Hashimoto encephalopathy

Key Points at a Glance

Highlights of This Disease

• Autoimmune encephalopathy with elevated anti-thyroid antibodies (prevalence: 2.1 per 100,000 people)
• Seizures (66%), cognitive dysfunction, and psychiatric symptoms are the main clinical features
• High responsiveness to steroid therapy (improvement rate over 91%)
• Can occur even with normal thyroid function (euthyroid cases 18–45% are most common)
• Delayed diagnosis leads to residual cognitive dysfunction in 25%. Early diagnosis and treatment are key

1. What is Hashimoto Encephalopathy?

Hashimoto Encephalopathy (HE) is an autoimmune encephalopathy associated with elevated anti-thyroid antibodies^1),2),5). It is also called SREAT or NAIM¹⁾. It was first reported by Brain et al. in 1966^3),4).

The prevalence is 2.1 per 100,000 people, making it a rare disease^1),3),4),5). It is more common in women, with a female-to-male ratio of about 4:1³⁾. The typical age of onset is 40–55 years (range 12–84 years)³⁾.

Q How rare is Hashimoto encephalopathy?

A

The prevalence is reported as 2.1 per 100,000 people. It is more common in women, with a female-to-male ratio of about 4:1. It typically occurs between 40 and 55 years of age, but can develop across a wide age range from 12 to 84 years.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Seizures: Seen in about 66% of cases. Often resistant to anticonvulsant medications^5),8)
• Cognitive impairment: Primarily memory loss and decreased concentration^5),6),7)
• Psychiatric symptoms: Hallucinations, delusions, depression, and catatonic states^1),5)
• Headache: Often the initial symptom
• Ataxia: Cerebellar ataxia and wide-based gait³⁾
• Stroke-like episodes: Presenting as acute neurological symptoms
• Impaired consciousness/coma: Seen in severe cases⁶⁾

Clinical Findings

Vasculitic Type

Main symptoms: Stroke-like episodes, seizures, psychomotor retardation

Features: Acute to subacute onset. Tends to follow a relapsing course³⁾

Diffuse Progressive Type

Main symptoms: Dementia, psychiatric symptoms

Characteristics: Slowly progressive course. Persistent decline in cognitive function is the main feature³⁾

Other clinical findings include the following.

• Myoclonus: Observed in approximately 38% of cases⁸⁾
• Tremor: Often occurs predominantly in the upper limbs^1),3)
• Parkinsonism: Rare but reported³⁾
• Ophthalmologic findings: In cases with thyroid eye disease (TED), exophthalmos and saccadic pursuit movements are observed.

Q What symptoms should raise suspicion for Hashimoto encephalopathy?

A

This disease should be suspected when unexplained seizures, cognitive dysfunction, or psychiatric symptoms appear acutely to subacutely. In particular, it must be considered in the differential diagnosis for seizures resistant to antiepileptic drugs or recurrent stroke-like episodes. A history of thyroid disease further increases suspicion.

3. Causes and Risk Factors

The pathophysiology of Hashimoto encephalopathy is not fully understood, but several hypotheses have been proposed^1),4).

Main pathophysiological hypotheses:

• Autoimmune vasculitis hypothesis: Autoimmune attack on cerebral blood vessels causes neurological symptoms¹⁾
• Direct TRH toxicity: Thyrotropin-releasing hormone exhibits neurotoxicity^1),4)
• Immune complex deposition: Antibody-antigen complexes deposit in the central nervous system^1),4)
• NAE antibody: Antibody against the N-terminus of alpha-enolase. Shows 90% specificity⁴⁾
• Molecular mimicry: Cross-reactivity due to structural similarity between thyroglobulin and myelin basic protein⁴⁾

Thyroid function is not necessarily decreased; functional status varies¹⁾.

Thyroid function status	Proportion
Normal	18–45%
Subclinical hypothyroidism	23–35%
Hypothyroidism (overt)	17–20%
Hyperthyroidism (thyrotoxicosis)	7%

There are also reports in patients with autoimmune predisposition such as Turner syndrome ⁸⁾.

4. Diagnosis and Examination Methods

Hashimoto encephalopathy is a diagnosis of exclusion, confirmed after ruling out other causes. The diagnostic criteria (7 items) proposed by Castillo et al. are used as a reference ⁵⁾.

Diagnostic Criteria (Castillo)	Content
1	Encephalopathy (seizures, psychiatric symptoms, cognitive decline, impaired consciousness)
2	Positive serum anti-thyroid antibodies (anti-TPO, anti-TG)
3	Normal or mildly decreased thyroid function
4	Exclusion of infectious, toxic, metabolic, and neoplastic processes
5	Exclusion of antibodies indicating other autoimmune diseases
6	Exclusion of vascular, neoplastic, and structural lesions on imaging
7	Neurological recovery with steroid therapy

Blood and cerebrospinal fluid tests

• Anti-TPO antibodies: High sensitivity. Essential for diagnosis
• Anti-TG antibodies (anti-thyroglobulin antibodies): Supplementary test
• NAE antibodies (anti-α-enolase N-terminal antibodies): Specificity 90%⁴⁾
• CSF (cerebrospinal fluid): Typically shows high protein and no pleocytosis. Anti-TPO antibodies are also detected in CSF ²⁾

Imaging and Electrophysiological Tests

• MRI: Normal in more than 50% of cases. Abnormal findings include FLAIR hyperintensity ^2),3),4)
• EEG (electroencephalogram): Characterized by slowing and triphasic waves ^3),5),6),8)
• SPECT (single-photon emission computed tomography): Useful as an adjunctive diagnostic tool ⁴⁾

Main differential diagnoses: Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease, anti-NMDA receptor encephalitis, etc.

