Autoimmune encephalopathy in children

1. AUTOIMMUNE
ENCEPHALOPATHY: WHEN TO
SUSPECT?
SHUBHANKAR MISHRA
ASSISTANT PROFESSOR, NEUROLOGY,
HITECH MEDICAL COLLEGE, BBSR, ODISHA

2. GREETINGS FROM THE LAND OF JAGANNATH

3. BEFORE STARTING THE PRESENTATION I WILL TELL YOU SOMETHING WHICH IS
MUCH NECESSARY FOR YOU.

4. THE CLOSEST ALLY OF A DOCTOR IS THE MEMORY.

5. A DOCTOR HAVING MEMORY LOSS IS
EQUIVALENT TO THE DESTRUCTION OF
NALANDA UNIVERSITY
NALANDA UNIVERSITY BEFORE 1193
NALANDA UNIVERSITY AFTER 1193

6. PREVENT MEMORY LOSS

11.  Autoimmune encephalitis (AE) refers to an increasingly
recognized group of inflammatory brain diseases.
 Many AE are associated with antibodies directed toward
extracellular antigens, such as synaptic receptors and ion
channels.
 Autoantibodies that bind to extracellular antigens are generally
pathogenic, whereas antibodies that bind intracellular antigens
are not considered pathogenic, instead general markers of
autoimmunity.
1. Van Mater H. Pediatric inflammatory brain disease: a diagnostic approach. Curr Opin Rheumatol 2014;26:553–561.

13.  Children with AE present with acute or subacute onset of
neuropsychiatric symptoms due to an underlying abnormal
immune response to the CNS.
 A number of different antibodies have been described in
children with AE.
1. Van Mater H. Pediatric inflammatory brain disease: a diagnostic approach. Curr Opin Rheumatol 2014;26:553–561.

14.  Currently, the most common autoantibodies in children target
the N-methyl-D-aspartate receptor (NMDAR), myelin
oligodendrocyte glycoprotein (MOG), and glutamic acid
decarboxylase 65 (GAD65). [2]
 It is also recognized that not all children with a clinical
phenotype of AE have a known autoantibody.
2. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort
study. Lancet Neurol 2013;12:157–165.

15. LET’S SEE TWO CASES

16. CASE 1
 14 female
 Recurrent vision loss
 One episode of seizure
 Drowsy with decreased motivation
to study for 3 months
 O/E Vision : 6/60 b/l eye
fundoscopy: normal
 NO focal neurological deficit

17.  Treated by ophthalmologists and psychiatrists.
 But how to connect the dots?
 Is the recurrent vision loss a feature of an opthalmological issue
or any other thing?
 How to connect seizure and drowsiness with vision loss?
 Where to localize?
 What is the probable pathology?

18. HISTORY AND
LOCALISATION ARE TWO
HANDS OF THE
NEUROLOGICAL
APPROACH

19. LOCALISATION & PROBABLE PROGRESSION
 RECURRENT VISION LOSS – OPTIC NERVE
 SEIZURE AND ENCEPHALOPATHY – CEREBRAL CORTEX
 PROLONGED PERIOD – SUBACUTE/CHRONIC WITH
RECURRENCE

20.  TYPICAL presentation of – MOGAD
 Came out to be both serum and CSF mog positive.

21. CASE - 2
 13-year boy
 3 months of violent behaviour
 Treated by psychiatrists as
schizophrenia
 Developed twisting of neck and
body. It was suspected as a drug-
induced phenomenon.

22.  Some questions hunt the mind.
 How to connect the dots?
 New onset behavioural issues might be organic.
 We should rule out all organic neurological causes before
levelling it as a primary psychiatric condition.
 But what about dystonia? Is it drug-induced or we are missing
something?

23.  Adolescent with progressive neuropsychiatric issues and
dystonia…
 Did it ring any bell?
 Yes, the first dd is Wilsons
 But blood and urine tests were normal.
 What next?

24.  The localization goes to cortex and deep grey matter.
 Clinically second probable pathology is Autoimmune.
 And he was found to be positive for NMDAR Ab.

