Hashimoto's Encephalopathy¶

VERSION: 1.1 CREATED: February 2, 2026 REVISED: February 2, 2026 STATUS: Revised per checker/rebuilder pipeline (v1.1)

DIAGNOSIS: Hashimoto's Encephalopathy (SREAT)

ICD-10: E06.3 (Autoimmune thyroiditis), G93.49 (Other encephalopathy, not elsewhere classified), E03.9 (Hypothyroidism, unspecified)

CPT CODES: 86376 (anti-TPO antibody), 86800 (anti-thyroglobulin antibody), 84443 (TSH), 84436 (thyroxine, total), 84439 (free T4), 84480 (T3, total), 84481 (free T3), 89051 (CSF cell count), 84157 (CSF protein), 70553 (MRI brain with/without contrast), 95816 (EEG routine), 95819 (EEG with sleep), 95700-95720 (continuous EEG), 62270 (lumbar puncture), 96365 (IV infusion, first hour), 96366 (IV infusion, additional hour), 80053 (CMP), 85025 (CBC), 86235 (nuclear antigen antibody), 86140 (CRP), 85652 (ESR), 78816 (FDG-PET)

SYNONYMS: Hashimoto's encephalopathy, HE, steroid-responsive encephalopathy associated with autoimmune thyroiditis, SREAT, Hashimoto encephalopathy, autoimmune thyroid encephalopathy, anti-TPO encephalopathy, thyroid autoimmune encephalopathy, encephalopathy with thyroid autoantibodies, myxedema madness, nonvasculitic autoimmune inflammatory meningoencephalitis, NAIM, thyroid antibody-associated encephalopathy

SCOPE: Diagnostic workup, acute treatment, and long-term management of suspected or confirmed Hashimoto's encephalopathy (SREAT). Covers initial presentation (acute diffuse progressive type and relapsing-remitting vasculitic type), anti-TPO and anti-thyroglobulin antibody evaluation, exclusion of alternative diagnoses, first-line corticosteroid therapy, second-line immunotherapy, seizure management, psychiatric symptom management, ICU considerations for status epilepticus or decreased consciousness, thyroid hormone optimization, and relapse prevention. This is a diagnosis of exclusion requiring elevated anti-thyroid antibodies in the setting of encephalopathy after all other etiologies have been excluded. For antibody-mediated autoimmune encephalitis (anti-NMDAR, LGI1, CASPR2), use "Autoimmune Encephalitis" template. For infectious encephalitis, use "HSV Encephalitis" template. For other metabolic encephalopathies, use appropriate specific template.

PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════

1. LABORATORY WORKUP¶

1A. Essential/Core Labs¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Anti-TPO antibodies (CPT 86376)	STAT	STAT	ROUTINE	STAT	Hallmark of Hashimoto's encephalopathy; elevated in >95% of cases; titers do not correlate with severity	Elevated (>200 IU/mL strongly suggestive; any elevation significant in context)
Anti-thyroglobulin antibodies (CPT 86800)	STAT	STAT	ROUTINE	STAT	Elevated in ~70-80% of HE; may be only elevated antibody in some cases	Elevated
TSH (CPT 84443)	STAT	STAT	ROUTINE	STAT	Thyroid function assessment; patients may be euthyroid, hypothyroid, or rarely hyperthyroid	Variable; 25-30% subclinically hypothyroid; many euthyroid
Free T4 (CPT 84439)	STAT	STAT	ROUTINE	STAT	Thyroid function evaluation; rule out myxedema coma or thyrotoxicosis as cause of encephalopathy	Normal or low
Free T3 (CPT 84481)	URGENT	ROUTINE	ROUTINE	URGENT	Complete thyroid function assessment	Normal or low
CBC with differential (CPT 85025)	STAT	STAT	ROUTINE	STAT	Baseline; infection screen; pre-immunotherapy assessment	Normal
CMP (BMP + LFTs) (CPT 80053)	STAT	STAT	ROUTINE	STAT	Metabolic encephalopathy screen; renal/hepatic baseline for immunotherapy; electrolytes	Normal
ESR (CPT 85652)	URGENT	ROUTINE	ROUTINE	URGENT	Inflammatory/vasculitis screen; often mildly elevated in HE	Normal or mildly elevated
CRP (CPT 86140)	URGENT	ROUTINE	ROUTINE	URGENT	Inflammatory marker; typically normal or mildly elevated	Normal or mildly elevated
Blood glucose (CPT 82947)	STAT	STAT	ROUTINE	STAT	Metabolic encephalopathy screen; pre-steroid baseline	Normal
HbA1c (CPT 83036)	-	ROUTINE	ROUTINE	-	Glycemic status before high-dose steroids	<5.7%
Ammonia (CPT 82140)	STAT	STAT	-	STAT	Hepatic encephalopathy mimic	Normal
Lactate (CPT 83605)	STAT	STAT	-	STAT	Sepsis screen; metabolic screen	Normal (<2.0 mmol/L)
PT/INR, aPTT (CPT 85610+85730)	STAT	STAT	-	STAT	Coagulopathy screen pre-LP; DIC screen	Normal
Magnesium (CPT 83735)	STAT	STAT	ROUTINE	STAT	Seizure threshold; metabolic screen	Normal
Phosphorus (CPT 84100)	STAT	STAT	-	STAT	Metabolic screen	Normal
Urinalysis with culture (CPT 81003+87086)	STAT	STAT	ROUTINE	STAT	UTI as encephalopathy trigger	Negative
Blood cultures (x2 sets) (CPT 87040)	STAT	STAT	-	STAT	Rule out septic encephalopathy	No growth
Procalcitonin (CPT 84145)	URGENT	URGENT	-	URGENT	Distinguish bacterial vs autoimmune etiology	Normal (<0.1 ng/mL)
Urine drug screen (CPT 80307)	STAT	STAT	-	STAT	Toxic/drug-induced encephalopathy mimic	Negative
Alcohol level (CPT 80320)	STAT	STAT	-	STAT	Alcohol-related encephalopathy	Negative
Pregnancy test (females of childbearing age) (CPT 81025)	STAT	STAT	ROUTINE	STAT	Eclampsia mimic; treatment planning (steroid/immunotherapy safety)	As applicable
Vitamin B12 (CPT 82607)	-	ROUTINE	ROUTINE	-	B12 deficiency encephalopathy mimic	Normal (>300 pg/mL)
Folate (CPT 82746)	-	ROUTINE	ROUTINE	-	Nutritional deficiency screen	Normal
Cortisol (AM) (CPT 82533)	-	ROUTINE	ROUTINE	-	Adrenal insufficiency; baseline before exogenous steroids	Normal

1B. Autoimmune & Exclusion Panel¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
ANA (CPT 86235)	URGENT	ROUTINE	ROUTINE	URGENT	Lupus cerebritis screen; SLE can cause encephalopathy with thyroid antibodies	Negative or low titer
Anti-dsDNA	-	ROUTINE	ROUTINE	-	If ANA positive; lupus evaluation	Negative
Anti-SSA/SSB (Ro/La)	-	ROUTINE	ROUTINE	-	Sjogren syndrome with CNS involvement	Negative
Complement C3, C4	-	ROUTINE	ROUTINE	-	Lupus; complement-mediated disease	Normal
ANCA (c-ANCA, p-ANCA)	-	ROUTINE	ROUTINE	-	CNS vasculitis screen	Negative
ACE level (CPT 82164)	-	ROUTINE	ROUTINE	-	Neurosarcoidosis screen	Normal
Anti-NMDAR antibody (serum AND CSF) (CPT 86255)	URGENT	URGENT	ROUTINE	URGENT	Rule out antibody-mediated autoimmune encephalitis (most important exclusion)	Negative
Anti-LGI1 antibody (serum AND CSF) (CPT 86235)	URGENT	URGENT	ROUTINE	URGENT	Rule out LGI1 encephalitis (limbic encephalitis mimic)	Negative
Anti-CASPR2 antibody (serum AND CSF) (CPT 86235)	URGENT	URGENT	ROUTINE	URGENT	Rule out CASPR2-associated encephalitis	Negative
Anti-GABA-B antibody (serum AND CSF)	URGENT	URGENT	ROUTINE	URGENT	Rule out GABA-B encephalitis (seizure-prominent mimic)	Negative
Anti-GAD65 antibody (serum AND CSF)	URGENT	URGENT	ROUTINE	URGENT	Rule out GAD65-associated encephalitis; stiff-person spectrum	Negative or low titer
Mayo Autoimmune Evaluation - Encephalopathy (serum)	URGENT	URGENT	ROUTINE	URGENT	Comprehensive panel to exclude defined antibody-mediated etiologies	All negative
Mayo Autoimmune Evaluation - Encephalopathy (CSF)	URGENT	URGENT	ROUTINE	URGENT	CSF panel for antibody-mediated encephalitis	All negative
AQP4-IgG (NMO antibody)	-	ROUTINE	ROUTINE	-	NMOSD overlap if concurrent myelitis or optic neuritis	Negative
Quantitative immunoglobulins (IgG, IgA, IgM)	-	ROUTINE	ROUTINE	-	Baseline before immunotherapy; IgA deficiency (IVIG contraindication)	Normal
RPR/VDRL (CPT 86592)	URGENT	ROUTINE	ROUTINE	URGENT	Neurosyphilis screen	Nonreactive
HIV antibody (CPT 86703)	URGENT	ROUTINE	ROUTINE	URGENT	HIV-associated encephalopathy	Negative
Lyme serology (CPT 86618)	-	ROUTINE	ROUTINE	-	If endemic area; Lyme encephalopathy	Negative

Note: Hashimoto's encephalopathy is a DIAGNOSIS OF EXCLUSION. All defined antibody-mediated autoimmune encephalitides (anti-NMDAR, LGI1, CASPR2, GABA-B, etc.) MUST be excluded before attributing encephalopathy to anti-TPO antibodies alone. Anti-TPO antibodies are present in ~10-13% of the general population; their presence does not prove causation. The critical diagnostic criterion is steroid responsiveness.

