There is development of antibodies against neuronal antigens in response to several triggers
(Table 1).
TABLE 1: Causative factors.
|
Triggers
|
Agents
|
Comments
|
Infections: Postviral immune
encephalitis
|
- HSV, VZV, EBV, HHV-6, CMV, HIV, and adenovirus
- Rickettsial
- Mycoplasma
- Triggers cause the release of brain-specific neoantigens and
trigger development of pathogenic antibodies
- Nonspecific stimulation of
range of antibodies
|
|
|
HSV
and AE:
- 30% of cases with
HSV encephalitis had anti- NMDAR
antibodies in CSF
- Anti-NMDAR
antibodies lead to relapse of HSV encephalitis (20%)
- Improve with immunotherapy
|
Postvaccinal:
|
|
|
Anti-NMDAR
|
|
|
|
|
|
Paraneoplastic:
|
|
þ Antibody-mediated neuronal cell destruction
- Less common in children
- Between 12 and 45
years: 40% associated with tumor (97%
females)
- <18 years: 31% paraneoplastic
- <14 years: 9% paraneoplastic
- 94% ovarian teratoma, 2% extraovarian teratoma
- 4%: Small cell carcinoma lung, testicular
teratoma, and breast
|
Tumor
|
|
antigens
|
|
shared by
|
|
neuronal cell
|
|
antigens
|
|
(AE: autoimmune encephalitis; CMV: cytomegalovirus; CSF: cerebrospinal fluid; DPT: diphtheria, pertussis,
tetanus; EBV: Epstein–Barr virus; HHV-6: human herpesvirus 6; HIV: human immunodeficiency virus;
HSV: herpes simplex virus; VZV: varicella-zoster virus)
AE is categorized as per the antigen location (cell surface or intracellular antigen) (Table 2):
TABLE 2: Categories of autoimmune encephalitis.
|
Antigen location
|
Type
of antibodies
|
Comments
|
Cell surface
|
þ Anti-NMDAR (most common)
- VGKC
- LGI1
- CASPR2
- Anti-GABA-A receptors
- Anti-GABA-B receptors
- Anti-Glycine
- Anti-D2 receptors
- Anti-AMPA receptors
- Anti-mGlu5
- Anti-neurexin3 alpha
- Anti-glutamate receptors
|
þ Common in children
- Lower association with malignancy
- Mediated by humoral immune system
- Better response to
immunotherapy
- Favorable outcome
|
Antigen location
|
Type
of antibodies
|
Comments
|
Intracellular
|
þ Anti-Hu
|
þ Less relevant in pediatric
- Usually, paraneoplastic
- Mediated by cytotoxic T-cells
- Respond poorly to immunomodulatory therapy
- Poorer outcomes
|
Clinical Features :
Anti-NMDAR encephalitis is prototype of AE and this will be discussed here.
It accounts for 4% of encephalitis in children.
It is most common cause of seropositive AE in children.
40% of all reported cases are below 18 years of age.
It may also contribute to recurrence of encephalitis after herpes simplex virus (HSV) encephalitis.
It was first described as a paraneoplastic syndrome in adult females in association with ovarian
teratomas. However, it is being increasingly recognized in men, women, and children, with and
without teratomas.
Pathogenesis: It is mostly postinfective. Immunoglobulin G1 (IgG1) NMDA antibodies bind
to NR1 subunits of NMDA receptors leading to their internalization. This lead to inhibition of
glutaminergic excitation to inhibitory neurons and in turn intense excitotoxicity.
The clinical course follows triphasic pattern: Prodrome, varied neurological manifestations, and
advanced disease (Flowchart 1).
Children have more pronounced seizures, movement disorders, speech abnormalities, sleep
problems, and behavioral issues.
Seronegative Autoimmune Encephalitis:
Only 40–50% cases with AE have positive antibodies
Definition of seronegative AE include:
• Rapid clinical progression of symptoms
• Exclusion of well-defined AE syndromes (e.g., typical limbic encephalitis)
• Absence of antibodies in CSF and serum antibody positivity
And two of the following:
• CSF pleocytosis
• CSF-specific oligoclonal bands or elevated CSF IgG index
• MRI findings suggestive of AE
• Brain biopsy showing inflammation
And exclusion of other causes
When to Suspect Autoimmune Encephalitis?
Autoimmune encephalitis should be suspected when a child present with varied combination of
following features:
Unusual manifestations in a child with acute encephalitis syndrome
- Adolescent girls
- Subacute to chronic course
- Polysymptomatic syndrome
- Encephalopathy
- Seizures: Focal, generalized, status epilepticus, multifocal, and super-refractory status epilepticus
- Movement, gait, and balance disorders
- Psychiatric features
- Autonomic disturbances
- Delirium and catatonia
- Cognitive slowing
- Relapse after treatment for viral encephalitis
- Involvement of multiple domains, e.g., cognition and extrapyramidal system, etc.
