by: Manohar Shroff, MD, FRCPC

1. Manohar Shroff, MD, FRCPC
Radiologist-in-Chief,
Staff Neuroradiologist
The Hospital for Sick Children
Professor of Radiology,
University of Toronto
Autoimmune Encephalitis in Children

2. DisclosuresObjectives
• Review concepts of Autoimmune Encephalitis,
focusing on those which occur more commonly in
children
• Review role of MRI in Autoimmune Encephalitis in
autoimmune encephalitis in children and discuss
imaging features in selected examples

3. DisclosuresInflammatory CNS Diseases
Antibody
Mediated
Encephalitis
Primary
Demyelination
(MS, ADEM)
Others: Primary
CNS vasculitis,
SLE, Sjogren’s,
etc.
Encephalitis: inflammatory disorder resulting in altered mental status, seizures or focal deficits

4. DisclosuresAutoimmune Mediated Encephalopathies
T cell response
More cytotoxic
B cell
response
Cell surface antigens
or Synaptic proteins
Intracellular
(onconeuronal)
antigens
Non-ParaneoplasticParaneoplastic
Group I Antibodies Group II Antibodies

5. DisclosuresAutoimmune Mediated Encephalopathies
Group II AntibodiesGroup I Antibodies
Intracellular Antigens Antigens on cell surface
Distinction clinically relevant: implications for therapy & prognosis
Group I Ab: less specific, increased ‘irreversible” neuronal damage,
decreased response to Rx, often underlying malignancy
Group II Ab: more specific, outcomes much better (reduction in
serum antibodies associated with improved neurologic outcomes)
Autoimmune Encephalitis: Pathophysiology & Imaging Review of an Overlooked Diagnosis.
Kelley BP, Patel SC, Marin HL et al. Am J Neurorad Feb 2017

6. DisclosuresAutoimmune Mediated Encephalitis
Cell surface antigensIntracellular antigens
Non- ParaneoplasticParaneoplastic
Neuronal surface antibody
associated syndromes (NSAb)
Anti-Yo
Anti-Ma2
Anti-Hu
Anti-CV2
Anti-Ri
Anti-NMDAr
Anti-AMPAR
Anti-GABA R
Anti-
VGKC
(LGI-1)
Classic Paraneoplastic
disorders

7. DisclosuresWhy talk about Autoimmune Encephalitis ?
>Under recognized, misdiagnosed as viral or neurodegenerative or
psychiatric disorder
Josep Dalmau
Knowledge level II

8. Case
12 year old girl
Increased forgetfulness
Drop in grades
Bouts of violent behavior
Paranoid at times.
Treated for Neuropsychiatric symptoms for 3 months

10. Differential DiagnosisDifferential Diagnosis & Work Up
Differential Diagnosis:
1. Viral Encephalitis
2. CNS vasculitis
3. Demyelination
4. Toxic / Metabolic Insult
5. Autoimmune Disorders
Work Up:
• MRI, EEG, etc.
• Serology & CSF markers
• Look for systemic disease
• Look for tumors elsewhere
• Brain biopsy !!!

11. Neuropsychiatric
symptoms
+/- Movement disorders
Anti NMDA
receptor antibodies
in CSF
Immunosupressive
therapy
Diagnosis: Anti-NMDAr Encephalitis
NMDAr = N-methyl-D-aspartate receptor

12. Courtesy:
Bejoy Thomas
NMDAr Encephalitis:
Association with Teratoma:
56% women > 18 years
30% women: 14 - 18 years
9% girls < 14 years
‘antibodies to neural tissue in teratoma’
22 yr old woman, with recent behavioral
changes and psychomotor symptoms

13. NMDAr: ionotropic glutamate receptor
very important for controlling synaptic plasticity and memory function

14. A journalist’s (patient’s) perspective on
NMDAr Encephalitis
NMDAr Encephalitis is a well described clinical syndrome

15. DisclosuresNMDAr Encephalitis: Clinical
In children < 12: behavioral, seizures, & movement
disorders more common; autonomic symptoms less common
Prodromal Phase
Psychiatric & Behavioral symptoms
Decreased consciousness, Seizures, dyskinesia,
choreoathetosis, autonomic instability

16. Anti-NMDAr Encephalitis
Agitation, Psychosis,
Catatonia, Memory
Deficits,
Speech Reduction,
Abnormal movements,
+ / - Seizures
Coma,
Hypoventilation,
+/ - dysautonomia
Prodrome
Clinical Worsening
Clinical Improvement
Often no memory of the disease

17. Extreme Delta Brush Pattern on EEG in
NMDAr Encephalitis
• Reported as a novel finding, in 30% cases
• Associated with a more prolonged illness
• Possibly Non-convulsive Status Epilepticus
• Seen normally in pre-terms – 32 weeks
Rythmic bursts of 8 -
32 Hz power