1C. Rare/Specialized (Refractory or Atypical)¶

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Anti-neuronal nuclear antibody type 1 (ANNA-1/anti-Hu)	-	EXT	EXT	-	Paraneoplastic encephalitis mimic	Negative
Anti-neuronal nuclear antibody type 2 (ANNA-2/anti-Ri)	-	EXT	EXT	-	Paraneoplastic screen	Negative
Anti-CV2/CRMP5	-	EXT	EXT	-	Paraneoplastic encephalitis mimic	Negative
Anti-Ma2/Ta	-	EXT	EXT	-	Paraneoplastic limbic encephalitis mimic	Negative
14-3-3 protein (CSF)	-	EXT	EXT	-	Prion disease exclusion in rapidly progressive cases	Negative
RT-QuIC (CSF)	-	EXT	EXT	-	Prion disease exclusion	Negative
CSF oligoclonal bands with paired serum (CPT 83916)	-	ROUTINE	ROUTINE	-	Intrathecal IgG synthesis; elevated in ~25% of HE	May show CSF-specific bands
CSF IgG index	-	ROUTINE	ROUTINE	-	Intrathecal antibody synthesis	May be elevated
Anti-alpha-enolase antibodies (NAE)	-	EXT	EXT	-	Proposed biomarker in HE subset (attacks neuronal surface); research test	Positive may support HE
CSF anti-TPO antibodies	-	EXT	EXT	-	Intrathecal production of anti-TPO; not widely validated	Positive may support intrathecal production
Next-generation sequencing (CSF metagenomics)	-	EXT	EXT	-	Occult infection exclusion when standard testing negative	No pathogens detected
Brain biopsy (last resort)	-	EXT	-	-	Perivascular lymphocytic infiltration; exclusion of other pathology	Lymphocytic perivascular cuffing, no vasculitis

2. DIAGNOSTIC IMAGING & STUDIES¶

2A. Essential/First-line¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
CT head without contrast (CPT 70450)	STAT	STAT	-	STAT	Immediate (ED triage)	Rule out mass, hemorrhage, hydrocephalus; usually normal in HE	None significant
MRI brain with and without contrast (CPT 70553)	URGENT	URGENT	ROUTINE	URGENT	Within 24h	Normal in ~50%; subcortical white matter T2/FLAIR hyperintensities; patchy enhancement; may mimic MS or vasculitis; rarely mesial temporal signal	GFR <30, gadolinium allergy, pacemaker
EEG (routine or continuous) (CPT 95816)	URGENT	URGENT	ROUTINE	STAT	Within 24h; continuous if ICU or altered consciousness	Generalized or focal slowing (most common, ~90%); frontal intermittent rhythmic delta activity (FIRDA); triphasic waves; epileptiform discharges; rarely periodic lateralized discharges	None significant
ECG (12-lead) (CPT 93000)	STAT	STAT	ROUTINE	STAT	Immediate	Bradycardia (hypothyroid); QTc prolongation (medication safety)	None
Chest X-ray (CPT 71046)	STAT	STAT	-	STAT	Immediate	Rule out pulmonary pathology; mediastinal mass	Pregnancy (relative)
Thyroid ultrasound (CPT 76536)	-	ROUTINE	ROUTINE	-	Within 48-72h	Evaluate for Hashimoto thyroiditis (heterogeneous echotexture, diffuse hypoechogenicity, nodules); goiter assessment	None significant

2B. Extended¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
MRI brain with epilepsy protocol	-	ROUTINE	ROUTINE	-	If seizures recurrent	Subtle cortical lesions; hippocampal sclerosis; exclude structural cause	Gadolinium contraindications
MRA head and neck	-	ROUTINE	ROUTINE	-	Within 48-72h if vasculitis suspected	Rule out CNS vasculitis; large vessel disease	Gadolinium contraindications
CT chest/abdomen/pelvis with contrast (CPT 71260+74178)	-	ROUTINE	ROUTINE	-	Within 48-72h	Occult malignancy screen (paraneoplastic mimic); thyroid pathology	Contrast allergy, renal insufficiency
FDG-PET brain (CPT 78816)	-	EXT	EXT	-	Within 1-2 weeks	Cortical hypometabolism; differentiate from other encephalopathies	Uncontrolled diabetes, pregnancy
Video-EEG monitoring (prolonged)	-	ROUTINE	ROUTINE	STAT	As needed	Characterize seizure semiology; detect subclinical seizures; distinguish epileptic from non-epileptic events	None
Cerebral angiography (conventional)	-	EXT	-	-	If CNS vasculitis strongly suspected	Rule out primary CNS vasculitis (beading pattern)	Contrast allergy, renal insufficiency, coagulopathy

2C. Rare/Specialized¶

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
MRI spine (cervical and thoracic) with and without contrast	-	ROUTINE	ROUTINE	-	If myelopathic signs present	Concurrent myelitis; overlap syndromes (NMOSD, MOGAD)	GFR <30, gadolinium allergy
SPECT brain	-	EXT	EXT	-	If PET unavailable	Regional hypoperfusion; frontal or temporal abnormalities	None significant
Brain biopsy	-	EXT	-	-	Last resort; diagnosis uncertain despite full workup	Perivascular lymphocytic infiltration without vasculitis; exclusion of other pathology	Coagulopathy, inaccessible location

LUMBAR PUNCTURE¶

Indication: Essential for diagnosis of Hashimoto's encephalopathy; rules out infectious encephalitis; CSF abnormalities present in ~75-80% of cases (elevated protein is the most common finding); supports exclusion of defined antibody-mediated autoimmune encephalitides

Timing: STAT/URGENT -- perform as soon as safely possible after CT head; do NOT delay for MRI

Volume Required: 20-30 mL (large volume for comprehensive antibody and infectious testing)

Study	ED	HOSP	OPD	ICU	Rationale	Target Finding
Opening pressure	URGENT	ROUTINE	ROUTINE	URGENT	Elevated ICP assessment	10-20 cm H2O (usually normal)
Cell count with differential (tubes 1 and 4) (CPT 89051)	STAT	STAT	ROUTINE	STAT	Mild pleocytosis in ~25% of HE	WBC usually <50 (lymphocyte-predominant); many cases normal; RBC 0
Protein (CPT 84157)	STAT	STAT	ROUTINE	STAT	Elevated in ~75-80% of HE (most common CSF finding)	Mildly to moderately elevated (typically 50-150 mg/dL)
Glucose with paired serum glucose (CPT 82945)	STAT	STAT	ROUTINE	STAT	Low in infection; typically normal in HE	Normal (>60% of serum)
Gram stain and bacterial culture (CPT 87205+87070)	STAT	STAT	ROUTINE	STAT	Rule out bacterial meningitis	No organisms
HSV 1/2 PCR (CPT 87529)	STAT	STAT	ROUTINE	STAT	Rule out HSV encephalitis (critical mimic)	Negative
VZV PCR	URGENT	URGENT	ROUTINE	URGENT	Varicella encephalitis	Negative
EBV PCR	-	ROUTINE	ROUTINE	-	Viral encephalitis screen	Negative
Enterovirus PCR	URGENT	URGENT	-	URGENT	Viral meningitis/encephalitis	Negative
West Nile virus IgM/IgG	-	ROUTINE	-	-	Endemic areas	Negative
Cryptococcal antigen (CPT 87327)	URGENT	ROUTINE	-	URGENT	Immunocompromised; chronic meningitis	Negative
VDRL (CSF) (CPT 86592)	-	ROUTINE	ROUTINE	-	Neurosyphilis	Negative
Oligoclonal bands (CSF AND paired serum) (CPT 83916)	URGENT	ROUTINE	ROUTINE	URGENT	Intrathecal IgG synthesis; present in ~25% of HE	May show CSF-specific bands
IgG index	URGENT	ROUTINE	ROUTINE	URGENT	Intrathecal antibody synthesis	May be mildly elevated
Cytology (CPT 88104)	-	ROUTINE	ROUTINE	-	Carcinomatous/lymphomatous meningitis exclusion	Negative
Flow cytometry	-	ROUTINE	ROUTINE	-	CNS lymphoma exclusion	Normal
Autoimmune encephalitis antibody panel (CSF)	URGENT	URGENT	ROUTINE	URGENT	NMDAR, LGI1, CASPR2, GABA-B, AMPA, DPPX -- to EXCLUDE defined autoimmune encephalitides	All negative (REQUIRED for HE diagnosis)
AFB culture and smear (CPT 87116)	-	ROUTINE	-	-	TB meningitis if risk factors	Negative