- CSF: Features of inflammation in absence of infection
Diagnosis:
Diagnosis relies on the clinical phenotype, CSF inflammation, MRI and electroencephalogram
(EEG) findings, antibody positivity, response to immunotherapy, and exclusion of other
causes (Table 3)
Adolescent females must be screened for tumors (association with ovarian teratomas).
TABLE 3: Diagnostic
tests for autoimmune encephalitis (AE).
|
Diagnostic tests
|
Comments
|
CSF examination
|
It is suggestive of CNS inflammation. About 80% cases
may have abnormal CSF in form of CSF pleocytosis (lymphocytic),
normal/mild elevation in proteins, normal glucose,
and elevated IgG index, oligoclonal bands, or CSF neopterin.
|
MRI brain (anti- NMDAR)
|
- Unilateral
or bilateral T2/FLAIR signal hyperintensities involving mesial temporal lobe,
hippocampal, cerebellar, and cerebral cortex.
- Hyperintensities may be seen throughout brain.
- Cortical enhancement in absence of restricted diffusion.
- MRI may be normal in 50–60% cases.
- PET scan can highlight involvement of mesial temporal lobes.
|
Diagnostic tests
|
Comments
|
EEG
|
- EEG is abnormal
in most patients. The findings are usually nonspecific including extreme or diffuse slowing, epileptiform discharges, and disorganized activity.
- Extreme delta brushes are seen in 30% of anti-NMDAR cases.
|
Antibody testing
|
þ Detection of pathogenic antibody is basis for diagnosis of AE.
- Positive: Definite cases; Negative: Suspected case.
- Methods: Cell-based assays with live or fixed eukaryotic cells or IgG-based assays.
- Testing both serum and CSF is preferred.
- However, in resource
limited setup, only CSF can be done as it is more
sensitive.
- In anti-NMDAR, CSF testing is more sensitive (100% vs. 86%).
- In protracted disease, delayed diagnosis, and after IVIG/PE, antibodies may be present only in CSF.
- Only 40–50% cases
with AE have
antibody positivity.
- It has limited utility of follow-up evaluation.
|
(CNS: central nervous system; CSF: cerebrospinal fluid; EEG: electroencephalogram; FLAIR: fluidattenuated
inversion recovery; IgG: immunoglobulin G; IVIG: intravenous immunoglobulin; PE: plasma
exchange; PET: positron emission tomography)
Differential Diagnosis:
It includes CNS infections [HSV and Japanese encephalitis (JE)], toxins, CNS vasculitis, inborn
errors of metabolism [osteoarthritis (OA) and mitochondrial], neoplasms, primary psychiatric
disorder, and subacute sclerosing panencephalitis (SSPE).
Differentiation between AE and acute infectious encephalitis is presented in Table 4.
TABLE 4: Differentiation between autoimmune encephalitis (AE) and acute
infectious encephalitis.
|
Salient features
|
Autoimmune encephalitis
|
Infectious encephalitis
|
Clinical manifestations
|
- Seizures,
movement disorders, speech
abnormalities, sleep problems, and behavioral issues
- Fever in 50%
þ Autonomic dysfunction
þ Rash is rare
|
- Fever, seizures, and altered sensorium.
- Most cases have fever.
- Rash may be present in VZV and HSV encephalitis.
|
CSF
|
Mild CSF pleocytosis
|
More CSF pleocytosis
|
Salient features
|
Autoimmune encephalitis
|
Infectious encephalitis
|
MRI brain
|
- It is recommended in children with suspected AE during initial evaluation and to rule out
alternate causes.
- MRI abnormalities seen in AE are commonly subtle
and may be discordant from dramatic clinical features.
- MRI may be normal (50–66%), especially early in the course.
þ Basal ganglia often
involved.
- Lateral temporal lobes
and insula less
commonly involved.
- There can be T2-weighted fluid- attenuated inversion recovery abnormalities
throughout the brain and in cortical and subcortical areas,
including temporal,
frontal, and parietal lobes; hippocampi and amygdalae, cerebellum; thalamus; and basal
ganglia.
- There may be contrast enhancement and abnormal diffusion-weighted images.
- Mesial temporal
lobe involvement in characteristic (HSV)
- Lateral temporal lobe and insula may be involved
- Basal ganglia spared
|
|
Treatment
|
- Immunotherapy (±surgical
removal of tumor)
|
Antiviral (acyclovir)
|
(CSF: cerebrospinal fluid; HSV: herpes simplex virus; VZV: varicella-zoster virus)
Treatment:
Prognosis is better with early diagnosis
and early initiation of immunotherapy.
Second-line agent also improves
prognosis in cases with poor response
to first-line therapy, severe disease,
and relapsing disease.
