 1949, the idea that WE lesions are a result of a disruption to the blood-brain barrier was introduced.<ref name=":02"/> Large proteins passing into the brain can put neurological tissue at risk of toxic effects. The blood-brain barrier junctions are typically found to have WE lesions located at that region of the brain.<ref name=":02"/>

An altered blood–brain barrier may cause a perturbed response to certain drugs and foods.<ref name="Cernicchiaro_2017">Template:Cite web Template:Self-published inlineTemplate:MEDRS</ref>

Diagnosis

Diagnosis of Wernicke encephalopathy or disease is made clinically.<ref name=EFNS/><ref>Template:Cite book</ref> Caine et al. in 1997 established criteria that Wernicke encephalopathy can be diagnosed in any patient with just two or more of the main symptoms noted above.<ref name=CAINE1997>Template:Cite journal</ref> The sensitivity of the diagnosis by the classic triad was 23% but increased to 85% taking two or more of the four classic features. These criteria are challenged because all the cases he studied were people who drank excessive amounts of alcohol. Some consider it sufficient to suspect the presence of the disease with only one of the principal symptoms.<ref name=pmid11304070/> Some British hospital protocols suspect WE with any one of these symptoms: confusion, decreased consciousness level (or unconsciousness, stupor or coma), memory loss, ataxia or unsteadiness, ophthalmoplegia or nystagmus, and unexplained hypotension with hypothermia. The presence of only one sign should be sufficient for treatment.<ref name="ReferenceA">Template:Cite report</ref>

The sensitivity of magnetic resonance imaging (MR) was 53% and the specificity was 93%. The reversible cytotoxic edema was considered the most characteristic lesion of WE. The location of the lesions were more frequently atypical among people who drank appropriate amounts of alcohol, while typical contrast enhancement in the thalamus and the mammillary bodies was observed frequently associated with alcohol misuse.<ref name="Zuccoli_2009"/> These abnormalities may include:<ref name="LOUGH2012" />

• Dorsomedial thalami, periaqueductal gray matter, mamillary bodies, tectal plate and brainstem nuclei are commonly affected.<ref>Template:Cite journal</ref> Involvement is always bilateral and symmetric. Value of DWI in the diagnosis of WE is minimal. Axial FLAIR MRI images represent the best diagnostic MRI sequence. Contrast material may highlight involvement of the mamillary bodies.

There appears to be very little value for CT scans.<ref name=EFNS/>

Thiamine can be measured using an erythrocyte transketolase activity assay,<ref name=EFNS/> or by activation by measurement of in vitro thiamine diphosphate levels.<ref name="EFNS" /> Normal thiamine levels do not necessarily rule out the presence of WE,<ref name=EFNS/> as this may be a patient with difficulties in intracellular transport.

Prevention

There are hospital protocols for prevention, supplementing with thiamine in the presence of: history of alcohol misuse or related seizures, requirement for IV glucose, signs of malnutrition, poor diet, recent diarrhea or vomiting, peripheral neuropathy, intercurrent illness, delirium tremens or treatment for DTs, and others.<ref name="ReferenceA"/><ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Some experts advise parenteral thiamine should be given to all at-risk patients in the emergency department.<ref name=EFNS/>

In the clinical diagnosis should be remembered that early symptoms are nonspecific,<ref name="Phee_2009" /><ref name="Johnson_2022" /> and it has been stated that WE may present nonspecific findings.<ref name=pmid17434099/> There is consensus to provide water-soluble vitamins and minerals after gastric operations.<ref>Template:Cite journal</ref>

In some countries certain foods have been supplemented with thiamine, and have reduced WE cases. Improvement is difficult to quantify because they applied several different actions. Avoiding or moderating alcohol consumption and having adequate nutrition reduces one of the main risk factors in developing Wernicke–Korsakoff syndrome.Template:Citation needed.

Treatment

Most symptoms will improve quickly if deficiencies are treated early. Memory disorder may be permanent.<ref name = "Cecil_2007" />

In patients suspected of WE, thiamine treatment should be started immediately.<ref name=pmid17434099/> Blood should be immediately taken to test for thiamine, other vitamins and minerals levels. Following this an immediate intravenous or intramuscular dose of thiamine should be administered<ref name = "Hauser_2010">Template:Cite book</ref> two or three times daily. Thiamine administration is usually continued until clinical improvement ceases.<ref name="EFNS"/>

Considering the diversity of possible causes and several surprising symptomatologic presentations, and because there is low assumed risk of toxicity of thiamine, because the therapeutic response is often dramatic from the first day, some qualified authors indicate parenteral thiamine if WE is suspected, both as a resource for diagnosis and treatment.<ref name=EFNS/> The diagnosis is highly supported by the response to parenteral thiamine, but is not sufficient to be excluded by the lack of it.<ref name="pmid18056751">Template:Cite journal</ref> Parenteral thiamine administration is associated with a very small risk of anaphylaxis.<ref>Thomson A, Guerrini I, Marshall EJ. "Incidence of Adverse Reactions to Parenteral Thiamine in the Treatment of Wernicke's Encephalopathy, and Recommendations." Alcohol and Alcoholism. 2019 Nov;54(6):609-614. doi:https://doi.org/10.1093/alcalc/agy091</ref>