5. Standard Treatment

First-Line: Steroid Therapy

Start with intravenous methylprednisolone (mPSL) 500–1,000 mg/day for 3–7 days (pulse therapy)^{2),3),5),6),8)}.

Then switch to oral prednisolone (PSL) 1–2 mg/kg/day^2),3). Taper gradually over about 6 months (every 15 days by 10 mg)³⁾.

Treatment outcomes:

• Improvement rate in a review of 251 cases: 91%²⁾
• Remission rate within 3 months: 93%⁷⁾
• Improvement rate with concurrent thyroid treatment: 92%⁵⁾

Anticonvulsant monotherapy is often insufficiently effective⁵⁾.

Second-line and beyond

• IVIG (intravenous immunoglobulin therapy): Used for steroid-refractory or relapsed cases^2),6)
• PLEX (plasma exchange therapy): Indicated for severe or steroid-refractory cases
• Immunosuppressants: azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil have been reported^3),8)

Precautions in treatment

Steroid pulse therapy is a short-term intensive administration of high-dose drugs, and attention must be paid to side effects such as infections, hyperglycemia, gastric ulcers, and osteoporosis. If relapse occurs, consider adding immunosuppressants. Anticonvulsants alone are often insufficient, and combination with immunotherapy is necessary.

Q How much improvement can be expected with steroid treatment?

A

A review of 251 cases reported an improvement rate of 91%. Data also show that 93% of patients achieve remission within 3 months. However, some patients may experience relapse or long-term cognitive impairment. Early initiation of treatment is important.

6. Pathophysiology

Brain biopsy findings show vasculitis with lymphocytic infiltration and gliosis ⁴⁾. Direct neurotoxicity of thyroid hormone itself has not been proven at this time ³⁾.

Role of NAE antibodies: Targeting the N-terminal domain of α-enolase, they are important biomarkers with 90% specificity ⁴⁾.

Molecular mimicry mechanism: A pathway from anti-TPO antibodies through immune complex formation to cross-reactivity with myelin basic protein is hypothesized⁴⁾.

Three clinical subtypes have been proposed⁴⁾:

• Acute encephalopathy type: Acute onset with impaired consciousness and seizures as the main features
• Psychiatric type: Mainly psychiatric symptoms. Presents schizophrenia-like symptoms.
• Slowly progressive type: Mainly slow decline in cognitive function.

It has been suggested that myelitis may occur as a process continuous with Hashimoto encephalopathy⁴⁾.

7. Latest Research and Future Perspectives (Research Stage Reports)

For patients: Please be sure to read

The following content is currently in the research stage or under clinical trial, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Ohira et al. (2024) reported a case of myelitis preceding NAE antibody-positive Hashimoto encephalopathy, suggesting that myelitis and Hashimoto encephalopathy may be sequential manifestations of the same autoimmune process⁴⁾.

Hicham et al. (2024) reported SREAT presenting with parkinsonism and discussed the association between antithyroid antibodies and multiple system atrophy (MSA) or cerebellar degeneration³⁾.

Foster et al. (2022) reported a case of Hashimoto encephalopathy with long-term cognitive impairment lasting over two years⁶⁾.

Katagiri et al. (2022) noted that cognitive decline persists in 25% of cases with delayed diagnosis, emphasizing the importance of early diagnosis and treatment⁷⁾.

Accumulating reports indicate that SPECT imaging can detect decreased cerebral blood flow and is useful as an adjunctive diagnostic tool in cases with normal MRI findings⁴⁾.

Q What is the long-term prognosis of Hashimoto encephalopathy?

A

The response to steroid treatment is generally good, but reports indicate that if diagnosis is delayed, cognitive dysfunction remains in 25% of patients. There are also cases where long-term cognitive dysfunction persists for more than two years. In cases with repeated relapses, maintenance therapy with immunosuppressants may be necessary.

8. References

1. Dhoat PS, Kaur A, Verma N, Jain D. Hashimoto’s encephalopathy versus catatonia: A diagnostic dilemma. J Family Med Prim Care. 2023;12:400-2.
2. Estaris J, Bansil S, Nishimura Y. Steroid-Responsive Encephalopathy Associated With Autoimmune Thyroiditis Masquerading Sepsis. Cureus. 2023;15(5):e38826.
3. Hicham G, Naji Y, Hrouch W, et al. Steroid-Responsive Encephalopathy Associated With Autoimmune Thyroiditis Presenting With Parkinsonism. Cureus. 2024;16(3):e56184.
4. Ohira K, Kanai D, Inoue Y. Myelitis preceding anti-N-terminal of α-enolase antibody-positive Hashimoto’s encephalopathy. Radiol Case Rep. 2024;19:4392-6.
5. Osman H, Panicker A, Nguyen P, et al. Hashimoto’s Encephalopathy: A Rare Cause of Seizure-like Activity. Cureus. 2021;13(4):e14626.
6. Foster P, Craig T, Jha P, et al. Lingering Effects: Hashimoto’s Encephalopathy. Cureus. 2022;14(7):e26809.
7. Katagiri N, Ohta R, Yamane F, Sano C. Hashimoto Encephalopathy of a Middle-Aged Man With Progressive Symptoms of Dementia. Cureus. 2022;14(7):e27518. doi:10.7759/cureus.27518. PMID:36060397; PMCID:PMC9424789.
8. Chelikani V, Rao DN, Balmuri S, et al. A Rare Case of Hashimoto’s Encephalopathy With Mosaic Turner Syndrome. Cureus. 2022;14(8):e28215.