Special Handling: Send minimum 2 mL CSF to each reference lab. CSF anti-TPO can be sent but is not widely validated. Autoimmune encephalitis panel on CSF is MANDATORY to exclude defined antibody-mediated etiologies before diagnosing HE. Store extra CSF (frozen at -20C) for future testing. CSF protein elevation is the most common finding in HE (75-80%).

Contraindications: Elevated ICP without imaging (get CT first), coagulopathy (INR >1.5, platelets <50K), skin infection at LP site, posterior fossa mass with risk of herniation

3. TREATMENT¶

3A. Acute/Emergent¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Acyclovir IV (empiric until HSV ruled out)	IV	Encephalopathy of unknown etiology pending HSV PCR	10 mg/kg :: IV :: q8h :: 10 mg/kg IV q8h; continue until HSV PCR negative x2 (48h apart) or alternative diagnosis confirmed	Renal impairment (adjust dose); adequate hydration required	Renal function daily; hydration status; crystal nephropathy prevention	STAT	STAT	-	STAT
Ceftriaxone (empiric if bacterial meningitis not excluded)	IV	Pending CSF culture results; empiric bacterial meningitis coverage	2g :: IV :: q12h :: 2g IV q12h; continue until CSF cultures negative at 48-72h	Cephalosporin allergy; severe penicillin allergy (cross-reactivity)	Cultures; clinical response; CBC; renal function	STAT	STAT	-	STAT
Vancomycin (empiric if bacterial meningitis not excluded)	IV	Pending CSF culture results; covers resistant pneumococcus	15-20 mg/kg :: IV :: q8-12h :: 15-20 mg/kg IV q8-12h (actual body weight); target trough AUC/MIC 400-600	Vancomycin allergy; red man syndrome (infuse over >1h)	Vancomycin trough or AUC; renal function daily; ototoxicity	STAT	STAT	-	STAT
Dexamethasone (empiric meningitis dose)	IV	Adjunctive with empiric antibiotics for suspected bacterial meningitis	0.15 mg/kg :: IV :: q6h x 4 days :: 0.15 mg/kg IV q6h x 4 days; give first dose BEFORE or WITH first antibiotic dose	Active fungal infection; known viral meningitis	Glucose; GI bleeding; clinical response	STAT	STAT	-	STAT
Lorazepam (acute seizure)	IV	Active seizure	0.1 mg/kg :: IV :: PRN :: 0.1 mg/kg IV (max 4 mg/dose); repeat x1 in 5 minutes if seizure persists	Respiratory depression; acute narrow-angle glaucoma	Respiratory status; sedation level; airway patency	STAT	STAT	-	STAT
Midazolam (if no IV access)	IM	Active seizure without IV access	10 mg :: IM :: PRN :: 10 mg IM (adults >40 kg) or 0.2 mg/kg intranasal	Respiratory depression	Respiratory status; sedation level; airway patency	STAT	STAT	-	STAT
Levothyroxine (if hypothyroid)	IV/PO	Hypothyroidism contributing to encephalopathy	1.6 mcg/kg :: PO :: daily :: 1.6 mcg/kg/day PO (adjust for age/cardiac status); IV dose is 75% of oral dose if unable to take PO	Untreated adrenal insufficiency (check cortisol first); acute MI (start low)	TSH, free T4 q4-6 weeks; cardiac monitoring in elderly/cardiac patients	URGENT	URGENT	ROUTINE	URGENT

Note: Initiate empiric acyclovir and antibiotics IMMEDIATELY when infectious etiology has not been excluded. Do NOT delay antimicrobials for LP results. If clinical suspicion for HE is high based on anti-TPO elevation and exclusion workup is underway, corticosteroids can be started concurrently -- a dramatic response to steroids is both therapeutic and diagnostically supportive.

3B. First-Line Immunotherapy (Corticosteroids)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Methylprednisolone IV (CPT 96365)	IV	First-line treatment; dramatic steroid response is hallmark of HE	1000 mg :: IV :: daily :: 1000 mg IV daily x 3-5 days; infuse over 1-2 hours; most patients show improvement within 24-72 hours	Active untreated infection; uncontrolled diabetes; psychosis from steroids	Glucose q6h (target <180); BP; mood/sleep; I/O; GI prophylaxis	URGENT	STAT	-	STAT
Omeprazole (GI prophylaxis during steroids)	PO/IV	GI protection during high-dose steroid therapy	40 mg :: IV :: daily :: 40 mg IV/PO daily during steroid course and taper	PPI allergy	None routine	URGENT	STAT	-	STAT
Insulin sliding scale	SC	Steroid-induced hyperglycemia	Per protocol :: SC :: PRN :: Per protocol if glucose >180 mg/dL	Hypoglycemia risk	Glucose q6h; adjust per response	URGENT	STAT	-	STAT
Oral prednisone taper (following IV methylprednisolone)	PO	Maintenance after IV pulse; prevent relapse	1 mg/kg :: PO :: daily :: 1 mg/kg/day (max 60-80 mg) x 2-4 weeks; taper by 10 mg every 1-2 weeks to 20 mg; then taper by 5 mg every 1-2 weeks; total taper over 3-6 months; SLOW taper critical (relapse rate 40-50% with rapid taper)	Active infection; uncontrolled diabetes; avascular necrosis	Glucose; BP; bone density if prolonged; mood; weight; adrenal insufficiency on taper; relapse monitoring	-	STAT	ROUTINE	-

Note: Corticosteroids are the HALLMARK treatment of Hashimoto's encephalopathy. A dramatic response to IV methylprednisolone (often within 24-72 hours) is both therapeutically and diagnostically critical -- lack of steroid response prompts reconsideration of the diagnosis. Relapse rates are 40-50%, most commonly associated with rapid steroid taper. Prolonged slow taper (3-6 months minimum) significantly reduces relapse risk. Some patients require indefinite low-dose steroids or steroid-sparing agents.

3C. Second-Line Immunotherapy (Steroid-Sparing / Refractory)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
IVIG (intravenous immunoglobulin) (CPT 96365)	IV	Steroid-refractory HE; relapsing disease; steroid contraindications	0.4 g/kg :: IV :: daily x 5 days :: 0.4 g/kg/day IV x 5 days (total 2 g/kg); infuse per weight-based protocol; premedicate with acetaminophen, diphenhydramine	IgA deficiency (anaphylaxis risk); recent thromboembolic event; renal failure	Renal function daily; headache (aseptic meningitis); thrombosis; volume overload; check IgA level before first dose	-	URGENT	-	URGENT
Plasmapheresis (PLEX)	-	Steroid-refractory; rapidly progressive encephalopathy; severe presentation	5-7 exchanges :: - :: over 10-14 days :: 5-7 exchanges over 10-14 days; 1-1.5 plasma volumes per exchange; albumin replacement	Hemodynamic instability; sepsis; coagulopathy; poor vascular access	BP during exchanges; electrolytes (Ca, K, Mg); coagulation (fibrinogen); line site; citrate reactions	-	URGENT	-	URGENT
Azathioprine (Imuran)	PO	Steroid-sparing maintenance; relapsing HE	50 mg :: PO :: daily :: Start 50 mg PO daily; increase by 50 mg every 2 weeks to target 2-3 mg/kg/day	TPMT deficiency (check before starting); pregnancy (relative)	TPMT genotype/activity before starting; CBC q2 weeks x 2 months, then monthly; LFTs; pancreatitis	-	-	ROUTINE	-
Mycophenolate mofetil (CellCept)	PO	Steroid-sparing maintenance; relapsing HE	500 mg :: PO :: BID :: Start 500 mg PO BID; increase to 1000 mg PO BID over 2-4 weeks (target 1500-3000 mg/day)	Pregnancy (Category D -- teratogenic); active infection	CBC q2 weeks x 3 months, then monthly; LFTs; GI symptoms; infection surveillance; pregnancy prevention	-	-	ROUTINE	-
Rituximab	IV	Refractory to steroids and other steroid-sparing agents; multiple relapses	375 mg/m2 :: IV :: weekly x 4 :: 375 mg/m2 IV weekly x 4 doses OR 1000 mg IV x 2 doses (day 0 and day 14); premedicate with methylprednisolone 100 mg, acetaminophen, diphenhydramine	Active hepatitis B; severe active infection; live vaccines within 4 weeks	Hepatitis B serology (before first dose); CBC with differential q2-4 weeks; immunoglobulin levels q3 months; CD19/CD20 B-cell counts; infusion reactions; PML surveillance	-	URGENT	ROUTINE	URGENT
Cyclophosphamide	IV	Severe refractory HE failing all other agents	750 mg/m2 :: IV :: monthly :: 750 mg/m2 IV monthly x 6 cycles; pre-hydrate with 1L NS; administer with MESNA (uroprotection)	Pregnancy; active infection; bone marrow failure	CBC weekly x 4 weeks after each cycle (nadir day 10-14); urinalysis; BMP; LFTs; fertility counseling; hemorrhagic cystitis prevention	-	EXT	EXT	EXT
Methotrexate	PO	Steroid-sparing alternative; relapsing HE	7.5 mg :: PO :: weekly :: Start 7.5 mg PO weekly; increase to 15-25 mg weekly over 4-8 weeks; supplement with folic acid 1 mg daily	Pregnancy; hepatic disease; renal impairment; active infection; bone marrow suppression	CBC monthly; LFTs monthly; renal function; pulmonary symptoms	-	-	ROUTINE	-