Therefore, if AE is suspected, start
empirical therapy immediately without
waiting for antibody results. However,
if antibody testing is not affordable or
not available, start empirical therapy
after excluding alternate causes.
A significant proportion of patients respond to first-line therapy
They show response to treatment within first 1–2 weeks of treatment initiation (Table 5).
TABLE 5: Agents and their recommended dosages.
|
Agents
|
Dose and comments
|
First line
|
Corticosteroids
|
- Corticosteroids are the cornerstone of
treatment with broad spectrum of anti-inflammatory activity and good penetration across blood–brain barrier.
- Methylprednisolone:
30 mg/kg/day (maximum 1
g/day) for 3–5 days, followed by sustained oral steroids (prednisolone 1–2 mg kg/day)
and slow taper
over 6–12 months.
|
IVIG or PE
|
- It is commonly used as alternatives and occasionally, concomitantly.
- IVIG (2 g/kg given over 5 days) or PE (5–7
exchanges of 50 mL/kg every
alternate
day).
- Early PE along
with corticosteroids have better outcomes than either alone.
- No evidence exists
regarding superiority of PE versus
IVIG.
- However, considering that
cases with AE are
often sick, IVIG might be easier.
- Common regimens used: Methylprednisolone ± IVIG or IVIG/PE during
acute stage in cases with inadequate response to methylprednisolone.
|
Second line
|
Rituximab
|
- It is chimeric monoclonal
antibody against CD20.
- Dose: 375 mg/m2 weekly for 4 weeks
or 750 mg/m2 (maximum
1 g) IV twice separated by 2 weeks.
- Resulting
in B-cell depletion and reduced proinflammatory CD4+ and CD8+
T cells.
- B-cell count after
2–4 weeks and 3–6 months.
- To consider redosing
if symptoms persist
or relapse.
- Well tolerated and serious adverse
events are rare.
- Infusion reactions 12%.
|
Cyclophosphamide
|
- It has broad cellular immune
suppression effects.
- Dose: Monthly IV infusions 500–1,000 mg/m2 BSA for 6–9 months.
- Limitations: Risks of infertility and secondary malignancies which depend on cumulative dose received.
- Doses <7.5 g/m2
are justified in sick patients.
- Concomitant rituximab and cyclophosphamide have been tried
without any increase in adverse effect
profile.
|
Third line
|
- When both first-
and second-line agents
fail
- Bortezomib (protease inhibitor-inhibits proinflammatory signaling cascade)
- Tocilizumab (anti-IL-6)
- Intrathecal steroids and methotrexate
|
(BSA: body surface area; IL-6: interleukin-6; IVIG: intravenous immunoglobulin; PE: plasma exchange)
Maintenance Therapy:
The options for maintenance therapy include:
Prednisolone for 6–12 months.
Monthly pulses of methylprednisolone (MP) or intravenous immunoglobulin (IVIG).
Mycophenolate mofetil (MMF), methotrexate, and azathioprine:
• Steroid-sparing agents (pediatric anti-NMDAR)
• They are used individually or in varying combinations
• Associated with a reduced risk of relapse if started after first event rather than
after subsequent ones
• Reasonably safe
Management of Relapse:
Relapses are not uncommon in AE.
10–25% of patients with anti-NMDAR relapse
Can be reduced by use of second-line therapies and chronic immunosuppression.
When they occur, they are managed with repeat dosing of the first-line agents.
Considering the concern of ongoing inflammatory activity, chronic immunosuppressive
therapy should be considered.
Azathioprine, MMF, or repeated dose of rituximab
Pediatric Intensive Care Unit Needs:
40–60% children with AE need pediatric intensive care unit (PICU) care.
They may need mechanical ventilation due to encephalopathy, status epilepticus,
and use of multiple antiepileptic drugs (AEDs). The principles of lung protective
ventilation should be followed.
For seizures and refractory status epilepticus, follow usual protocol.
To induce and maintain sleep, relieve agitation and emotional imbalance, one can
use benzodiazepines, clonidine, or chloral hydrate. Avoid neuroleptics as they are
associated with high incidence of rigidity and neuroleptic malignant syndrome.
Monitor for autonomic dysfunction.
Dystonia can be treated with benzodiazepines, pacitane, clonidine, or baclofen.
Maintain strict fluid balance and infection control practices.
Early liberation from the mechanical ventilation and PICU.
Prognosis :
Majority (90%) respond to first-line therapy within 4 weeks.
Those failed first-line therapy, 57% responded to second-line therapy.
At 2-year follow-up:
• 80% patients had a good outcome
• Mortality in 4–6%
Predictors of poor outcome:
• Delayed diagnosis and treatment (immunomodulation)
• PICU admission, altered sensorium, and dysautonomia
• Polysymptomatic presentation.
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