Hypothalamus and Hashimoto’s Thyroiditis: A Link Between the Brain and Thyroid Health

Hashimoto's Encephalopathy (HE): A Detailed Medical Overview

Introduction

Hashimoto's Encephalopathy (HE), also termed steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), represents a rare, potentially reversible, autoimmune-mediated neuropsychiatric syndrome. It is most often associated with Hashimoto's thyroiditis (chronic lymphocytic thyroiditis), an autoimmune destruction of the thyroid gland.

Though rare—with an estimated prevalence of 2.1 per 100,000—it poses significant diagnostic challenges due to its diverse clinical manifestations and the absence of a universally accepted diagnostic gold standard. Prompt recognition is essential, as timely corticosteroid therapy can dramatically reverse symptoms.

Pathophysiology

The precise pathophysiological mechanism underlying HE remains incompletely elucidated. Several hypotheses include:

Autoimmune-mediated cerebral vasculitis or perivasculitis.
Circulating autoantibodies causing direct or indirect neurotoxicity.
Disruption of the blood-brain barrier with intrathecal antibody production.
Cross-reactivity of thyroid antibodies with CNS antigens.

Notably, TPO antibodies (thyroid peroxidase antibodies) are frequently elevated, but they do not appear directly pathogenic within the CNS. Instead, they serve as markers of underlying thyroid autoimmunity.

Clinical Presentation

HE has a heterogeneous presentation, often mimicking other neurological or psychiatric disorders. Its onset can be acute or subacute.

Common Neuropsychiatric Manifestations

Symptom Category	Common Presentations
Cognitive dysfunction	Confusion, memory loss, dementia-like syndromes
Seizures	Generalized tonic-clonic seizures, status epilepticus, myoclonus
Movement disorders	Myoclonus, tremor, ataxia
Psychiatric symptoms	Psychosis, hallucinations, mood disorders
Sleep disturbances	Hypersomnia, insomnia
Stroke-like episodes	Transient focal neurological deficits
Other	Headaches, aphasia, dysarthria

The variability necessitates high clinical suspicion, particularly in patients with unexplained encephalopathy and positive thyroid autoantibodies.

Laboratory Investigations

Thyroid Function Tests

Test	Findings
TSH (Thyroid-Stimulating Hormone)	Elevated in primary hypothyroidism; may be normal in euthyroid patients
Free T4 (fT4)	Often reduced in hypothyroidism
Free T3 (fT3)	May remain normal or slightly elevated
Reverse T3 (rT3)	Occasionally elevated, though not routinely tested

Note: HE can occur in euthyroid, hypothyroid, or hyperthyroid states.

Thyroid Autoantibodies

Antibody	Clinical Relevance
Thyroid peroxidase antibodies (TPO-Ab)	Elevated in ~80-90% of HE cases
Thyroglobulin antibodies (Tg-Ab)	Elevated in ~30-70%
TSH receptor antibodies (TRAb)	Rarely positive in HE

Cerebrospinal Fluid (CSF) Analysis

Elevated protein (mild-to-moderate: 45–100 mg/dL).
Mild lymphocytic pleocytosis (usually <10 cells/mm³).
Occasionally, oligoclonal bands may be present.
Intrathecal synthesis of thyroid antibodies is rare but has been reported.

Inflammatory Markers

Generally, systemic markers like ESR and CRP are normal or mildly elevated.
ANA, anti-dsDNA, and other autoimmune panels may be non-specific.

Neurophysiological Studies

Electroencephalography (EEG)

Generalized slowing (theta and delta activity).
Focal slowing or epileptiform discharges.
Rarely, triphasic waves mimicking metabolic encephalopathy.

Neuroimaging

MRI Brain:

May be normal in 50–60% of patients.
Possible findings include:
- Nonspecific subcortical white matter hyperintensities (T2/FLAIR).
- Cerebral atrophy (reversible or irreversible).
- Vasogenic edema, particularly in acute settings.
- Diffuse leptomeningeal enhancement (rare).

PET/SPECT:

May reveal focal or global hypometabolism.
Occasionally used to differentiate from neurodegenerative or primary psychiatric disorders.

Diagnostic Criteria

There are no universally accepted diagnostic criteria. However, many clinicians rely on the following:

Encephalopathy with seizures, cognitive dysfunction, or psychiatric symptoms.
Presence of thyroid autoantibodies (especially TPO-Ab).
Exclusion of other causes of encephalopathy (infectious, metabolic, toxic, neoplastic, or vascular).
Favorable response to corticosteroids.

Differential Diagnosis

Autoimmune encephalitis (anti-NMDA receptor, VGKC, GAD65)
Limbic encephalitis
Creutzfeldt-Jakob disease
Central nervous system vasculitis
Multiple sclerosis
Paraneoplastic syndromes
Primary psychiatric illness
Metabolic or toxic encephalopathy

Treatment

1. Corticosteroid Therapy

First-line: High-dose intravenous methylprednisolone (e.g., 500–1000 mg/day for 3–5 days), followed by oral prednisone taper (starting 1 mg/kg/day).
Clinical improvement often occurs within days to weeks.
Long-term maintenance may be necessary to prevent relapses.

2. Thyroid Hormone Replacement

Levothyroxine to correct hypothyroidism.
Euthyroid status is important but not sufficient alone to treat encephalopathy.

3. Immunosuppressive Therapy (for steroid-refractory cases)

Azathioprine
Mycophenolate mofetil
Cyclophosphamide
Rituximab
Intravenous immunoglobulin (IVIG)
Plasma exchange (PLEX)

4. Symptomatic Management

Anticonvulsants for seizure control.
Antipsychotics or mood stabilizers for psychiatric symptoms.
Physical and cognitive rehabilitation as needed.

Prognosis

Favorable in most cases if recognized and treated early.
Some patients may achieve complete remission.
Relapses occur in approximately 20–25% of cases, requiring ongoing monitoring.
Delayed diagnosis may result in irreversible cognitive deficits.

Role of Other Hormones: Dopamine and Aldosterone

While not central to HE’s pathogenesis, secondary neuroendocrine dysregulation may contribute to symptomatology:

Hormone	Relevance

Dopamine:
Hypothyroidism may downregulate dopaminergic activity, contributing to depression, psychomotor slowing, and anhedonia.

Aldosterone:
Reduced thyroid function may impair aldosterone synthesis, exacerbating orthostatic hypotension, fatigue, and electrolyte imbalance.

These alterations may partially reverse with normalization of thyroid function and resolution of encephalopathy.

Conclusion

Hashimoto’s Encephalopathy represents a complex autoimmune neuropsychiatric condition linked to thyroid autoimmunity. Early recognition, exclusion of other etiologies, and prompt immunosuppressive therapy are central to optimal outcomes. Despite its rarity, clinicians must maintain vigilance, especially when confronted with unexplained encephalopathy accompanied by thyroid autoantibodies.

References:

Cleveland Clinic. Hypothalamus: Anatomy, Function & Disorders.
https://my.clevelandclinic.org/health/body/21201-endocrine-system
Hashimoto Thyroiditis
https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/thyroid-disorders/hashimoto-thyroiditis
ScienceDirect. Hypothalamic-Pituitary-Thyroid Axis Overview.
https://www.sciencedirect.com/topics/neuroscience/hypothalamic-pituitary-thyroid-axis
Hashimoto's encephalopathy: A rare proteiform disorder
https://pubmed.ncbi.nlm.nih.gov/26849953/

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