Wernicke encephalopathy (WE), also Wernicke's encephalopathy, 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). 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.Ropper A, Brown R. Princ. of Neurology, Adams & Victor. 8º ed. McGraw Hill 2007.
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. While it is commonly regarded as a condition particular to malnourished people who abuse alcohol, it can be caused by a variety of diseases. It is treated with thiamine supplementation, which can lead to improvement of the symptoms and often complete resolution, particularly in those where alcohol abuse is not the underlying cause. 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.
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.
Signs and symptoms The classic triad of symptoms found in Wernicke encephalopathy is: Ophthalmoplegia: later expanded to include other eye movement disorders; typically affecting the lateral rectus muscle. 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.
Other possible symptoms include: Pupillary changes, Retinal haemorrhage, papilledema, and impaired vision and hearing. Fatiguability, apathy, irritability, drowsiness, psychological slowing and/or motor slowing. Dysphagia, blushing, sleep apnea, epilepsy and stupor. Lactic acidosis. Memory impairment, amnesia, depression, and psychosis. Hypothermia, polyneuropathy, and hyperhidrosis.
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. 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.
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. The lack of thiamine sometimes affects other major energy consumers, the myocardium, and also patients may have developed cardiomegaly. Heart failure with lactic acidosis syndrome has been observed. Cardiac abnormalities are an aspect of the WE, which was not included in the traditional approach, and are not classified as a separate disease. Infections have been pointed out as one of the most frequent triggers of death in WE. Furthermore, infections are usually present in pediatric cases.
In the last stage, other symptoms may occur: hyperthermia, increased muscle tone, spastic paralysis, choreic dyskinesias, and coma.
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.
Early symptoms are nonspecific, and it has been stated that WE may present nonspecific findings. In Wernicke Korsakoff's syndrome some single symptoms are present in about one-third.
Location of the lesion Depending on the location of the brain lesion, different symptoms are more frequent: 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 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. 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. Korsakoff's occurs much more frequently in WE due to chronic alcoholism. 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. In Korsakoff's, atrophy of the thalamus and the mammillary bodies and frontal lobe involvement is usually observed. In a study, half of Wernicke–Korsakoff cases had good recovery from the amnesic state, which may take from 2 months to 10 years.
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. Without being exhaustive, the documented causes of Wernicke encephalopathy have included: pancreatitis, liver dysfunction, chronic diarrhea, celiac disease, Crohn's disease, uremia, thyrotoxicosis vomiting, hyperemesis gravidarum, malabsorption, gastrointestinal surgery or diseases incomplete parenteral nutrition, starvation/fasting chemotherapy, renal dialysis, diuretic therapy, stem cell/marrow transplantation cancer, AIDS, Creutzfeldt–Jakob disease, febrile infections 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. 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. The APOE epsilon-4 allele, involved in Alzheimer's disease, may increase the chance of developing neurological symptoms.
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. Thiamine is involved in: Metabolism of carbohydrates, releasing energy. Production of neurotransmitters including glutamic acid and GABA. Lipid metabolism, necessary for myelin production. Amino acid modification. Probably linked to the production of taurine, of great cardiac importance.
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. 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. Focal lactic acidosis also causes secondary oedema, oxidative stress, inflammation and white matter damage.
Pathological anatomy
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.
Lesions can be reversed in most cases with immediate supplementation of thiamine.
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. Chronic cases can present the atrophy of the mammillary bodies.
In 1949, the idea that WE lesions are a result of a disruption to the blood-brain barrier was introduced. 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.
An altered blood–brain barrier may cause a perturbed response to certain drugs and foods.
Diagnosis Diagnosis of Wernicke encephalopathy or disease is made clinically. 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. 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. 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.
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. These abnormalities may include: Dorsomedial thalami, periaqueductal gray matter, mamillary bodies, tectal plate and brainstem nuclei are commonly affected. 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.