Hashimoto's encephalopathy

Hashimoto's Encephalopathy is a rare condition associated with Hashimoto's thyroiditis. It was first described in 1966. It is sometimes referred to as a neuroendocrine disorder, although the condition's relationship to the endocrine system is widely disputed.

Up to 2005 there were almost 200 published case reports of this disease. Between 1990 and 2000 43 cases were published. Since that time, research has expanded and numerous cases are being reported by scientists around the world, suggesting that this rare condition is likely to have been significantly undiagnosed in the past. Over 100 scientific articles on Hashimoto's Encephalopathy were published between 2000 and 2013. 

History
The first case of HE was described by Brain et al. in 1966. The patient was a 48-year-old man with hypothyroidism, multiple episodes of encephalopathy, stroke-like symptoms and Hashimoto’s thyroiditis confirmed by elevated anti-thyroid antibodies.

Definition
A relapsing encephalopathy occurring in association with Hashimoto's thyroiditis, with high titers of anti-thyroid antibodies. Clinically, the condition may present one or more symptoms. Onset is often gradual and may go unnoticed by the patient and close associates to the patients. Symptoms sometimes resolve themselves within days to weeks, leaving a patient undiagnosed. For many other patients, the condition may result in ongoing problems with a variety of manifestations, often confusing clinicians due to the diffuse nature of symptoms.

Epidemiology
The prevalence has been estimated to be 2.1/100,000 with a male to female ratio of 1:4. The mean age of onset is 44 with 20% of cases presenting before the age of 18 years. Most reported cases occur during the patient's fifth decade of life.

Aetiology
The mechanism of pathogenesis is not known but it has been assumed to be an autoimmune disorder. Consistent with this hypothesis alpha-enolase has been identified as an autoantigen in the disease.

Pathology
Very little is known about the pathology of HE. Post-mortem studies of some individuals have shown lymphocytic vasculitis of venules and veins in the brain-stem and a diffuse gliosis involving gray matter more than white matter.

Clinical features
The onset of symptoms tends to be fairly gradual and to occur over 1–7 days.

Symptoms of Hashimoto's encephalopathy may include:


 * personality changes
 * aggression
 * delusional behavior
 * concentration and memory problems
 * coma
 * disorientation
 * headaches
 * jerks in the muscles (myoclonus - 65% cases)
 * lack of coordination (ataxia - 65% cases)
 * partial paralysis on the right side
 * psychosis
 * seizures (60% cases)
 * sleep abnormalities (55% cases)
 * speech problems (transient aphasia - 80% cases)
 * status epilepticus (20% cases)
 * tremors (80% cases)

Laboratory and radiological findings

 * Increased liver enzyme levels (55% cases)
 * Increased thyroid-stimulating hormone (55% cases)
 * Increased erythrocyte sedimentation rate (25% cases)

Cerebrospinal fluid findings:
 * Raised protein (25% cases)
 * Negative for 14–3–3 protein
 * May contain antithyroid antibodies


 * Magnetic resonance imaging abnormalities consistent with encephalopathy (26% cases)
 * Single photon emission computed tomography shows focal and global hypoperfusion (75% cases)
 * Cerebral angiography is normal

Thyroid hormone abnormalities are common (>80% cases):
 * subclinical hypothyroidism (35% cases)
 * overt hypothyroidism (20% cases)
 * hyperthyroidism (5% cases)
 * euthyroid on levothyroxine (10% cases)
 * euthyroid not on levothyroxine (20% cases)

Thyroid antibodies - both anti-thyroid peroxidase antibodies (anti-TPO, anti-thyroid microsomal antibodies, anti-M) and antithyroglobulin antibodies (anti-Tg) - in the disease are elevated but their levels do not correlate with the severity.

Electroencephalogram studies while almost always abnormal (98% cases) are usually non diagnostic. The most common findings are diffuse or generalized slowing or frontal intermittent rhythmic delta activity. Prominent triphasic waves, focal slowing, epileptiform abnormalities, photoparoxysmal and photomyogenic responses may be seen.

Differential diagnosis

 * Alzheimer's disease
 * Cerebrovascular accidents (stroke)
 * Creutzfeldt-Jakob disease (CJD)
 * Viral encephalitis

Treatment
Because most patients respond to steroids or immunosuppressant treatment, this condition is now also referred to as steroid-responsive encephalopathy.

Initial treatment is usually with oral prednisone (50–150 mg/day) or high dose IV methylprednisolone (1 g/day) for 3–7 days. Thyroid hormone treatment is also included if required.

Failure of some patients to respond to this first line treatment has produced a variety of alternative treatments including azathioprine, cyclophosphamide, chloroquine, methotrexate, periodic intravenous immune globulin and plasma exchange. There have been no controlled trials so the optimal treatment is not known.

Seizures, if present, are controlled with typical antiepileptic agents.

Prognosis
Duration of treatment is usually between 2 and 25 years. Earlier reports suggested that 90% of cases stay in remission after discontinuation of treatment, however this is at odds with more recent studies which suggest that relapse commonly occurs after initial high dose steroid treatment. Left untreated, it can result in coma and death.

Alternative names

 * Steroid-responsive encephalopathy associated with autoimmune thyroiditis, SREAT
 * Nonvasculitic autoimmune meningoencephalitis, NAIM
 * Encephalopathy Associated with Autoimmune Thyroid Disease, EAATD