Encephalopathy

Despite the numerous and varied causes of encephalopathy, at least one symptom present in all cases is an altered mental state.

Encephalopathy is a term that refers to brain disease, damage, or malfunction. Encephalopathy can present a very broad spectrum of symptoms that range from mild, such as some memory loss or subtle personality changes, to severe, such as dementia, seizures, coma, or death.

In general, encephalopathy is manifested by an altered mental state that is sometimes accompanied by physical manifestations (for example, poor coordination of limb movements).

The term encephalopathy, in most cases, is preceded by various terms that describe the reason, cause, or special conditions of the patient that lead to brain malfunction. For example, anoxic encephalopathy means brain damage due to lack of oxygen, and hepatic encephalopathy means brain malfunction due to liver disease.

Additionally, some other terms either describe body conditions or syndromes that lead to a specific set of brain malfunctions. Examples of these are metabolic encephalopathy and Wernicke's encephalopathy (Wernicke's syndrome) usually due to a thiamine deficiency or other metabolic issue. There are more than 150 different terms that modify or precede "encephalopathy" in the medical literature; the purpose of this article is to introduce the reader to the main categories of conditions that fall under the broad term of encephalopathy.

There is no single predominant cause of encephalopathy. Encephalopathy encompasses a wide range of brain disorders marked by altered brain function, which can manifest in various ways depending on the underlying cause.

Encephalopathy causes are both numerous and varied. Examples of causes of encephalopathy include:

• infectious (bacteria, viruses, parasites, or prions),
• anoxic (lack of oxygen to the brain, including traumatic causes),
• alcoholic (alcohol toxicity),
• hepatic (for example, liver failure or liver cancer),
• uremic (renal or kidney failure),
• metabolic diseases (hyper- or hypocalcemia, hypo- or hypernatremia, or hypo- or hyperglycemic),
• brain tumors,
• toxic chemicals (mercury, lead, or ammonia),
• alterations in pressure within the brain (often from bleeding, tumors, or abscesses), and
• poor nutrition (inadequate vitamin B1 intake or alcohol withdrawal).

These examples do not cover all of the potential causes of encephalopathy but are listed to demonstrate the wide range of causes.

Although numerous causes of encephalopathy are known, the majority of cases arise from several major categories (some examples in parentheses):

• infection (HIV, Neisseria meningitides, herpes, and hepatitis B and hepatitis C),
• liver damage (alcohol and toxins),
• brain anoxia or brain cell destruction (including trauma and stroke ), and
• kidney failure (uremic).

Some drugs may cause encephalopathy; for example, posterior reversible encephalopathy syndrome (PRES) may occur due to the use of drugs like tacrolimus and cyclosporine. This syndrome manifests with symptoms of headache, confusion, and seizures.

Autoimmune encephalopathy occurs when the immune system unintentionally targets healthy brain cells, which leads to inflammation and a range of neurological symptoms. Some specific causes or conditions associated with autoimmune encephalopathy include:

• Autoimmune antibodies: Certain antibodies specifically target brain tissue. These include antibodies against voltage-gated potassium channel (VGKC) complexes, anti-N-methyl-d-aspartate (NMDA) receptor antibodies (linked to anti-NMDA receptor encephalitis), and antibodies against additional neuronal targets such as LGI1 and CASPR2.
• Systemic autoimmune disorders: Diseases such as systemic lupus erythematosus (SLE) or Sjögren's syndrome can involve the brain, leading to encephalopathy as part of their systemic effects.
• Infectious diseases: Autoimmune encephalopathy is also linked to streptococcal infections and conditions such as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS). These are associated with the bacteria Streptococcus pyogenes.
• Paraneoplastic syndromes: These occur when cancer-fighting antibodies unintentionally attack normal cells in the nervous system. This usually happens in response to a tumor, often before it is detected.
• Hashimoto's encephalopathy: Also referred to as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), it is linked to autoimmunity against thyroid antigens.

Hepatic encephalopathy occurs due to liver dysfunction, which impairs the liver’s ability to remove toxins from the blood. The risk factors for hepatic encephalopathy include:

• Chronic liver disease/cirrhosis
• Acute liver failure
• Infections
• Electrolyte imbalances like low sodium levels
• Certain medications, such as diuretics or sedatives
• Gastrointestinal bleeding
• High-protein diet
• Impaired kidney function
• Increased absorption of toxins due to poor bowel movements
• Surgical procedures aimed at relieving pressure in the veins around the liver, which can cause release of toxins; for example, complications from transjugular intrahepatic portosystemic shunt (TIPS) placement

Despite the numerous and varied causes of encephalopathy, at least one symptom present in all cases is an altered mental state. The altered mental state may be subtle and develop slowly over years (for example, in hepatitis the decreased ability to draw simple designs, termed apraxia) or be profoundly obvious and develop rapidly (for example, brain anoxia leading to coma or death in a few minutes). Often, symptoms of altered mental status can present as inattentiveness, poor judgment, or poor coordination of movements.