25.  So the only thing is
 Take a good history and keep your eyes open
 Think hard and pressurize your prefrontal cortex

26.  Diagnosing AE is challenging.
 Overlap in clinical presentations between
the types of AE
inflammatory brain diseases
infections
metabolic diseases
and psychiatric disorders.[1]
1.Van Mater H. Pediatric inflammatory brain disease: a diagnostic approach. Curr Opin Rheumatol 2014;26:553–561.

27.  It is especially difficult in children because of the complexity of
normal behavioural changes during childhood and the limited
capacity of younger children to describe their symptoms.

28.  Compared to adults with AE, children may manifest important
differences in symptoms, paraclinical findings, comorbidities,
treatment response, and prognosis.[1]
 There is an urgent need to recognize pediatric AE because treatment
delays worsen prognosis and increase the risk of permanent
neurocognitive deficits.[2,3]
 That’s why the diagnostic criteria should be different from the adult
AE.
1. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central
nervous system autoantigens. J Neurol Neurosurg Psychiatry 2013;84:748–755.
2. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol
2013;12:157–165.
3. Armangue T, Titulaer MJ, Malaga I, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis – clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013;12:157–165.

29.  AE in adults, which requires
(1)subacute onset over less than 3 months of working memory
deficits, altered mental status, or psychiatric symptoms
(2)at least one of the following: new focal CNS findings/ seizures
not explained by a preexisting disorder/ CSF pleocytosis, and/or
MRI features suggestive of encephalitis; and
(3)reasonable exclusion of alternative causes.
Specific neurologic syndromes were given criteria, including limbic
encephalitis, anti-NMDAR encephalitis, and autoantibody-negative
AE.
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.

30. ADULT AE vs PED AE
 These AE criteria required modification to be applied to children.
 For example, deficits in working memory are challenging to identify
in younger children.
 Also, children are less likely to present with a well-defined
neurologic syndrome and, even in anti-NMDAR encephalitis, the
sequence of symptom development may differ from adults.
 Furthermore, the differential diagnosis for a child presenting with
temporal lobe seizures and cognitive slowing is broad, whereas this
presentation in adults suggests limbic encephalitis or acquired
temporal pathology.

31. ADULT AE vs PED AE
 Children with AE likely differ from adults in their clinical presentations due to
the evolution of neuronal circuits, neuroreceptor densities and myelination
during normal development.
 Children with AE are more likely to present with multifocal neuropsychiatric
symptoms, rather than isolated clinical syndromes.
 For example, children with GAD65 antibodies may not present with the classic
stiff-person syndrome or cerebellar degeneration seen in adults.
 Children with anti-NMDAR-associated encephalitis are more likely to present
with movement abnormalities, agitation, insomnia, seizures, speech deficits,
ataxia, and/or hemiparesis, whereas memory deficits, psychiatric
manifestations, and central hypoventilation are more common in adults with
the same antibody.
 Pediatric AE is less associated with tumours compared with adults.

32. AE VS PANS
In pediatric acute-onset neuropsychiatric syndrome
(PANS), patients often experience a relapsing-
remitting course with rapid progression to
maximum symptom severity and rapid return to
previous function over hours or days, sometimes
without therapy. Cognition is normal.
Typically, children with AE are previously healthy
and present with rapid onset of neuropsychiatric
symptoms. Prodromal symptoms including fever
occur in over 50% of patients. Between disease
onset and initiation of therapy, symptoms typically
persist over time. The decline in cognition is a
cardinal feature.

33. DOMAINS OF COGNITION
mnemonics (m.a.l.e.p.g.)
 MEMORY – TEMPORAL LOBE, FRONTAL LOBE
 ATTENTION- FRONTAL LOBE
 LANGUAGE- FRONTAL LOBE, TEMPORAL LOBE
 EXECUTIVE FUNCTION- FRONTAL LOBE
 PRAXIS – PARIETAL LOBE
 GNOSIS – OCCIPITAL LOBE

34. COMMON CLINICAL CLUES
IN PED AE
 Neurologic manifestations of Ped-
AE include
altered level of consciousness
Confusion
disturbed sleep
movement disorders and seizures.

