Sero negative autoimmune encephalotis

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Seronegative Autoimmune Encephalitis

Definition

Seronegative autoimmune encephalitis (AE) refers to a clinical syndrome consistent with autoimmune encephalitis in which no pathogenic autoantibody is detectable in serum or CSF using currently available assays. It is also called antibody-negative probable autoimmune encephalitis (ANPAE) under the Graus criteria (2016, updated commentary 2023 by Dalmau & Graus, Lancet Neurol 22:529-540).

The absence of antibodies likely reflects:

Undiscovered or novel antigens not yet in commercial panels
Low antibody titers below assay detection limits
Predominantly T-cell mediated pathology without prominent humoral response
Antibodies restricted to the CNS compartment (absent in serum, possibly missed in CSF)
Technical limitations of cell-based vs. tissue-based assays

Epidemiology

Autoimmune encephalitis overall accounts for approximately 25% of all encephalitis cases, with an incidence now estimated to be similar to infectious encephalitis (Adams and Victor's Principles of Neurology, 12th Ed.). A significant fraction - estimates range from 20-50% depending on the testing panel used - remains seronegative after comprehensive workup. Seronegative cases skew toward older patients and more often present with atypical phenotypes compared to antibody-positive subtypes.

Pathophysiology

The autoimmune encephalitides can be divided into:

Category	Mechanism	Antibody Targets
Cell-surface/synaptic	Antibody-mediated; potentially reversible	NMDAR, LGI1, CASPR2, AMPAR, GABAB/A, DPPX, GlyR
Intracellular/nuclear	T-cell cytotoxicity; less treatment-responsive	Hu, Yo, Ri, Ma2, CV2/CRMP5
Seronegative	Unknown; mixed T/B cell or novel undetected antibodies	None detected

In seronegative cases, CSF may show lymphocytic pleocytosis and elevated protein, suggesting inflammation is genuinely present. Some seronegative patients have a predominantly T-cell infiltrate on neuropathology.

Goldman-Cecil Medicine, p. 4031

Clinical Presentation

The clinical phenotype of seronegative AE mirrors seropositive disease. Onset is typically subacute (< 3 months) and includes:

Core features:

Progressive cognitive decline and memory impairment (short-term > long-term)
Behavioral and personality changes - agitation, aggression, disinhibition
Psychiatric symptoms - psychosis, hallucinations, depression, catatonia
Seizures (focal or generalized; often refractory)
Decreased level of consciousness
Autonomic instability (tachycardia, blood pressure lability, hyperthermia)

Syndromic patterns to recognize:

Limbic encephalitis - amnestic syndrome + behavioral change + temporal lobe seizures
Diffuse cortical encephalitis - resembling NMDAR-AE phenotype (psychosis, movement disorder, autonomic dysfunction, decreased consciousness)
Brainstem encephalitis - diplopia, dysphagia, ataxia, hypersomnolence

Key clinical clue: psychiatric symptoms predominate early, leading to misdiagnosis as primary psychiatric illness and delaying immunotherapy.

Adams and Victor's Principles of Neurology, 12th Ed., p. 947
Goldman-Cecil Medicine, p. 4031-4032

Diagnostic Criteria (Graus 2016 Framework)

Possible Autoimmune Encephalitis (can be seronegative) - requires ALL 3:

Subacute onset (< 3 months) of memory deficits, altered mental status, or psychiatric symptoms
At least ONE of the following:
- New focal CNS findings
- New-onset seizures not explained by a pre-existing disorder
- CSF pleocytosis (> 5 WBC/mm³)
- MRI features suggestive of encephalitis
Reasonable exclusion of alternative causes

Probable Antibody-Negative AE (ANPAE) - requires ALL 4:

Meets criteria for possible AE
All of the following:
- No antibody found in serum AND CSF
- No evidence of underlying neoplasm (with appropriate age/risk factor workup)
- Exclusion of well-defined alternatives
CSF pleocytosis OR MRI abnormalities consistent with encephalitis
No better explanation

The 2023 Dalmau-Graus update (Lancet Neurol) refined the utility and pitfalls of these criteria, particularly for antibody-negative disease, emphasizing that a negative antibody test does not rule out AE.

Investigations

CSF Analysis

Lymphocytic pleocytosis (5-100 WBC/µL) in ~60-80% of cases
Mildly elevated protein
Elevated IgG index or oligoclonal bands (supportive, not specific)
Kappa free light chains - emerging as a marker of intrathecal synthesis
Send CSF (not just serum) for antibody testing - serum may be false negative for NMDAR antibodies especially

MRI Brain

T2/FLAIR hyperintensity in mesial temporal lobes, hippocampus (limbic encephalitis pattern)
Cortical diffuse signal change in NMDAR-type
May be normal in up to 50% of confirmed AE cases - a normal MRI does not exclude AE

EEG

Diffuse or multifocal slowing
Temporal lobe epileptiform discharges
Extreme delta brush - highly suggestive of NMDAR encephalitis
Non-convulsive status epilepticus (NCSE) is common