Other serious symptoms that may occur include:

• lethargy,
• dementia,
• seizures,
• tremors,
• muscle twitching and myalgia,
• Cheyne-Stokes respiration (an altered breathing pattern seen with brain damage, increased intracranial pressure and coma), and
• coma.

Often the severity and type of symptoms are related to the severity and cause of the brain disease or damage. For example, alcohol-induced liver damage (alcoholic cirrhosis) can result in involuntary hand tremors (asterixis), while severe anoxia (lack of oxygen) may result in a coma with no movement.

Other symptoms may not be as severe and may be more localized such as cranial nerve palsies (damage to one of the 12 cranial nerves that exit the brain). Some symptoms may be very subtle and result from repeated injury to the brain tissue. For example, chronic traumatic encephalopathy (CTE), due to injuries like concussions repeatedly sustained by football players and others who play contact sports, may cause slow changes over time that are not easily diagnosed. Such injury may lead to chronic depression or other personality changes that can result in life-changing consequences.

Even infants and children can suffer encephalopathy. Similar symptoms can occur in the perinatal period if the neonate had any compromise to brain blood flow during its development.

• Rasmussen's encephalitis is a rare disease that is seen in children that progresses to intractable seizures if untreated. It may be due to autoantibody development.
• Another rare form of encephalopathy that usually develops in younger people (about ages 4-20 years) is the MELAS syndrome ("Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes") due to faulty DNA in the patient's mitochondria (a tiny part within the cell that is responsible for energy conversion).

Diagnosis of encephalopathy is usually made with clinical tests done during the physical examination (mental status tests, memory tests, and coordination tests) that document an altered mental state. In most cases, findings on clinical tests either diagnose or presumptively diagnose encephalopathy, which is then confirmed with additional tests. Usually, the diagnosis occurs when the altered mental state accompanies another primary diagnosis such as chronic liver disease, kidney failure, anoxia, or many other diagnoses.

Consequently, physicians may utilize several different tests at the same time to diagnose both the primary condition (the cause of encephalopathy) and the encephalopathy itself. This approach to diagnosis is done by most physicians because encephalopathy is a complication that occurs because of a primary underlying health problem. The most frequently utilized tests are listed below with some of the major primary causes the tests may help diagnose the condition:

• Complete blood count or CBC (infections or loss of blood)
• Blood pressure (high or low blood pressure)
• Metabolic tests (blood levels of electrolytes, glucose, lactate, ammonia, oxygen, and liver enzymes)
• Drugs or toxin levels (alcohol, cocaine, amphetamines, and many others)
• Blood and body fluid cultures and analyses (infections of many types)
• Creatinine (kidney function)
• CT and MRI scans (brain swelling, infections, anatomical or structural abnormalities/issues)
• Doppler ultrasound (abnormal blood flow to tissues or abscesses)
• Encephalogram or EEG (brain damage or abnormal brain wave patterns)
• Autoantibody analysis (dementia caused by antibodies that destroy neurons)
• Review of the person's medications, as some medications (for example, cyclosporine) may be responsible for symptoms

This list is not exhaustive, and not all of the above tests need to be done on every patient. Specific testing is usually ordered by the treating physician according to the symptoms and history of the patient.

Treatment of encephalopathy varies with the primary cause of the symptoms. Consequently, not all cases of encephalopathy are treated the same.

Some examples of different "encephalopathy treatments" for different causes:

• Short-term anoxia (usually less than two minutes): Oxygen therapy
• Long-term anoxia: Rehabilitation
• Short-term alcohol toxicity: IV fluids or no therapy
• Long-term alcohol abuse (cirrhosis or chronic liver failure): Oral lactulose, low-protein diet, antibiotics
• Uremic encephalopathy (due to kidney failure): To correct the underlying physiologic cause, dialysis, kidney transplant
• Diabetic encephalopathy: Administration of glucose to treat hypoglycemia and insulin to treat hyperglycemia, tight control of blood glucose levels
• Hypo- or hypertensive encephalopathy: Medications to raise (for hypotensive) or reduce (for hypertensive) blood pressure

The key to treating any encephalopathy is to understand the basic cause and thus design a treatment plan to reduce or eliminate the cause(s).