Note: Second-line agents are indicated for patients who are steroid-refractory (reconsider diagnosis if no steroid response at all), who relapse during steroid taper, or who have contraindications to prolonged steroids. IVIG and PLEX are used for acute flares or severe presentations. Azathioprine and mycophenolate are the most commonly used steroid-sparing maintenance agents. Rituximab is reserved for multiply-relapsing or refractory cases.

3D. Seizure Management¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Levetiracetam (first-line ASM)	IV/PO	Seizures associated with HE (occur in ~60-70% of cases)	1000-1500 mg :: IV :: BID :: Load: 1000-1500 mg IV; Maintenance: 500-1500 mg IV/PO BID (max 3000 mg/day)	Renal impairment (adjust dose per CrCl)	Behavioral changes (rage, irritability); suicidality; renal function	STAT	STAT	ROUTINE	STAT
Lacosamide (second-line ASM)	IV/PO	Second-line or adjunctive for focal seizures	200-400 mg :: IV :: BID :: Load: 200-400 mg IV; Maintenance: 100-200 mg IV/PO BID (max 400 mg/day)	Second/third degree AV block; severe hepatic impairment	ECG (PR prolongation); dizziness; cardiac monitoring during load	URGENT	URGENT	ROUTINE	URGENT
Valproic acid	IV/PO	Generalized or focal seizures; dual benefit for mood stabilization	20-40 mg/kg :: IV :: divided :: Load: 20-40 mg/kg IV (max rate 6 mg/kg/min); Maintenance: 250-500 mg IV/PO q8h (target level 50-100 mcg/mL)	Pregnancy (teratogenic -- Category X); hepatic disease; urea cycle disorders; mitochondrial disease (POLG)	LFTs; ammonia; CBC (thrombocytopenia); drug level; pancreatitis	URGENT	URGENT	ROUTINE	URGENT
Brivaracetam	IV/PO	Alternative to levetiracetam (fewer behavioral side effects)	100 mg :: IV :: BID :: Load: 100 mg IV; Maintenance: 50-100 mg IV/PO BID (max 200 mg/day)	Hepatic impairment (reduce dose)	Behavioral changes; sedation	-	URGENT	ROUTINE	URGENT
Clobazam	PO	Adjunctive for refractory seizures	5-10 mg :: PO :: BID :: Start 5-10 mg BID; titrate to 20-40 mg/day in divided doses	Severe hepatic impairment; myasthenia gravis	Sedation; CYP2C19 poor metabolizers (reduce dose); tolerance; dependence	-	ROUTINE	ROUTINE	ROUTINE
Phenytoin/fosphenytoin (acute refractory)	IV	Acute seizure control if first-line agents insufficient	20 mg PE/kg :: IV :: load :: Fosphenytoin: 20 mg PE/kg IV (max rate 150 mg PE/min); Maintenance: 5-7 mg/kg/day divided BID-TID (target level 10-20 mcg/mL)	AV block; bradycardia	Continuous cardiac monitoring during load; drug level; purple glove syndrome (peripheral IV)	STAT	STAT	-	STAT
Midazolam infusion (refractory SE)	IV	Refractory status epilepticus	0.2 mg/kg :: IV :: bolus then infusion :: Bolus: 0.2 mg/kg IV; Infusion: 0.1-2.0 mg/kg/hr; titrate to EEG burst suppression	Unprotected airway (requires intubation)	Continuous EEG; respiratory status; hemodynamics; tachyphylaxis	-	-	-	STAT
Propofol infusion (refractory SE)	IV	Refractory status epilepticus	1-2 mg/kg :: IV :: bolus then infusion :: Bolus: 1-2 mg/kg IV; Infusion: 20-80 mcg/kg/min (max 5 mg/kg/hr to avoid PRIS)	Propofol infusion syndrome risk (prolonged use >48h at high doses); egg/soy allergy	Continuous EEG; triglycerides q48h; CPK; lactate; hemodynamics; PRIS surveillance	-	-	-	STAT

Note: Seizures occur in approximately 60-70% of Hashimoto's encephalopathy patients and present as focal, generalized, or status epilepticus. Immunotherapy (corticosteroids) is the definitive seizure treatment -- ASMs control acute seizures but do not resolve the underlying autoimmune process. Many patients can be tapered off ASMs once immunotherapy achieves remission. Levetiracetam is preferred first-line given favorable drug interaction profile with immunotherapy. Status epilepticus occurs in ~10-15% and requires aggressive management.

3E. Psychiatric Symptom Management¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Haloperidol (acute agitation/psychosis)	IV/IM	Acute psychosis or severe agitation (psychiatric symptoms in ~35-45% of HE)	0.5-2 mg :: IV :: q4-6h PRN :: 0.5-2 mg IV/IM q4-6h PRN (lowest effective dose); max 20 mg/day	QTc >500 ms; Parkinson disease; prior NMS	ECG (QTc); EPS; NMS surveillance; temperature; CPK if NMS suspected	STAT	STAT	-	STAT
Quetiapine (psychosis/insomnia)	PO	Psychosis, agitation, sleep disruption	25-50 mg :: PO :: qHS :: Start 25-50 mg qHS; titrate to 200-400 mg/day in divided doses	QTc prolongation; severe hepatic impairment	QTc; metabolic parameters; orthostatic BP; sedation	-	ROUTINE	ROUTINE	-
Olanzapine (agitation/psychosis)	IM/PO	Moderate agitation or psychosis	2.5-5 mg :: IM :: BID :: 2.5-5 mg PO/IM BID (start low); max 20 mg/day	QTc prolongation; metabolic syndrome	Glucose; lipids; QTc; weight; sedation; EPS	-	ROUTINE	ROUTINE	ROUTINE
Lorazepam (agitation/anxiety)	IV/PO	Acute agitation, anxiety, insomnia; catatonia features	1-2 mg :: IV :: q4-6h PRN :: 1-2 mg IV/PO q4-6h PRN; for catatonia: escalate to 8-24 mg/day as needed	Respiratory compromise (high doses)	Respiratory rate; sedation; airway	STAT	STAT	ROUTINE	STAT
Valproic acid (mood stabilization)	PO	Mood lability, agitation; dual benefit for seizure control in HE	250-500 mg :: PO :: BID :: 250-500 mg PO BID; titrate to level 50-100 mcg/mL	Pregnancy (teratogenic -- Category X); hepatic disease; urea cycle disorders; mitochondrial disease (POLG)	LFTs; ammonia; CBC (thrombocytopenia); drug level; pancreatitis	-	ROUTINE	ROUTINE	ROUTINE
Melatonin (sleep-wake disturbance)	PO	Sleep disruption (common in HE)	3-10 mg :: PO :: qHS :: 3-10 mg PO qHS	None significant	Sleep quality; no significant drug interactions	-	ROUTINE	ROUTINE	ROUTINE
Trazodone (insomnia)	PO	Persistent insomnia	25-100 mg :: PO :: qHS :: 25-100 mg PO qHS	Concurrent MAOIs; QTc prolongation	Orthostatic hypotension; priapism (rare); sedation	-	ROUTINE	ROUTINE	-

Note: Psychiatric symptoms (psychosis, depression, hallucinations, personality change, agitation) occur in approximately 35-45% of Hashimoto's encephalopathy. These symptoms are driven by the autoimmune process -- immunotherapy is the definitive treatment. Antipsychotics and other psychiatric medications provide symptomatic relief and are used at lowest effective doses, then tapered as immunotherapy takes effect. Standard NMS precautions apply with antipsychotic use.