35. SEIZURE
 Seizures are the most
common feature in AE and
may be the predominant
manifestation.
 Seizures may be focal or
generalized and are often
multifocal.

36. MOVEMENT
DISORDER
 Over one-third of patients with AE have
abnormal movements, such as ataxia, chorea,
dystonia, myoclonus, or tremor.
 Both seizures and movement disorders can
be highly refractory to standard treatments
in children with AE.

38. COGNITIVE
IMPAIRMENT
 Some degree of cognitive impairment is seen
in the overwhelming majority of AE patients
and is considered a cardinal symptom.
 Assessing memory deficits in young children
may be challenging; however, developmental
regression, language loss or speech
impairments may be presenting features of
pediatric AE.

39. BEHAVIOURAL
CHANGE
 Behavioural changes, such as repetitive or
stereotypical behaviours, irritability,
hyperactivity, hypersexuality, insomnia and
anger outbursts, are common in pediatric AE.

40. NEUROPSYCHIATRIC FEATURES
 Psychiatric symptoms may range from mood
swings and mild personality changes to
fulminant psychosis and occur in over 50% of
AE patients.
 New-onset psychosis in children younger than
13 years is uncommon and considered a red flag
for an underlying medical, rather than primary
psychiatric, condition.
 It is critical to assess for cognitive changes,
seizures, movement abnormalities, or other
neurologic symptoms in children with acute
psychiatric symptoms, as these symptoms are
suggestive of AE.

41. NEW APPROACH
TO
PED–AE
&
DIAGNOSTIC CRITERIA
Tania Cellucci, Heather Van Mater, Francesc Graus, et al. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric
patientDOI 10.1212/NXI.0000000000000663 Neurol Neuroimmunol Neuroinflamm 2020;7;

43. DIAGNOSTIC FLOW
CHART

44. DIAGNOSTIC
CATEGORIES
OF PED-AE

45. COMMON PED –
AE VARIANTS

46. RARE
PED – AE VARIANTS

47. NMDAR
ENCEPHALITIS

49. DELTA BRUSH

50.  A - Type 1, normal brain MR
imaging findings.
 B - Type 2, Lesions are in the
left hippocampus with bilateral
mild volume loss in the
hippocampus.
 C – Type 3, Lesions are in the
right frontal lobe (white arrow)
middle cerebellar peduncle
(white arrow) and brain stem.
 D, Type 4, lesions located in the
bilateral frontal lobe, temporal
lobe, insula (white arrows),
hippocampus, and cingulate
gyrus, with volume loss in the
left hippocampus.
 E, Histogram of the 4 types of
brain MR imaging appearances.

51. POST HERPES AUTOIMMUNE ENCEPHALITIS

52.  Serendipity is a factor in many discoveries in science and
medicine, but perseverance is the key to success.
 The scientific story of post-herpes simplex virus I autoimmune
encephalitis (HSVE-AE) is laden with keen observations, chance
findings and coincidences, but it is also a story of persistence.

53.  A retrospective analysis of 44 HSE patients treated at a German
university hospital then identified NMDAR antibodies in 30% of
these individuals.
 The presence of prolonged, atypical, or relapsing symptoms
after virus encephalitis must be actively determined, requiring
early follow-up visits of patients, and should always prompt the
search for underlying autoantibodies.

59. TOO MUCH NEUROLOGY IS NEUROTOXIC
– Dr. SHUBHANKAR MISHRA

62. TAKE HOME MESSAGE
 PED-AE is a not-so-uncommon disease.
 Subacute encephalopathy with movement disorders
neuropsychiatric changes or focal neurological deficits is a key to
suspect.
 If a post-encephalitis patient has clinical deterioration or new
movement disorder suspect it as AE.
 In every case, we might not get an antibody positivity.
 Take a good history and connect the dots.
 Early diagnosis provides marvellous results.