Autoimmune encephalitis in children

DR. GAJANAN YELME

SENIOR RESIDENT

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

• 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.

• Birth history:

• 2 nd order male child

Delivered at 32 weeks of gestation

Vaginal delivery

B. wt.- 1600gms

8 days of hospitalization in nicu

• Developmental history:

developmental milestones achieved

normally as per age.

• Family history:

no h/o similar illness in family

no h/o contact with TB

• 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

• 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- ++

Video Courtesy: Dr. snehamayee

• INVESTIGATIONS:

• CBC – wnl

• SE – wnl

• CSF study – normal, viral markers- negative

• CSF NMDA receptor study –negative

• MRI – normal

• EEG – generalized seizures

• 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)

• 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

Video Courtesy : Dr. pranoy

OVERVIEW

• Encephalitis –

ofrom Greek enkephalos (―brain) and itis ―inflammation)

oEncephalomyelitis

oMeningoencephalitis

oEtiologies

• AUTOIMMUNE ENCEPHALITIS:

anti-LGI1 encephalitis

anti- N-methyl-D-aspartic acid receptor (anti-NMDAR) encephalitis

CASPR2

GABA-B

AMPA encephalitis

• Exact incidence is not known.

• a multicenter study in the United Kingdom -4%

• California Encephalitis Project - anti-NMDA receptor encephalitis surpassed any viral encephalitis

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

• 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

oMRI 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.

Mechanism for clinical features

NMDAR in inhibitory GABAergic neurons and glutamatergicsynapses

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

• Confirmation of diagnosis –

• Demonstrating NMDA receptor antibodies in serum or cerebrospinal fluid

• The levels of antibodies in cerebrospinal fluid correlate better with symptom outcome

• 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.

• symptoms 1st to improve:

autonomic instability, dyskinesias, level of

consciousness, and seizures.

• After recovering consciousness, the psychiatric manifestations can reemerge, and impulsivity, behavioral disinhibition.

• multidisciplinary approach - nursing, psychiatrists, cognitive rehabilitators, physiatrists and families.

• clinical relapse in 20% of children with anti-NMDA encephalitis.

LIMBIC ENCEPHALITIS

• Definition:

• characterised by subacute developmentof short term memory loss, behaviouralchange and seizures involving thetemporomedial lobes , the amygdalae,and cingulate gyrus with variableevidence of CSF inflammation andneuronal antibodies

• antibodies against the neuronal secretedprotein called leucine-rich glioma-inactivated 1 (LGI1)

• LGI1 - secreted neuronal protein thatinteracts with the presynaptic andpostsynaptic proteins ADAM23 andADAM22 -modulate synaptictransmission

• 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

• 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

HASHIMOTO

ENCEPHALOPATHY• Previous steroid responsive encephalopathy

associated with autoimmune thyroiditis.

• Now encephalopathy associated with autoimmune thyroid disease

• 52% hypothyroid , 48% normal thyroid function

• 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

• Thyroid peroxidase antibodies.

o10% healthy adults

oOther disorders GABA,LGI1 and NMDR receptor antibodies.

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.

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

• Investigations :

o inflammatory CSF (lymphocytic pleocytosisand oligoclonal bands) and lymphocytic cuffing in histopathology of the basal ganglia,

oFDG-PET scan demonstrates basal ganglia hypermetabolism.

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

Therapeutic strategies and

outcomes• no consensus guidelines

• pulsed steroids followed by high dose oral prednisone, and IVIg and/or plasmapheresisas 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

• 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).

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?

Case senarios• Treatment of antibody negative patients:

An 8-year-old boy presented with a 3 week history of focalseizures, 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 serumand CSF anti- NMDAR, VGKC complex, and D2R antibody testingwas negative. Given this was a severe presentation and theclinical phenotype was reminiscent of autoimmune encephalitis,he was treated with first-line therapy in the form of IV steroidsand IVIg. Ten days after first-line therapy there was noimprovement so second-line therapy with rituximab wascommenced. Within 5 days of rituximab he began improving andsubsequently made a good clinical recovery over 6 weeks,returning to baseline function.

• 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.

• Management of relapsing anti-NMDAR encephalitis:

Focal seizures, speech disturbance, chorea, and agitation. CSFoligoclonal bands were positive. This presentation was prior tothe initial descriptions of anti-NMDAR encephalitis, howevergiven the high index of suspicion for autoimmune encephalitis,she was treated with IV steroids and IVIg. Her diagnosis wasconfirmed as anti- NMDAR encephalitis in 2009 withretrospective testing of acute serum and CSF samples. She hashad three subsequent relapses which were treated successfullywith IV and oral steroids. Given the relapsing course and steroidresponsiveness, she was started on oral mycophenolate mofetiland has been free of relapses for the last 2 years.

Future directions• identification of novel antigens

• early initiation of immune therapy

• efficacious therapeutic strategies

Video Courtesy: Dr. chinmay

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