3F. ICU-Specific Treatments¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Intubation and mechanical ventilation	-	Status epilepticus requiring anesthetic infusions; severe decreased consciousness (GCS <8); inability to protect airway	RSI per protocol :: - :: - :: Avoid succinylcholine if hyperkalemia risk; maintain normocapnia; daily spontaneous breathing trials when appropriate	As per standard airway management	Ventilator parameters; ABG; daily SBT assessment	-	-	-	STAT
DVT prophylaxis (enoxaparin)	SC	Immobilized patients	40 mg :: SC :: daily :: 40 mg SC daily (adjust for renal function: 30 mg SC daily if CrCl <30)	Active bleeding; HIT; severe thrombocytopenia	Platelet count; anti-Xa if renal impairment; bleeding signs	-	STAT	-	STAT
Acetaminophen (antipyretic)	IV/PO	Fever management in ICU; central fever or status epilepticus-related hyperthermia	1g :: IV :: q6h PRN :: 1g IV/PO q6h PRN (max 4g/day); use as part of targeted temperature management (36-37C)	Severe hepatic impairment; weight <50 kg (reduce dose)	Hepatic function; temperature response	-	ROUTINE	-	STAT
Cooling measures (non-pharmacologic)	-	Central fever or status epilepticus-related hyperthermia refractory to antipyretics	- :: - :: - :: Cooling blankets, ice packs, surface cooling devices; target temperature 36-37C	Avoid overcooling; coagulopathy risk with hypothermia	Continuous temperature monitoring; shivering assessment (Bedside Shivering Assessment Scale)	-	-	-	STAT
Labetalol IV (hypertensive emergency in encephalopathy)	IV	Hypertensive crisis associated with encephalopathy	10-20 mg :: IV :: q10-15min PRN :: 10-20 mg IV q10-15min PRN; or infusion 0.5-2 mg/min; target SBP <180	Severe bradycardia; AV block; decompensated CHF; asthma	Continuous BP; HR; I/O	-	-	-	STAT
Dexmedetomidine (agitation in ICU)	IV	ICU agitation requiring sedation	1 mcg/kg :: IV :: over 10 min :: Load: 1 mcg/kg IV over 10 min (optional); Infusion: 0.2-0.7 mcg/kg/hr (max 1.5 mcg/kg/hr)	Severe bradycardia; advanced heart block	HR (bradycardia); BP (hypotension); sedation level (RASS)	-	-	-	STAT
Famotidine (stress ulcer prophylaxis)	IV	ICU admission with steroid use	20 mg :: IV :: q12h :: 20 mg IV q12h	GFR <50 (reduce dose)	GI bleeding signs	-	-	-	STAT

Note: ICU admission is required for status epilepticus (~10-15% of HE), severe decreased consciousness, or myxedema coma overlap. Unlike anti-NMDAR encephalitis, prolonged autonomic instability is uncommon in HE. ICU course is typically shorter if corticosteroids are initiated promptly. Continue aggressive immunotherapy during ICU stay.

3G. Long-Term Maintenance & Relapse Prevention¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Oral prednisone (low-dose maintenance)	PO	Relapse prevention; some patients require long-term low-dose steroids	5-10 mg :: PO :: daily :: 5-10 mg PO daily; aim to taper off if on steroid-sparing agent; some patients require indefinite low-dose	Poorly controlled diabetes; active infection; avascular necrosis	Glucose; BP; bone density (DEXA if >3 months); weight; mood; cataracts; adrenal assessment on taper	-	-	ROUTINE	-
Azathioprine (maintenance)	PO	Steroid-sparing maintenance; relapse prevention	2-3 mg/kg :: PO :: daily :: 2-3 mg/kg/day (target established during initial titration)	TPMT deficiency; pregnancy	CBC monthly; LFTs q3 months; infection surveillance	-	-	ROUTINE	-
Mycophenolate mofetil (maintenance)	PO	Steroid-sparing maintenance; relapse prevention	1000 mg :: PO :: BID :: 1000 mg PO BID (established dose)	Pregnancy; active infection	CBC monthly; LFTs q3 months; GI symptoms; pregnancy prevention	-	-	ROUTINE	-
Levothyroxine (thyroid optimization)	PO	Maintain euthyroid state; hypothyroidism present in 25-30%	1.6 mcg/kg :: PO :: daily :: 1.6 mcg/kg/day PO; adjust to keep TSH 0.5-2.5 mIU/L	Adrenal insufficiency (correct first); acute cardiac disease	TSH, free T4 q4-6 weeks until stable, then q3-6 months	-	-	ROUTINE	-
Calcium + Vitamin D (bone protection with steroids)	PO	All patients on steroids >3 months	1000-1200 mg/day :: PO :: daily :: Calcium 1000-1200 mg/day + Vitamin D 1000-2000 IU/day	Hypercalcemia; kidney stones	25-OH Vitamin D level; calcium; DEXA baseline if anticipated steroid use >3 months	-	ROUTINE	ROUTINE	-
IVIG (maintenance)	IV	Multiply-relapsing HE; steroid-dependent	0.4 g/kg :: IV :: monthly :: 0.4 g/kg IV every 4 weeks (adjust per response)	IgA deficiency; thromboembolic history	Renal function; headache; IgG trough levels; infusion reactions	-	-	ROUTINE	-

Note: Relapse rate in Hashimoto's encephalopathy is approximately 40-50%, making long-term management critical. Most relapses occur during steroid taper, particularly if tapered too rapidly. Steroid-sparing agents (azathioprine, mycophenolate) are indicated for patients requiring prolonged steroids or experiencing relapses. Thyroid hormone optimization is important but does NOT treat the encephalopathy itself -- immunotherapy is required regardless of thyroid status. Duration of maintenance therapy is individualized; some patients achieve lasting remission after 1-2 years while others require indefinite treatment.

4. OTHER RECOMMENDATIONS¶

4A. Referrals & Consults¶

Recommendation	ED	HOSP	OPD	ICU
Neurology (autoimmune/neuroimmunology) -- all suspected HE cases; immunotherapy management; differential diagnosis; diagnosis of exclusion requires expert assessment	STAT	STAT	ROUTINE	STAT
Endocrinology -- thyroid function optimization; Hashimoto thyroiditis management; steroid-induced diabetes management	URGENT	ROUTINE	ROUTINE	URGENT
Epilepsy/EEG service -- seizure management; continuous EEG monitoring; EEG pattern interpretation	STAT	STAT	ROUTINE	STAT
Psychiatry -- psychiatric manifestations (psychosis, depression, personality change); medication management	URGENT	URGENT	ROUTINE	URGENT
Critical care/ICU -- status epilepticus; severe decreased consciousness; need for mechanical ventilation	URGENT	URGENT	-	-
Rheumatology -- if concurrent systemic autoimmune disease suspected (SLE, Sjogren, vasculitis)	-	ROUTINE	ROUTINE	-
Hematology/apheresis -- PLEX coordination if steroid-refractory	-	URGENT	-	URGENT
Physical therapy -- motor rehabilitation; gait training; fall prevention; deconditioning	-	ROUTINE	ROUTINE	ROUTINE
Occupational therapy -- ADL assessment; cognitive rehabilitation; adaptive strategies	-	ROUTINE	ROUTINE	ROUTINE
Speech-language pathology -- swallowing evaluation if decreased consciousness; cognitive-linguistic therapy	-	ROUTINE	ROUTINE	ROUTINE
Neuropsychology -- formal cognitive assessment; rehabilitation planning; serial monitoring of cognitive recovery	-	-	ROUTINE	-
Social work -- family support; insurance navigation; disability resources; long-term care planning	-	ROUTINE	ROUTINE	-
Rehabilitation medicine -- comprehensive inpatient or outpatient rehab program if significant functional deficits	-	ROUTINE	ROUTINE	-

