autoimmune encephalitis in children

1. DR. GAJANAN YELME
SENIOR RESIDENT

2. CASE SUMMARY
• 4 year old male child
• Presented with
oc/o cough , cold for 5 days
oc/o mild grade fever 5 days
oc/o seizure followed by altered sensorium
since 15 days prior to admission

3. • Hospitalization for 15 days in pvt. hosp. prior
to admission in our hospital
• Mechanical ventilation for approx. 10 days
followed by tracheostomy tube insertion.
• Past history: no similar illness in past.

4. • Birth history:
• 2 nd order male child
Delivered at 32 weeks of gestation
Vaginal delivery
B. wt.- 1600gms
8 days of hospitalization in nicu

5. • Developmental history:
developmental milestones achieved
normally as per age.
• Family history:
no h/o similar illness in family
no h/o contact with TB

6. • AT ADMISSION : child was in status epilepticus
oGC very sick
oPR- 148/min
oRR-56/min. Pressure sores over back and
scalp
oSaturation 96% with tracheostomy tube
attached to oxygen @2 l/min
oGCS -6/15

7. • Systemic examinations.
• Resp. system- conducted sounds present b/l
• CVS- s1s2 normal
• Abdominal examination- no organomegaly
• CNS- GCS-6/15 on tracheostomy tube with T
piece
tone –
reflexes- ++

8. Video Courtesy: Dr. snehamayee

9. • INVESTIGATIONS:
• CBC – wnl
• SE – wnl
• CSF study – normal, viral markers- negative
• CSF NMDA receptor study –negative
• MRI – normal
• EEG – generalized seizures

11. • HOSPITAL COURSE:
• Received IVIG plus steroid from pvt. Hospital
• Multiple antiepileptics (phynetoin,
phenobarbitone, leveteracetam, valproate,
vigabatrine, lacosamide, oxcarbamazepine)
• Ketogenic diet started (? availability)
• Inj. Cyclophoshamide (Day 6 admission)

12. • Condition today :
• Abnormal movements , no seizures
• Tracheostomy tube in situ
• Child able to sit and walks with support
• GCS improved
• Playing with his toys , mobiles recognizes
parents

13. Video Courtesy : Dr. pranoy

14. OVERVIEW
• Encephalitis –
ofrom Greek enkephalos (―brain) and
itis ―inflammation)
oEncephalomyelitis
oMeningoencephalitis
oEtiologies

15. • AUTOIMMUNE ENCEPHALITIS:
anti-LGI1 encephalitis
 anti- N-methyl-D-aspartic acid
receptor (anti-NMDAR) encephalitis
 CASPR2
GABA-B
AMPA encephalitis

16. • Exact incidence is not known.
• a multicenter study in the United Kingdom -
4%
• California Encephalitis Project - anti-NMDA
receptor encephalitis surpassed any viral
encephalitis

17. ANTI NMDR RECEPTOR
ENCEPHALITIS
• Leading cause of autoimmune encephalitis in
children and adolescents.
• Stages :
1. Stage1 – prodromal phase
2. Stage 2 – psychiatric and behavioral problems
3. Stage 3 – Decreased level of consciousness
• Behavioral changes included new-onset
temper tantrums, agitation, aggression, and
changes in mood or personality

18. • Ovarian teratoma is associated in up to 50% of
the cases
• Investigations :
oCSF
o lymphocytic pleocytosis,
o elevated protein levels
o oligoclonal bands
• EEG – extreme delta brush

19. o MRI demonstrate medial temporal lobe
attenuated inversion recovery high signal or
focal areas of hyperintensity in the frontal or
parietal cortex
o fluorodeoxyglucose positron emission
tomography (FDG-PET) scan show cortical
hypermetabolism in acute stages, and
hypometabolism in more subacute stages of
the illness.

21. Mechanism for clinical features
NMDAR in inhibitory GABAergic neurons and glutamatergic
synapses
increase of extracellular glutamate
1. frontostriatal syndrome – neuropsychiatric manifestations,
2. disinhibition of brainstem central pattern generators
accounting for the complex movement disorders
3. disruption of the medullary-pontine network accounting for
central hypoventilation

22. • Confirmation of diagnosis –
• Demonstrating NMDA receptor
antibodies in serum or cerebrospinal fluid
• The levels of antibodies in cerebrospinal
fluid correlate better with symptom
outcome

23. • Treatment :
first line of immunotherapies including
corticosteroids, intravenous
immunoglobulin, or plasma exchange
Rituximab and cyclophosphamide, alone
or combined, are often effective in adults
Approximately 80% of patients have
substantial or full recovery.

24. • symptoms 1st to improve:
autonomic instability, dyskinesias, level of
consciousness, and seizures.
• After recovering consciousness, the psychiatric
manifestations can reemerge, and impulsivity,
behavioral disinhibition.

25. • multidisciplinary approach - nursing,
psychiatrists, cognitive rehabilitators,
physiatrists and families.
• clinical relapse in 20% of children with anti-
NMDA encephalitis.