Autoantibody Panel (serum AND CSF)

Send a comprehensive panel in both fluids simultaneously:

Cell-surface: NMDAR (GluN1), LGI1, CASPR2, AMPAR, GABAB, GABAA, DPPX, GlyR, IgLON5, mGluR1/5
Intracellular: Hu, Yo, Ri, CV2/CRMP5, Ma2, GAD65, GFAP
Systemic: TPO (Hashimoto), AQP4 (NMOSD), MOG-IgG

Malignancy Workup

CT chest/abdomen/pelvis as initial screen
FDG-PET whole body if CT negative and clinical suspicion for paraneoplastic AE
Testicular ultrasound in young men (seminoma/germ cell)
Pelvic MRI/ultrasound in women (ovarian teratoma)

Additional

Metabolic screen: electrolytes, ammonia, thyroid, B12, cortisol
Infectious workup: HSV, CMV, EBV, VZV, HHV6, enteroviruses, HIV, syphilis, cryptococcus (CSF)
Metagenomics NGS of CSF if available and high suspicion of infection

Treatment

Treatment should be initiated promptly based on clinical suspicion, without waiting for antibody results. Time to immunotherapy correlates with outcome.

First-Line Immunotherapy

Agent	Dose	Duration
IV methylprednisolone	1000 mg/day IV x 5 days	May continue weekly x 6-12 weeks
IV immunoglobulin (IVIG)	0.4 g/kg/day x 5 days (or 2 g/kg over 2-5 days)	Can repeat monthly
Plasmapheresis (PLEX)	5-7 exchanges over 10-14 days	For refractory or severe cases

First-line agents are often combined (steroids + IVIG, or steroids + PLEX) in severe or rapidly progressive disease.

Second-Line Immunotherapy (for inadequate first-line response)

Agent	Dose
Rituximab	375 mg/m² weekly x 4, or 1000 mg x 2 (2 weeks apart)
Cyclophosphamide	750 mg/m² IV monthly
Tocilizumab (anti-IL-6R)	4-8 mg/kg IV every 4 weeks
Mycophenolate mofetil	1000-1500 mg twice daily (long-term maintenance)
Azathioprine	2-3 mg/kg/day (long-term maintenance)

Rituximab and cyclophosphamide are often used together as a second-line combination.

Symptomatic Management

Seizure control: levetiracetam, lacosamide, valproate (NMDAR-AE: avoid carbamazepine which may worsen)
Psychiatric symptoms: low-dose antipsychotics with caution; benzodiazepines for agitation
Autonomic instability: close monitoring in ICU setting
Goldman-Cecil Medicine, p. 4032; Adams and Victor's Neurology, p. 947

Prognosis

Seronegative AE has a heterogeneous prognosis. Key points:

Early immunotherapy is the strongest predictor of good outcome - even in seronegative cases
A 2023-2024 systematic review (PMC12794537) found that seronegative AE patients show meaningful improvement with immunotherapy, though response rates may be somewhat lower than seropositive NMDAR-AE
Seronegative patients tend to have higher relapse rates in some series
Functional recovery can occur even after prolonged illness with aggressive immunotherapy
Prognosis is worse in paraneoplastic cases where the primary cancer drives the immune response

Differential Diagnosis

Key mimics that must be excluded:

Viral encephalitis - HSV most common, treat with acyclovir empirically until excluded
Prion disease - rapid cognitive decline; CSF 14-3-3, RT-QuIC, MRI DWI
Creutzfeldt-Jakob disease (CJD)
Toxic/metabolic encephalopathy - hepatic, uremic, Wernicke
Primary psychiatric disorder - exclusion of diagnosis, not first step
CNS vasculitis - CSF, angiography
Neurodegenerative disease with atypical rapid onset
Anti-NMDAR encephalitis triggered by prior herpes simplex encephalitis - recognize this post-HSV autoimmune complication

Summary Algorithm

Subacute encephalopathy + behavioral/psychiatric change
        ↓
Exclude infection (acyclovir empirically if HSV possible)
Exclude metabolic/toxic/structural causes
        ↓
Send: CSF (cell count, protein, glucose, culture, HSV PCR, comprehensive antibody panel)
      Serum (comprehensive antibody panel)
      MRI brain with contrast
      EEG
      CT/PET body (malignancy)
        ↓
Meets possible/probable AE criteria?
        ↓ YES
Initiate first-line immunotherapy (do NOT wait for antibody results)
        ↓
Reassess at 2-4 weeks
  - Improved → continue/taper
  - No improvement → escalate to second-line
        ↓
Seronegative with poor response → consider rituximab ± cyclophosphamide

Recent literature note: A 2025 Nature Reviews Disease Primers review (de Bruijn, Leypoldt, Dalmau; PMID 40935848) provides an updated overview of AE. Dalmau and Graus's 2023 Lancet Neurology commentary specifically addresses the diagnostic utility and pitfalls for antibody-negative disease - this is the most relevant recent reference for seronegative AE.

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