Complications of encephalopathy vary from none to profound mental impairments that lead to death. The complications can be similar in some cases. Also, many investigators consider encephalopathy itself to be a complication that arises from a primary health problem or primary diagnosis.

Complications depend on the primary cause of encephalopathy and can be illustrated by citing a few examples from the wide variety of causes:

• Hepatic (liver) encephalopathy (brain swelling with herniation, coma, death)
• Metabolic encephalopathy (irritability, lethargy, depression, tremors; occasionally, coma or death)
• Anoxic encephalopathy (wide range of complications, from none in short-term anoxia to personality changes, severe brain damage to death in long-term anoxic events)
• Uremic encephalopathy (lethargy, hallucinations, stupor, muscle twitching, seizures, death)
• Hashimoto's encephalopathy (confusion, heat intolerance, dementia)
• Wernicke's encephalopathy (mental confusion, memory loss, decreased ability to move eyes)
• Bovine spongiform encephalopathy (BSE) or "mad cow disease" (ataxia, dementia, and myoclonus or muscle twitching without any rhythm or pattern)
• Shigella encephalopathy (headache, stiff neck, delirium, seizures, coma)
• Infectious causes of pediatric encephalopathy (irritability, poor feeding, hypotonia or floppy baby syndrome, seizures, death)

The best way to understand potential complications is to discuss these with the diagnosing doctor who can discuss the possible problems associated with the specific cause(s) of the type of encephalopathy.

The prognosis for a patient with encephalopathy depends on the initial causes and, in general, the length of time it takes to reverse, stop, or inhibit those causes and the permanent damage done to the brain. Consequently, the prognosis varies from patient to patient and ranges from complete recovery to a poor prognosis that often leads to permanent brain damage or death.

This highly variable prognosis is exemplified by patients that get encephalopathy from hypoglycemia. If patients with hypoglycemia are given glucose at the first signs of encephalopathy (for example, irritability and mild confusion), most patients recover completely. Delays in correcting hypoglycemia (hours to days) may lead to seizures or coma, which may be halted by treatment with complete or partial recovery (minimal permanent brain damage). A long delay or multiple delays in treatment can lead to a poor prognosis with extensive brain damage, coma, or death.

Although the symptoms and time frame vary widely from patient to patient and according to the initial causes of encephalopathy (see above sections for examples of causes), the prognosis of each case usually follows the pattern described in the hypoglycemic example above and depends upon the extent and rapidity with which the underlying cause is treated. The doctor or team of doctors treating the underlying cause of encephalopathy can offer the best information on the individual's prognosis.

Many cases of encephalopathy can be prevented. The key to prevention is to stop or limit the chance of developing any of the multitudes of causes of encephalopathy. If encephalopathy develops, the quicker the underlying cause is treated, the more likely that severe encephalopathy can be prevented.

Examples of prevention (and situations to avoid) are listed below:

• Diabetic encephalopathy: Follow your prescribed diabetes management plan, including taking glucose measurements when appropriate. Take all medications as directed.
• Hepatic encephalopathy: Avoid alcohol intoxication, drug overdoses, and IV injections of illegal drugs.
• Anoxic encephalopathy: Prevent choking on food. Avoid risky behavior that could lead to head and neck trauma. Avoid exposure to carbon monoxide.
• Hypertensive encephalopathy: Monitor blood pressure; take antihypertensive medication as directed and do not stop or change medications without consulting a doctor.
• Infectious encephalopathy: Avoid physical contact with individuals known to be infected with organisms that may cause encephalopathy such as N. meningitidis or Shigella.
• Uremic encephalopathy: Do not skip or avoid scheduled dialysis. Take all medications as directed and have frequent assessments of mental status.

Methods for prevention of encephalopathy are about as numerous as the underlying causes; however, some cases of encephalopathy may not be preventable (for example, congenital and accidental traumatic encephalopathy).

Depending on the underlying cause and severity, encephalopathy may signify a medical emergency. The condition is characterized by a wide range of symptoms that point to brain malfunction, including agitation, seizures, altered consciousness, disorientation, muscle weakness, and, in extreme situations, coma. Prompt medical diagnosis and treatment are essential because these symptoms can rapidly worsen and become life-threatening.