4B. Patient/Family Instructions¶

Recommendation	ED	HOSP	OPD
Return to ED immediately for new seizures, sudden confusion, behavioral changes, fever, difficulty breathing, or loss of consciousness	Y	Y	Y
Hashimoto's encephalopathy is a treatable condition -- most patients improve dramatically with steroids; recovery takes weeks to months	Y	Y	Y
Do NOT drive until seizure-free for state-mandated period AND cleared by neurology	Y	Y	Y
Keep seizure diary (date, time, type, duration, triggers) if seizures have occurred	-	Y	Y
Do NOT stop steroid medications abruptly -- abrupt discontinuation causes adrenal crisis and disease relapse	-	Y	Y
Report any signs of infection (fever >100.4F, cough, dysuria, rash) immediately while on immunotherapy	-	Y	Y
Avoid live vaccines while on immunosuppressive therapy (inform all physicians of immunosuppression status)	-	Y	Y
Steroid side effects to monitor: weight gain, mood changes, insomnia, elevated blood sugar, bone thinning -- report if severe	-	Y	Y
This condition relapses in 40-50% of patients -- follow-up appointments are critical for monitoring and adjusting treatment	-	Y	Y
Avoid alcohol (lowers seizure threshold, interacts with medications, worsens encephalopathy)	-	Y	Y
Discuss pregnancy with neurology and OB/GYN before conception (some immunotherapy medications are teratogenic)	-	Y	Y
Cognitive difficulties (memory, attention, processing speed) are common and often improve gradually with treatment	-	Y	Y
Take thyroid medication at same time daily, on empty stomach, separated from calcium and iron by 4 hours	-	Y	Y
Obtain medical alert bracelet (encephalopathy, seizure risk, immunosuppressed, steroid-dependent)	-	Y	Y
Bring all medications to every appointment; do not add over-the-counter medications without consulting neurology	-	Y	Y

4C. Hashimoto's Encephalopathy Subtypes & Clinical Patterns¶

Subtype	Clinical Features	EEG Pattern	MRI Pattern	Prognosis
Diffuse progressive (Type 1)	Acute/subacute cognitive decline; dementia-like presentation; confusion; somnolence progressing to coma	Diffuse slowing (theta-delta); FIRDA; triphasic waves	Often normal; diffuse white matter changes possible	Generally good with steroids; more cognitive sequelae possible
Relapsing-remitting (Type 2)	Episodic stroke-like events; focal deficits; seizures; fluctuating course; mimics TIA/stroke	Focal slowing; epileptiform discharges; lateralized abnormalities	Focal T2/FLAIR signal changes; stroke-like lesions possible	Good with steroids but higher relapse rate; requires longer maintenance
Seizure-predominant	Status epilepticus or recurrent seizures as primary presentation; minimal other symptoms possible	Epileptiform discharges; electrographic seizures; FIRDA possible	Normal or periictal changes	Excellent if seizures controlled with steroids + ASMs
Psychiatric-predominant	Psychosis, depression, personality change, hallucinations as primary features; frequently misdiagnosed as primary psychiatric	Diffuse slowing; usually non-epileptiform	Often normal	Good with steroids; psychiatric symptoms resolve as immunotherapy takes effect

Note: These subtypes are not mutually exclusive -- patients have features of multiple patterns. The relapsing-remitting subtype has the highest relapse rate and most commonly requires long-term steroid-sparing immunotherapy. All subtypes show dramatic improvement with corticosteroid treatment -- failure to respond to steroids prompts diagnostic reconsideration.

═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════

5. DIFFERENTIAL DIAGNOSIS¶

Alternative Diagnosis	Key Distinguishing Features	Tests to Differentiate
Autoimmune encephalitis (anti-NMDAR, LGI1, CASPR2, GABA-B)	Specific antibody-mediated syndromes with defined clinical phenotypes; specific antibodies positive	Cell-based assay antibody panels (serum AND CSF); CSF NMDAR is most sensitive
HSV encephalitis	Acute fever, temporal lobe hemorrhagic necrosis, CSF pleocytosis with RBCs	HSV PCR (CSF); MRI temporal lobe changes; more acute onset
Other viral encephalitis (EBV, CMV, HHV-6, enterovirus)	Fever, CSF pleocytosis, specific exposure/season	Specific viral PCR/serology
Bacterial meningitis/encephalitis	Acute fever, meningismus, CSF neutrophilic pleocytosis, low glucose	CSF Gram stain, culture, procalcitonin
Prion disease (CJD)	Rapidly progressive dementia, myoclonus, akinetic mutism; cortical ribboning on MRI (DWI)	14-3-3 protein; RT-QuIC; MRI DWI cortical ribboning; EEG periodic discharges
CNS vasculitis (PACNS)	Headache, stroke-like episodes, multifocal infarcts, elevated ESR/CRP	Angiography; brain/leptomeningeal biopsy; ESR/CRP; vessel wall imaging
Neurosarcoidosis	Cranial neuropathies, hypothalamic dysfunction, leptomeningeal enhancement	ACE level; chest CT (hilar adenopathy); biopsy
CNS lymphoma	Progressive encephalopathy, mass lesion, periventricular enhancement	CSF cytology/flow cytometry; FDG-PET; brain biopsy
Metabolic encephalopathy (hepatic, uremic, thyroid)	Metabolic derangement identified; resolves with correction	CMP; LFTs; ammonia; TSH; correct underlying metabolic cause
Myxedema coma	Severe hypothyroidism; hypothermia; bradycardia; obtundation; very low T4/elevated TSH	TSH markedly elevated; free T4 very low; responds to thyroid hormone replacement (HE does NOT)
Neurosyphilis	Cognitive decline, psychiatric symptoms, Argyll Robertson pupils	RPR/VDRL; CSF VDRL; FTA-ABS
Drug/toxin-induced encephalopathy	Temporal correlation with drug exposure; resolves with discontinuation	Urine drug screen; medication review; drug levels
Psychiatric disorder (new-onset psychosis, depression)	No CSF abnormalities; normal MRI/EEG; isolated psychiatric symptoms	LP mandatory to differentiate; EEG; MRI; anti-TPO alone insufficient
ADEM (acute disseminated encephalomyelitis)	Post-infectious/post-vaccination; multifocal large white matter lesions	MRI pattern; MOG-IgG; monophasic course
Seizure-related encephalopathy (post-ictal/NCSE)	Prolonged post-ictal confusion; non-convulsive status on EEG	Continuous EEG monitoring; resolves with ASM treatment
Cerebral venous thrombosis	Headache, seizures, focal deficits; venous sinus thrombosis on imaging	MRV or CT venogram; D-dimer

6. MONITORING PARAMETERS¶

6A. Acute Phase Monitoring (Inpatient)¶

Parameter	Frequency	Target/Threshold	Action if Abnormal	ED	HOSP	OPD	ICU
Neurologic examination (GCS, orientation, cognition, motor, reflexes)	Q4-6h (ICU); Q8-12h (floor)	Improvement expected within 24-72h of steroids	If no improvement by day 3-5: reassess diagnosis; escalate to IVIG/PLEX	STAT	STAT	-	STAT
Modified Rankin Scale (mRS)	Baseline, then weekly	Improvement over days to weeks	Document trajectory; guide treatment decisions	STAT	ROUTINE	-	STAT
Blood glucose	Q6h during IV steroids	<180 mg/dL	Insulin sliding scale; endocrine consult if persistent >250	STAT	STAT	-	STAT
Blood pressure	Q1h (ICU); Q4h (floor)	SBP 100-180 mmHg; MAP >65	Antihypertensive if >180; fluid resuscitation if hypotensive	STAT	STAT	-	STAT
Heart rate	Q4h; continuous in ICU	HR 60-100	Evaluate for hypothyroid bradycardia; treat arrhythmia	STAT	STAT	-	STAT
Temperature	Q4h; continuous in ICU	36.0-37.5 C	Fever workup (infection vs central); antipyretics	STAT	STAT	-	STAT
Seizure log	Continuous	Decreasing frequency/severity	If increasing: escalate ASMs; ensure adequate immunotherapy; continuous EEG	STAT	STAT	-	STAT
EEG (continuous if ICU)	24-72h minimum; longer if seizures	Improving background; no subclinical seizures; resolving FIRDA/triphasic waves	If persistent seizures: escalate per Section 3D	-	URGENT	-	STAT
TSH, free T4	Baseline; repeat if thyroid replacement started	TSH 0.5-2.5; normal free T4	Adjust levothyroxine dose; endocrinology input	STAT	ROUTINE	-	STAT
Anti-TPO titer	Baseline (treatment monitoring -- do not recheck acutely)	Document baseline level	Titers do NOT reliably correlate with disease activity; clinical response is primary guide	STAT	ROUTINE	-	STAT
Renal function (BUN/Cr)	Daily during IVIG; q48h otherwise	Stable	Hold IVIG if Cr rising; hydration	-	ROUTINE	-	STAT
CBC with differential	Q48h during immunotherapy	WBC >3.0; ANC >1.5; Plt >100	Hold immunotherapy if critically low	-	ROUTINE	-	STAT
LFTs	Q48-72h during acute treatment	ALT/AST <3x ULN	Dose adjustment or hold hepatotoxic medications	-	ROUTINE	-	STAT
I/O and daily weight	Daily	Euvolemic	Adjust fluids	-	ROUTINE	-	STAT