18. • Leading cause of autoimmune encephalitis in children and
adolescents; 40% of patients less than 18 years
• Female adolescents
• Can be a manifestation of SLE>> up to 25 % of SLE
patients have anti-NMDAR (NR2) in their sera.
Anti-NMDAr Encephalitis
UK Registry (2010):
2nd leading cause of Encephalitis after ADEM
California Encephalitis Project (2012):
more common than any of the Viral Encephalitis

19. Diagnosis: Anti-NMDAr EncephalitisWhat is the role of MRI ?
THE MANY FACES OF ANTI NMDAr ENCEPHALITIS
Most common finding on MRI:
NORMAL
MRI used to exclude other diseases

20. Diagnosis: Anti-NMDAr EncephalitisRole of Neuroimaging in NMDAr Encephalitis ?
• NORMAL initial MRI (66 to 89%) – unique feature
• Specific symptoms, EEG, normal MRI: consider the
diagnosis prospectively
• Limbic involvement may be suggestive
• Otherwise wide variation in T2-FLAIR hyperintense signal
changes, transient enhancement
• Typically no diffusion restriction or hemorrhage
• FDG-PET more sensitive for temporal lobe abnormalities

21. DisclosuresNMDAr Encephalitis: Treatment
Remove Tumor: ovarian tumors rare in children
Steroids, IV immunoglobulin or plasma exchange
fails in 30 to 40%
Rituximab – effective
monoclonal chimeric Ab against CD20
depletes B cell lymphocytes
Cyclophosphamide – used in children when Rituximab fails
Diagnosis & Treatment of Autoimmune Encephalitis; Lancaster E. J Clin Neurol 12 (1): 1-13, 2016

22. DisclosuresNMDAr Encephalitis: Outcomes
Like daffodils in the early days of spring, my neurons were
re-sprouting receptors as the winter of illness ebbed.
…….Susannah Cahalan, Brain on Fire
Animal studies show that antibodies cause titer dependent decrease
of synaptic NMDAr with minimal neuronal cell damage, explaining
potential reversibility even in patients severely ill for several months
80% or more have complete of substantial recovery. Relapses can
occur

23. Disclosures
Autoimmune Serologic Evaluation for NMDAr
How is it done ?
Cultures of mouse tissue (e.g. hippocampal
neurons) are incubated with the CSF of the patient
Indirect immunofluorescence assay

24. Paraneoplastic Encephalitis:
uncommon in children
Syndrome can develop during early stages of cancer
Extensive workup needed
Periodic cancer screening for at least 5 years
Paraneoplastic antibodies +/-
60% of patients with PNDs
Well characterized
Biomarkers, not pathogenic
Anti-Hu
Anti-Yo
Anti-CV2
Anti-Ma2
Anti-Ri
Strongly supports
diagnosis of PND
even if no tumor is
found at initial
evaluation
Symptoms depends on the site of involvement
Not just limited to Limbic encephalitis

25. Anti – Yo Antibody
Almost always associated with cerebellar degeneration
Ataxia, nystagmus and dysarthria
Women
Ovarian and breast malignancies
Brainstem volume is preserved
3 months

26. Anti – Ma2 Paraneoplastic Encephalitis
Young adolescents/men
Testicular germ cell tumors
Contrast enhancement +
20 M, hyperphagia, hypersomnia
and endocrinopathy
Hypothalamic and pituitary
dysfunction, Vertical gaze palsy

27. Anti –Ma2 Paraneoplastic Encephalitis
Pediatr Neurol. 2014 Apr;50(4):433-4. Anti-Ma2-associated paraneoplastic encephalitis in a male adolescent with
mediastinal seminoma. Bosemani T, Huisman TA, Poretti A.
Limbic system
Diencephalon
 Upper brainstem
Screening for tumor - CT
Seminoma, extra-testicular location
Immunotherapy + resection of tumor

28. Ophelia Syndrome:
Hodgkin’s Lymphoma & Encephalopathy
The Ophelia syndrome: Memory loss in Hodgkin's disease. Carr I: Lancet 1:844-845, 1982 (Dr. Carr’s 15 y old daughter)
Lancaster E, et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology. 2011;77:1698–1701.
“a little of the sparkling
precision of her conversation
had gone.”
“a neatly excised piece of memory
for about eighteen months.”
“perhaps a circulating
neurotransmitter-like molecule
secreted by the tumor”
Antigen: mGluR5

29. Neuroblastoma, Opsoclonus Myoclonus,
Cerebellar Volume Loss
• Anti-neuronal, anti-Purkinje cell and other antibodies have been
associated with OMS, differences in adults vs children
• No specific biomarker
• 50% of OMS in children will have NB, 2% of all NB will have OMS

30. Case
16 year old girl, severe intractable vomiting 4-6
times/day “vomits at the sight of food”
-Blurring of vision, increased sleepiness,
decreased appetite, back pain
-Suicidal ideations

31. Vomiting + blurring
vision + myelitis
+
Cord lesion,
periventricular/CST
lesions
Anti Aquaporin
4 antibodies
NMO-IgG binds
selectively to
aquaporin-4
Diagnosis: Neuromyelitis Optica