People who consume excessive amounts of alcohol may have poor dietary intakes of several vitamins, and impaired thiamine absorption, metabolism, and storage; they may thus require higher doses.<ref name="Phee_2009">Template:Cite book</ref>

If glucose is given, such as in people with an alcohol use disorder who are also hypoglycaemic, thiamine must be given concurrently. If this is not done, the glucose will rapidly consume the remaining thiamine reserves, exacerbating this condition.<ref name=pmid17434099/>

The observation of edema in MR, and also the finding of inflation and macrophages in necropsied tissues,<ref name="Powell_2003">Template:Cite book</ref> has led to successful administration of antiinflammatories.<ref>Template:Cite journal</ref><ref>Template:Cite journal (article in French)</ref>

Other nutritional abnormalities should also be looked for, as they may be exacerbating the disease.<ref name="Brown_2007">Template:Cite book</ref><ref name = "Zarranz_2007">Template:Cite book</ref> In particular, magnesium, a cofactor of transketolase which may induce or aggravate the disease.<ref name=pmid17434099/>

Other supplements may also be needed, including: cobalamin, ascorbic acid, folic acid, nicotinamide, zinc,<ref>Template:Cite book</ref><ref>Template:Cite book</ref> phosphorus (dicalcium phosphate)<ref name="Thomson_2002">Template:Cite journal</ref> and in some cases taurine, especially suitable when there cardiocirculatory impairment.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Patient-guided nutrition is suggested. In patients with Wernicke–Korsakoff syndrome, even higher doses of parenteral thiamine are recommended. Concurrent toxic effects of alcohol should also be considered.<ref name="Thompson_2012" /><ref name="Thomson_2002" />

Epidemiology

There are no conclusive statistical studies, all figures are based on partial studies.

Wernicke's lesions were observed in 0.8 to 2.8% of the general population autopsies, and 12.5% of people with an alcohol use disorder. This figure increases to 35% of such individuals if including cerebellar damage due to lack of thiamine.<ref name="Torvik_1982">Template:Cite journal</ref>

Most autopsy cases were from people with an alcohol use disorder. Autopsy series were performed in hospitals on the material available which is unlikely to be representative of the entire population. Considering the slight affectations, previous to the generation of observable lesions at necropsy, the percentage should be higher. There is evidence to indicate that Wernicke encephalopathy is underdiagnosed.<ref name="Harper1986">Template:Cite journal</ref><ref>Template:Cite journal</ref> For example, in one 1986 study, 80% of cases were diagnosed postmortem.<ref name="Harper1986" /> Is estimated that only 5–14% of patients with WE are diagnosed in life.<ref name="Torvik_1982" /><ref name="Blansjaar_1992">Template:Cite journal</ref>

In a series of autopsy studies held in Recife, Brazil, it was found that only 7 out of 36 had consumed excessive amounts of alcohol, and only a small minority had malnutrition.<ref>Template:Cite journal</ref> In a reviewed of 53 published case reports from 2001 to 2011, the relationship with alcohol was also about 20% (10 out of 53 cases).<ref name="LOUGH2012" />

WE related to alcohol misuse is more common in males and is more common in females when not related to alcohol misuse.<ref name=":02"/> In alcohol-related cases, WE patients average the age of 40, and non-alcohol-related cases typically occur in younger people.<ref name=":02"/>

History

WE was first identified in 1881 by the German neurologist Carl Wernicke, although the link with thiamine was not identified until the 1930s.Template:Citation needed

Carl Wernicke discovered the sensory center of speech. Wernicke figured out that Broca's area was not the only center of speech, it was also able to distinguish motor aphasia from sensory aphasia.<ref name=":2">Template:Cite journal</ref> He also pointed to the possibility of conduction aphasia since he came to understand the arrangement of the brain's extrinsic and intrinsic connections. He demonstrated that the sensory information reached its corresponding area in the cerebral cortex through projection fibers. From there, this information, following the association system, would be distributed to different regions of the cortex, integrating sensory processing.<ref name=":2" />

He reported three patients with WE, including two men (aged 33 and 36) who were alcoholics and one woman (aged 20) who ingested sulfuric acid, leading to pyloric stenosis. All three had ocular motor abnormalities and he performed an autopsy on each, providing a clinical-pathological correlation.<ref>Template:Cite journal</ref>

A similar presentation of this disease was described by the Russian psychiatrist Sergei Korsakoff in a series of articles published 1887–1891;<ref name="LOUGH2012" /> where the chronic version of WE was described as Korsakoff's Syndrome, involving symptoms of amnesia.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Wernicke-Korsakoff syndrome despite"/>