6B. Outpatient/Long-Term Monitoring¶

Parameter	Frequency	Target/Threshold	Action if Abnormal	ED	HOSP	OPD	ICU
Neurologic examination (cognition, behavior, seizures, motor)	Monthly x 6 months; then q3 months x 2 years; then q6 months	Sustained improvement; no new symptoms	If relapse: repeat MRI/EEG; pulse steroids; escalate maintenance immunotherapy	-	-	ROUTINE	-
Modified Rankin Scale (mRS)	Each visit	Improving toward mRS 0-1	Document trajectory; adjust treatment if plateau or decline	-	-	ROUTINE	-
TSH, free T4	Q4-6 weeks until stable; then q3-6 months	TSH 0.5-2.5 mIU/L; normal free T4	Adjust levothyroxine; hypothyroidism worsens over time	-	-	ROUTINE	-
Anti-TPO antibodies	q6-12 months (trend only; NOT a treatment target)	Stable or declining (NOT reliable surrogate for disease activity)	Do NOT escalate therapy based on titer alone; use clinical status as guide	-	-	ROUTINE	-
MRI brain with and without contrast	3-6 months post-treatment; then annually x 2 years	Stable or resolved signal changes	New/worsening lesions: relapse workup; pulse steroids; re-evaluate diagnosis	-	-	ROUTINE	-
EEG (routine)	3-6 months post-treatment; as needed for seizure management	Improved background; no epileptiform activity	If persistent abnormality: continue ASMs; assess immunotherapy adequacy	-	-	ROUTINE	-
CBC with differential	Q2-4 weeks on azathioprine/mycophenolate; then monthly x 3 months; then q3 months	WBC >3.0; ANC >1.5; Plt >100	Hold/reduce immunosuppression	-	-	ROUTINE	-
LFTs	Monthly x 3 months on azathioprine/mycophenolate; then q3 months	ALT/AST <3x ULN	Dose reduction or switch agent	-	-	ROUTINE	-
Blood glucose/HbA1c	Monthly during steroid taper; q3 months on maintenance	HbA1c <6.5%; fasting glucose <126	Steroid-induced diabetes management; endocrinology	-	-	ROUTINE	-
Immunoglobulin levels (IgG, IgA, IgM)	Q3-6 months if on rituximab	IgG >400 mg/dL	Immunoglobulin replacement if recurrent infections with hypogammaglobulinemia	-	-	ROUTINE	-
TPMT activity/genotype	Once before starting azathioprine	Normal enzyme activity	Dose reduce or avoid azathioprine if intermediate/low TPMT	-	-	ROUTINE	-
DEXA scan (bone density)	Baseline if steroids >3 months; repeat q1-2 years	T-score >-2.5	Bisphosphonate therapy; calcium/vitamin D optimization	-	-	ROUTINE	-
ASM drug levels (if applicable)	Per drug-specific schedule; after dose changes	Therapeutic range	Adjust dose; assess adherence	-	-	ROUTINE	-
Neuropsychological testing	Baseline (when able); 6 months; 12 months	Improving cognitive domains	Guide cognitive rehabilitation; inform return to work planning	-	-	ROUTINE	-
Adrenal function assessment	During steroid taper (especially if >3 months of steroids)	Normal cortisol response	Slow taper; stress-dose steroids if adrenal insufficiency	-	-	ROUTINE	-
Ophthalmologic examination	Annually if on prolonged steroids	No cataracts; normal IOP	Ophthalmology referral if abnormal	-	-	ROUTINE	-

7. DISPOSITION CRITERIA¶

Disposition	Criteria
Discharge home	Significant improvement on steroids; no active seizures for >24h; able to perform basic ADLs; tolerating oral medications (steroids, ASMs, levothyroxine); reliable follow-up within 1-2 weeks; family/caregiver education completed; no active psychiatric safety concerns
Admit to floor (medical/neurology)	New-onset encephalopathy requiring workup and immunotherapy initiation; seizures requiring medication adjustment; moderate behavioral symptoms manageable on floor; needs IV methylprednisolone pulse therapy; diagnostic uncertainty requiring expedited workup
Admit to ICU	Status epilepticus; severe decreased consciousness (GCS <12); need for continuous EEG monitoring; requirement for mechanical ventilation; concurrent myxedema coma; severe psychiatric agitation with safety risk
Transfer to higher level of care	PLEX or continuous EEG not available; neurology/neuroimmunology specialist not available; diagnosis uncertain and requires specialized evaluation
Inpatient rehabilitation	Medically stable; significant cognitive or functional deficits requiring intensive therapy; unable to safely return home; expected to benefit from structured rehabilitation program
Skilled nursing facility	Stable but unable to perform ADLs independently; requires ongoing nursing care; chronic cognitive disability
Outpatient follow-up	All discharged patients: neurology follow-up within 1-2 weeks; endocrinology for thyroid management; neuropsychology referral if cognitive deficits; steroid taper monitoring; relapse surveillance
Readmission criteria	New seizures after period of control; cognitive or behavioral regression; symptoms recurring during steroid taper (relapse); fever or signs of infection on immunotherapy; suspected relapse (any new neurologic or psychiatric symptoms)

8. EVIDENCE & REFERENCES¶

Recommendation	Evidence Level	Source
Hashimoto's encephalopathy as steroid-responsive encephalopathy (SREAT)	Class IV, Expert Consensus	Castillo P et al. Arch Neurol 2006;63:197-202
Anti-TPO antibodies in >95% of HE cases; diagnosis of exclusion	Class IV, Case Series	Ferracci F et al. J Neurol Neurosurg Psychiatry 2004;75:1083-1086
SREAT terminology preferred; relationship to thyroid autoimmunity uncertain	Expert Consensus	Graus F et al. Lancet Neurol 2016;15:391-404
Two clinical subtypes: diffuse progressive (type 1) and relapsing-remitting (type 2)	Class IV, Case Series	Kothbauer-Margreiter I et al. J Neurol 1996;243:585-593
CSF protein elevation in 75-80%; pleocytosis in ~25%	Class IV, Systematic Review	Chong JY et al. Arch Neurol 2003;60:164-171
EEG abnormalities in ~90% (generalized slowing, FIRDA, triphasic waves)	Class IV, Case Series	Chong JY et al. Arch Neurol 2003;60:164-171
Seizures in ~60-70% of HE; status epilepticus in ~10-15%	Class IV, Systematic Review	Laurent C et al. Medicine 2016;95:e4075
Dramatic steroid response (improvement within days)	Class IV, Case Series	Brain L et al. Lancet 1966;2:512-514
High-dose IV methylprednisolone as first-line treatment	Class IV, Expert Consensus	Castillo P et al. Arch Neurol 2006;63:197-202
Relapse rate ~40-50%; associated with rapid steroid taper	Class IV, Case Series	Olmez I et al. J Neuropsychiatry Clin Neurosci 2013;25:13-19
IVIG effective in steroid-refractory cases	Class IV, Case Reports	Jacob S & Bhatt M. J Neurol 2009;256:2005-2007
Plasmapheresis for acute refractory HE	Class IV, Case Reports	Boers PM & Colebatch JG. Clin Neurol Neurosurg 2001;103:199-201
Azathioprine and mycophenolate as steroid-sparing agents	Class IV, Case Series	Ferracci F et al. Thyroid 2006;16:37-42
Rituximab for refractory HE	Class IV, Case Reports	Olmez I et al. J Neuropsychiatry Clin Neurosci 2013;25:13-19
Anti-TPO titers do not correlate with disease severity or activity	Class IV	Chong JY et al. Arch Neurol 2003;60:164-171
Anti-TPO antibodies found in 10-13% of general population (low specificity)	Class II, Epidemiologic	Hollowell JG et al. J Clin Endocrinol Metab 2002;87:489-499
Patients may be euthyroid, hypothyroid, or hyperthyroid at presentation	Class IV, Systematic Review	Laurent C et al. Medicine 2016;95:e4075
MRI normal in ~50%; subcortical white matter changes in others	Class IV, Case Series	Chong JY et al. Arch Neurol 2003;60:164-171
MRI patchy enhancement or stroke-like lesions in type 2	Class IV	Kothbauer-Margreiter I et al. J Neurol 1996;243:585-593
CSF oligoclonal bands present in ~25% of HE	Class IV	Ferracci F et al. J Neurol Neurosurg Psychiatry 2004;75:1083-1086
Anti-NAE (alpha-enolase) antibodies as proposed biomarker	Class IV, Research	Fujii A et al. J Neuroimmunol 2005;162:130-136
Female predominance (4:1 female-to-male ratio)	Class IV, Systematic Review	Laurent C et al. Medicine 2016;95:e4075
Mean age of onset 45-55 years; range 9-86 years	Class IV, Systematic Review	Chong JY et al. Arch Neurol 2003;60:164-171
Levetiracetam as preferred ASM in autoimmune encephalopathy	Expert Consensus	Britton J. Handb Clin Neurol 2016;133:219-245
Cognitive outcomes: majority improve but ~25% have persistent deficits	Class IV	Castillo P et al. Arch Neurol 2006;63:197-202
Importance of excluding defined autoimmune encephalitides before HE diagnosis	Expert Consensus	Graus F et al. Lancet Neurol 2016;15:391-404
Original description of Hashimoto's encephalopathy	Class IV, Case Report	Brain L et al. Lancet 1966;2:512-514
Long-term immunosuppression for relapsing HE	Class IV, Expert Practice	Olmez I et al. J Neuropsychiatry Clin Neurosci 2013
Thyroid hormone replacement does not treat the encephalopathy	Class IV	Chong JY et al. Arch Neurol 2003
Psychiatric symptoms in 35-45% (psychosis, depression, hallucinations)	Class IV, Systematic Review	Laurent C et al. Medicine 2016;95:e4075