27. LIMBIC ENCEPHALITIS
• Definition:
• characterised by subacute development
of short term memory loss, behavioural
change and seizures involving the
temporomedial lobes , the amygdalae,
and cingulate gyrus with variable
evidence of CSF inflammation and
neuronal antibodies

28. • antibodies against the neuronal secreted
protein called leucine-rich glioma-
inactivated 1 (LGI1)
• LGI1 - secreted neuronal protein that
interacts with the presynaptic and
postsynaptic proteins ADAM23 and
ADAM22 -modulate synaptic
transmission

29. • In 1968 , as Para neoplastic syndrome
• median age of patients is 60 years
• Severe short term memory loss
• hyponatremia and myoclonic-like movements,
described as faciobrachial dystonic seizures

30. • 70% of the patients improve with t/t.
• Other antibodies associated- antibodies
against intracellular antigens (eg, Hu, CRMP5,
Ma2) or against cell surface or synaptic
proteins (eg (AMPA) [GABA(B)] [mGluR5])
• Ophelia syndrome

31. HASHIMOTO
ENCEPHALOPATHY
• Previous steroid responsive encephalopathy
associated with autoimmune thyroiditis.
• Now encephalopathy associated with
autoimmune thyroid disease
• 52% hypothyroid , 48% normal thyroid
function

32. • Clinical features : non specific
Stroke like symptoms, tremors ,myoclonus,
transient aphasia, sleep and behavior
abnormality, hallucinations, seizures.
• CSF- protein elevated
• EEG- generalized slowing
• MRI- normal

33. • Thyroid peroxidase antibodies.
o10% healthy adults
oOther disorders GABA,LGI1 and NMDR
receptor antibodies.

34. RASMUSSEN ENCEPHALITIS
• Progressive refractory partial seizures,
cognitive deterioration and focal deficit occurs
with gradual atrophy of one hemisphere.
• AMPA, munc 18-1.
• High dose methylprednisolone and ivig.
• Tacrolimus.

35. BASAL GANGLION
ENCEPHALITIS
• specifically affecting the basal ganglia
• isolated subcortical features including
movement disorders such as parkinsonism,
dystonia, or chorea.
• hypersomnolence and psychiatric features
such as attention deficit, emotional lability,
obsessive-compulsive disorder, and psychosis

36. • Investigations :
oinflammatory CSF (lymphocytic pleocytosis
and oligoclonal bands) and lymphocytic
cuffing in histopathology of the basal
ganglia,
oFDG-PET scan demonstrates basal ganglia
hypermetabolism.

37. • MRI reveals basal ganglia swelling and T2-
weighted hyperintensity and sometimes
brainstem signal change, with follow-up scans
showing basal ganglia atrophy and gliosis.

39. Therapeutic strategies and
outcomes
• no consensus guidelines
• pulsed steroids followed by high dose oral
prednisone, and IVIg and/or plasmapheresis
as first-line therapy
• DOSAGE:
- 3–5 days of pulsed IV methylprednisolone
(30 mg/kg/day up to 1 g/day) followed by high
dose oral prednisone (1–2 mg/kg/day) and 2
g/kg of IVIg administered over two to five doses

40. • Non response:
• within 1–2 weeks should lead to
consideration of three to five exchanges
with plasmapheresis, or commencement
of second-line therapy such as
cyclophosphamide or rituximab
• respond slowly to immune therapy
(weeks rather than days).

41. Therapeutic challenges
• What defines failure of first-line treatment?
• At what stage is it reasonable to escalate therapy to
second-line agents?
• Do patients who have a particularly significant
clinical episode warrant second-line therapy despite
improvement with first-line therapy?
• To what degree does second-line therapy reduce the
relapse rate?
• What role does maintenance immunosuppression
have?

42. Case senarios
• Treatment of antibody negative patients:
An 8-year-old boy presented with a 3 week history of focal
seizures, a hyperkinetic movement disorder, and mutism,
requiring a 2 month intensive care unit and hospital admission.
CSF showed 20 106/L monocytes but viral studies, and serum
and CSF anti- NMDAR, VGKC complex, and D2R antibody testing
was negative. Given this was a severe presentation and the
clinical phenotype was reminiscent of autoimmune encephalitis,
he was treated with first-line therapy in the form of IV steroids
and IVIg. Ten days after first-line therapy there was no
improvement so second-line therapy with rituximab was
commenced. Within 5 days of rituximab he began improving and
subsequently made a good clinical recovery over 6 weeks,
returning to baseline function.

43. • Role of second-line therapy:
A 4-year-old girl presented with a 2 week history of focal seizures
and psychosis. CSF analysis revealed 12 106/L monocytes and
was positive for anti-NMDAR encephalitis. She was treated with
first-line therapy in the form of IV steroids and IVIg. She started
to improve rapidly within 2 weeks of therapy, and returned to
baseline by 8 weeks. Her serum anti-NMDAR antibody status
remained positive 1 year after presentation although the patient
was clinically well.

44. • Management of relapsing anti-NMDAR encephalitis:
Focal seizures, speech disturbance, chorea, and agitation. CSF
oligoclonal bands were positive. This presentation was prior to
the initial descriptions of anti-NMDAR encephalitis, however
given the high index of suspicion for autoimmune encephalitis,
she was treated with IV steroids and IVIg. Her diagnosis was
confirmed as anti- NMDAR encephalitis in 2009 with
retrospective testing of acute serum and CSF samples. She has
had three subsequent relapses which were treated successfully
with IV and oral steroids. Given the relapsing course and steroid
responsiveness, she was started on oral mycophenolate mofetil
and has been free of relapses for the last 2 years.

45. Future directions
• identification of novel antigens
• early initiation of immune therapy
• efficacious therapeutic strategies

46. Video Courtesy: Dr. chinmay

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