33. Bilateral optic neuritis with swelling and hyper intensity of entire
orbital segment in FLAIR axial images and moderate enhancement
on post contrast image
Symmetric medial thalamic hyper intensities(A), diffuse
periventricular hyper intensity (B) Cystic appearing white matter
(C) and cord lesions (D)
Distribution of aquaporin receptors along the ventricular system and
central. Clinical manifestations like endocrine disturbances,
hypersomnolence, hiccoughs and vomiting may be seen depending on
the area involved
Composite picture shows the typical areas of involvement in NMO
Sudhakar, S, et al…Indian J Pediatr. 2016 Sep;83(9):965-82

34. Immunosuppressive
therapy
Misdiagnosing NMOSD for MS in children is harmful as standard treatments
for MS such as beta interferon, fingolimod or natalizumab can result in
worsening of NMOSD.
Rx strategies that target the cellular and soluble components of the humoral
immune response in NMOSD, such as plasma exchange and B-cell depletion
(e.g., rituximab), are effective in the prevention of NMOSD relapses
Why differentiate NMOSD from other demyelination

35. When to think of Autoimmune Encephalitis ?
Young age , psychiatric symptoms, followed by
rapidly progressive or subacute onset of multifocal
neurological symptoms, normal MRI
Inflammatory markers in CSF
Neural-specific autoantibody
Personal or family history of autoimmunity
or cancer and cancer risk factors
Young patients with limbic findings on MRI: NMDAr is
also an important consideration

36. • Anti NMDAr Encephalitis
• Anti Aquaporin 4
• Anti-Ma2
• Anti-CAPSR2
• Anti GAD
• Anti TPO
• Lupus
• Rasmussen’s Encephalitis
11 year old girl with seizures
HASHIMOTOS ENCEPHALOPATHY
Anti TPO antibodies +ve
Pediatric Autoimmune Encephalitis
Autoimmune Encephalitis in Children; Armangue T, et al. J Clin Neurol 27 (11): 1460-69, 2012

37. Immune privilege of the brain, can be
disadvantaged by inflammation
Herpes simplex encephalitis is a robust trigger of
synaptic autoimmunity
Some patients may develop overlapping syndromes,
including anti-NMDAr encephalitis & NMO or other
demyelinating diseases.
Neuroscience for kids;
faculty.washington.edu

38. Overlapping Immune Syndromes
Overlapping demyelinating syndromes and anti NMDAr
receptor encephalitis.
Titulaer MJ, et al. Ann Neurol, 2014
12 out of 691 NMDAr pts: preceded or followed by NMOSD
11 our of 691 NMDAr pts: concurrent demyelination

39. Myelin Oligodendrocyte Glycoprotein
(MOG)
 MOG associated diseases:
Reindi & Rostasy, Neurol Neuroimmunol Neuroinflamm
February 2015
 MOG antibodies present in some cases of ADEM,
optic neuritis, multiphasic demyelination and AQP4
negative NMO
 AQP4 antibodies not present in 40% NMO like
disease, and even less frequent in children

40. Relapsing Demyelinating Syndrome:
Autoantibodies in non-MS phenotypes
• 34/41 (82.9%) patients with RDS other than MS were
positive for either AQP4-Abs or MOG-Abs
• 30.7% (8/26) of NMOSD cases tested were AQP4-Ab-
positive
• 83.3% (15/18) of AQP4-Ab negative NMOSD cases
were MOG-Ab positive
• No patients had Abs to both antigens
• MOG-Abs were found in 100% (9/9) of MDEM tested
cases and 33.3% (2/6) of RION tested cases
Hacohen, et al: Neurology. 2017 Jul 18;89(3):269-278)

41. Hacohen, et al: Neurology. 2017 Jul 18;89(3):269-278)

42. Courtesy: Dr. Felice D’Arco, GOSH, London
When ADEM like features (recurrent), AQ4 –ve NMOSD, and particularly if
involvement of middle cerebellar peduncles, test for MOG Ab
MOG mainly found in Children, not in Adults
MOG positive cases, possibly better clinical outcomes
MOG Antibody Associated Diseases:
subset of NMOSD or different disease ?

44. Conclusions
 Consider Autoimmune cause, when encephalopathy of unclear
cause and CSF shows inflammatory markers
 NMDAr encephalitis, know it well – typical clinical syndrome, often
normal MRI, and more frequent occurrence in young females
 Limbic changes on MRI; consider autoimmune, paraneoplastic
causes, in addition to infectious causes
 NMOSD, MOG positive diseases: evolving topics

45. Acknowledgements
Dr. Pradeep Krishnan, Neuroradiologist, SickKids
Dr. Anvita Pauraunik, Neuroradiologist, Calgary
Dr. Sniya Sudhakar, Neuroradiologist, CMC, Vellore
Dr. Ann Yeh, Neurologist, SickKids