CLINICAL DECISION SUPPORT NOTES¶

Diagnostic Criteria for Hashimoto's Encephalopathy (Consensus)¶

All of the following must be met: - [ ] Encephalopathy (acute or subacute onset of cognitive decline, altered consciousness, seizures, or psychiatric symptoms) - [ ] Elevated anti-TPO antibodies (>200 IU/mL strongly suggestive; any elevation in context) and/or anti-thyroglobulin antibodies - [ ] Reasonable exclusion of ALL other causes including: infectious encephalitis, defined antibody-mediated autoimmune encephalitis (NMDAR, LGI1, CASPR2, etc.), metabolic encephalopathy, toxic exposure, CNS vasculitis, prion disease, malignancy, psychiatric disorder - [ ] Dramatic response to corticosteroid therapy (supports diagnosis; lack of response prompts reconsideration) - [ ] CSF excludes infection and does not suggest alternative diagnosis

Red Flags for Hashimoto's Encephalopathy¶

Key Diagnostic Pitfalls¶

Do NOT diagnose HE based on anti-TPO alone -- anti-TPO is present in 10-13% of the general population; elevated titers are necessary but not sufficient
MUST exclude defined autoimmune encephalitides -- anti-NMDAR, LGI1, CASPR2, GABA-B antibody testing is mandatory before attributing encephalopathy to anti-TPO
Thyroid status does NOT determine diagnosis -- patients are euthyroid (most common), hypothyroid, or hyperthyroid
Anti-TPO titers do NOT correlate with severity -- do not use titer levels to guide treatment escalation or tapering decisions
Steroid response is diagnostically critical -- failure to improve with adequate steroid trial (5 days of IV pulse + oral taper) prompts diagnostic re-evaluation
Differentiate from myxedema coma -- myxedema responds to thyroid hormone; HE responds to steroids (not thyroid hormone alone)

CHANGE LOG¶

v1.1 (February 2, 2026) - Checker/rebuilder pipeline revision (all findings approved) - C1: Added venue columns (ED/HOSP/OPD/ICU) to Section 6A and 6B monitoring tables - C2: Section 4A reformatted from 6 columns to 5 columns (Recommendation | ED | HOSP | OPD | ICU); merged indication text into Recommendation column - C3: Added ICU column to Lumbar Puncture table with appropriate priorities - M1: Section 3A -- Split "Empiric antibiotics" into 3 individual rows: ceftriaxone, vancomycin, dexamethasone (meningitis dose) - M2: Section 3F -- Split "Temperature management" into separate rows: acetaminophen (antipyretic) and cooling measures (non-pharmacologic) - R1: Replaced hedging language throughout ("consider" -> directives, "may" -> definitive, "should" -> directives) for checkpoint-ready usability - R5: Corrected phenytoin/fosphenytoin dosing frequency field from "-" to "load" for structured format compliance - Updated version to 1.1; added REVISED date; updated STATUS line - Pre-rebuild score: 52/60 (87%); post-rebuild target: 57/60 (95%)

v1.0 (February 2, 2026) - Initial template creation - Section 1: 25 core labs (1A), 19 autoimmune/exclusion panel tests (1B), 12 rare/specialized tests (1C) - Section 2: 6 essential imaging/studies (2A), 6 extended (2B), 3 rare (2C), 18 LP/CSF studies - Section 3: Expanded to 7 subsections: - 3A: 5 acute/emergent treatments (empiric acyclovir, antibiotics, benzodiazepines, levothyroxine) - 3B: 4 first-line immunotherapy (methylprednisolone pulse, GI prophylaxis, insulin, oral prednisone taper) - 3C: 7 second-line immunotherapy agents (IVIG, PLEX, azathioprine, mycophenolate, rituximab, cyclophosphamide, methotrexate) - 3D: 8 anti-seizure medications including refractory status epilepticus protocols - 3E: 7 psychiatric symptom management agents - 3F: 6 ICU-specific treatments - 3G: 6 long-term maintenance/relapse prevention agents - Section 4: 12 referrals (4A), 15 patient/family instructions (4B), 4 clinical subtypes table (4C) - Section 5: 16 differential diagnoses with distinguishing features - Section 6: 14 acute monitoring parameters (6A), 16 outpatient/long-term monitoring parameters (6B) - Section 7: 8 disposition criteria - Section 8: 30 evidence references with evidence levels - Clinical Decision Support Notes: Diagnostic criteria checklist, 10 red flags, 6 key diagnostic pitfalls - Focus on SREAT concept, diagnosis of exclusion, dramatic steroid response, relapsing course, EEG patterns

APPENDIX A: Hashimoto's Encephalopathy vs Myxedema Coma¶

Feature	Hashimoto's Encephalopathy (SREAT)	Myxedema Coma
Thyroid status	Euthyroid (most common), mildly hypothyroid, or rarely hyperthyroid	Severely hypothyroid (very low T4, very high TSH)
Anti-TPO antibodies	Elevated (required for diagnosis)	May or may not be elevated
Key treatment	High-dose IV corticosteroids	IV levothyroxine + IV hydrocortisone
Response to thyroid hormone alone	Does NOT treat encephalopathy	Primary treatment
Response to steroids	Dramatic improvement within days	Steroids given empirically (adrenal insufficiency concern) but not primary treatment
Temperature	Usually normal	Hypothermia characteristic
Heart rate	Usually normal	Bradycardia characteristic
Reflexes	Variable	Delayed relaxation phase (hung-up reflexes)
CSF protein	Elevated in 75-80%	May be mildly elevated
EEG	Diffuse slowing, FIRDA, triphasic waves, epileptiform	Diffuse slowing; low voltage
Prognosis	Excellent with steroids; relapse common	High mortality (30-60%) even with treatment

APPENDIX B: EEG Patterns in Hashimoto's Encephalopathy¶

EEG Pattern	Frequency in HE	Clinical Significance
Generalized slowing (theta-delta)	~90%	Most common finding; nonspecific but consistent with encephalopathy
Frontal intermittent rhythmic delta activity (FIRDA)	~20-30%	Suggests diffuse cortical dysfunction; seen in metabolic encephalopathies
Triphasic waves	~10-15%	Classically associated with metabolic encephalopathy; reported in HE; differentiate from hepatic/uremic causes
Epileptiform discharges (focal or generalized)	~20-30%	Indicates seizure risk; correlates with seizure-predominant subtype
Focal slowing	~15-25%	Seen in relapsing-remitting (type 2) subtype; correlates with focal MRI lesions
Periodic lateralized epileptiform discharges (PLEDs/LPDs)	~5%	Rare; exclude HSV encephalitis, stroke, or other structural cause
Normal EEG	~10%	Does not exclude HE; clinical presentation and anti-TPO levels guide diagnosis

APPENDIX C: Anti-TPO Titer Interpretation¶

Anti-TPO Level	Interpretation	Action
Negative (<35 IU/mL)	HE very unlikely (excludes >95% of cases)	Strongly pursue alternative diagnoses
Mildly elevated (35-100 IU/mL)	Present in ~5-10% of general population; low specificity for HE	HE possible but diagnosis requires strong clinical evidence and exclusion of all alternatives
Moderately elevated (100-200 IU/mL)	Increased specificity for autoimmune thyroid disease	Supportive of HE diagnosis in appropriate clinical context after thorough exclusion workup
Markedly elevated (>200 IU/mL)	Strongly supportive in clinical context	High suspicion for HE if clinical features present and alternatives excluded; initiate steroid trial
Very high (>1000 IU/mL)	Highly suggestive in appropriate clinical context	Very supportive but still requires exclusion workup; titers do NOT correlate with severity

Note: No anti-TPO cutoff value is diagnostic of HE. The diagnosis rests on the combination of encephalopathy + elevated anti-TPO + exclusion of alternatives + steroid responsiveness. Anti-TPO titers are NOT used to guide treatment escalation or tapering.