NORD gratefully acknowledges Jeehun Lee, MD, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, for assistance in the preparation of this report.
Hashimoto encephalopathy is a rare disorder characterized by impaired brain function (encephalopathy). The exact cause is unknown, but it is believed to be an immune-mediated disorder or a disorder in which there is inflammation resulting from abnormal functioning of the immune system. Affected individuals have the presence of antithyroid antibodies in their body. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Antithyroid antibodies are ones that mistakenly target thyroid tissue. However, it is unclear whether these antibodies play any role in the development of Hashimoto encephalopathy or are a coincidental finding. The main signs and symptoms are related to the encephalopathy. The onset of impaired brain function is rapid (acute), while other times it can develop slowly over many years. The specific symptoms, severity, and course of the disorder can vary greatly among affected individuals. The disorder often responds to therapy with corticosteroids.
Some researchers believe there is a relationship between Hashimoto encephalopathy and Hashimoto thyroiditis, an autoimmune disorder in which antithyroid antibodies mistakenly damage the thyroid. The name Hashimoto encephalopathy comes from the presence of antithyroid antibodies and encephalopathy occurring together. Whether these two disorders are linked in any way is not fully understood. Because there is no evidence that the antithyroid antibodies in Hashimoto encephalopathy contribute to brain damage, and because most of the affected individuals have a normal-functioning thyroid, some researchers believe these are coincidental findings. Some physicians have preferred the name steroid-responsive encephalopathy associated with autoimmune thyroiditis or SREAT instead of Hashimoto encephalopathy.
The most important symptom is impaired brain function (encephalopathy), namely, altered mental status. It is impairment of the cognition, attention, orientation, sleep-wake cycle and consciousness.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals and families should talk to their physicians and medical team about their specific case, associated symptoms and overall prognosis.
The specific symptoms and severity of the disorder can vary greatly from one individuals to another. The disorder may follow a relapsing and remitting course, which means that symptoms of cognitive decline and altered consciousness go through cycles where they worsen and improve.
In some individuals, the disorder will be slowly progressive rather than relapsing and remitting. In these individuals, there is a progressive pattern of cognitive decline including confusion, hallucinations, dementia, and, impairment of the sleep-wake cycle including difficulty in maintaining sleep and sleeping for longer periods of time than usual. Depression may be the initial sign in this form.
Although there are two distinct patterns of disease development for Hashimoto encephalopathy, the specific signs and symptoms can overlap. The severity, progression and specific symptoms associated with the disorder can vary greatly from one person to another.
Additional symptoms that can develop include seizures, fatigue, jitteriness or nervousness, overresponsive reflexes (hyperreflexia), poor appetite, confusion, loss of blood flow to an area of the brain called the cerebrum (cerebral ischemia), altered consciousness, and loss of contact with reality (psychosis). Sometimes, individuals may develop tremors, abnormal jerky movements (myoclonus), poor coordination of voluntary movements (ataxia), and slurred speech (dysarthria).
Affected individuals may be inattentive, lack concentration, and fail to understand basic concepts. They can also exhibit behavioral changes including depression, anxiety, emotional instability, social withdrawal, and changes in their personality.
The disorder can follow a limited course that resolves without treatment (self-limited), follow a course where the disease becomes worse over time (progressive), or follow a relapsing and remitting course.
Many people with Hashimoto encephalopathy have a normal-functioning thyroid (euthyroid) despite the presence of antithyroid antibodies. Other individuals may have an underactive thyroid (hypothyroidism) or overactive thyroid (hyperthyroidism). The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate that chemical processes (metabolism) that influence the body’s heart rate, body temperature and blood pressure.
The exact cause of Hashimoto encephalopathy is unknown. However, some clinical researchers believe that the disorder is most likely the result of an abnormal immune system response to an infection or other trigger. Many researchers suggest that the disorder may represent, in part, an abnormal immune reaction directed against the body’s own tissues (autoimmune disorder). In autoimmune disorders, the body’s natural defenses (e.g. antibodies, lymphocytes) against substances that are perceived as foreign (antigens) inappropriately begin to attack healthy tissues for unknown reasons. When antibodies mistakenly target healthy tissue, they may be referred to as autoantibodies.
Individuals with Hashimoto encephalopathy have varying levels of antithyroid antibodies. The presence of antithyroid antibodies means that a person’s immune system is not functioning properly. However, despite the presence of these antibodies, there has been no evidence to confirm that they play a role in the brain damage that characterizes this disorder. Also, the specific levels of antithyroid antibodies in the body does not correlate with the severity of the neurological symptoms.
Researchers have discovered the presence of anti-alpha enolase antibodies. Alpha enolase is an enzyme expressed in most tissues of the body. The presence of two autoantibodies, anti-alpha enolase and antithyroid antibodies, supports the theory that there is an active autoimmune process affecting individuals with Hashimoto encephalopathy. Some researchers speculate that the autoimmune process may involve inflammation and damage to blood vessels within the brain (autoimmune cerebral vasculitis). However, more research is necessary to determine the exact, underlying mechanisms that cause Hashimoto encephalopathy.
Hashimoto encephalopathy is a rare disease that affects women more often than men. The disorder is estimated to affect 2.1 per 100,000 individuals in the general population. It can affect children, but only approximately 60 affected children have been described in the medical literature. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population.
A diagnosis of Hashimoto encephalopathy is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. By definition, Hashimoto encephalopathy must have detectable levels of antithyroid antibodies in the body. However, there is no correlation between the amount of antibody levels and the presence or severity of symptoms. Antithyroid antibodies are relatively common in the general population, so this finding must occur in individuals with the characteristic findings associated with Hashimoto encephalopathy and in whom other potential diagnoses have been ruled out.
Clinical Testing and Workup
Blood tests may reveal high levels of antithyroid antibodies. Cerebrospinal fluid, which is the clear fluid that supports and protects the brain and spinal cord, may be studied, which may show nonspecific findings including abnormally high levels of certain proteins.
Physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and slowing of background activity. An EEG can also be used to help to detect seizures.
Specialized imaging techniques may be performed including magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. An MRI is usually normal, and is used to exclude other causes of encephalopathy. In uncommon instances can show widespread (diffuse) or specific (focal) changes in white matter.
Hashimoto encephalopathy is treated with medications known as corticosteroids. Corticosteroids are used to treat inflammation and affected individuals have responded very well to this treatment. The best dose (optimal dose) is unknown, but will vary based on several factors including a person’s age, overall health, and individual tolerance of the medication. Treatment usually begins with high doses of corticosteroids, which are then slowly lowered (tapered off). Long-term therapy with high-doses of corticosteroids is associated with significant side effects, so the high doses are initially used to bring the disorder under control before the doses are lowered. In most individuals, symptoms usually improve or go away completely within a few months although people required treatment for as long as two years.
If corticosteroids are ineffective or cannot be tolerated by an individual, other medications specifically mediations that suppress the activity of the immune system (immunosuppression) have been tried including azathioprine and cyclophosphamide. In patients who do not fully respond to the corticosteroid therapy, other therapeutic options such intravenous immune globulin (IVIG) or plasmapheresis could be considered. The mechanism of IVIG is associated with neutralizing circulatory autoantibodies.
Plasmapheresis can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual.
Some individuals may relapse and require another course of corticosteroid therapy, or immunosuppressive therapy.
Sometimes, anti-seizure (anti-convulsants) medications may be necessary to treat seizures and antipsychotic medication for the patients who are suffering from psychiatric symptoms or delirium.
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