5. Vasculitis asso. encephalopathy
Primary CNS vasculitis
Secondary CNS vasculitis
• SLE
• Sjogren’s
• APLA syn
• Behcet’s
• other - PAN, WG, CSS
Uncertain etiology but responsive to immunotherapy
Neurosarcoidosis
Hypereosinophilic syndromes
6. Antibodies in AE
Antibodies
associated
with AE
Abs against
intracellular
antigens
Markers but not
pathogenic
Levels remain
high despite
improvement
Cell/ synaptic
surface Abs
Pathogenic
Levels rapidly ↓
with
immunotherapy
7. Anti-NMDA Receptor Encephalitis
Clinical features-
Age- 5–76 yrs, mean age- 23 years--- female (80-
90%)
Disease evolution – 5 phases
phase 1 or “prodromal phase,” - flu like illness
phase 2 or “psychiatric phase,” –
behavioral disturbances, psychosis, hallucinations,
agitation and paranoia;
temper tantrums or hyperactivity in children.
8. Language disintegration- echolalia, ↓verbal output
& then mutism.
phase 3 –
Alteration of sensorium (88%) and seizures (76%).
Frank dysautonomia (70%)- cardiac arrhythmias,
hypo or hyperthermia, central hypoventilation
(66%), apneic spells and BP fluctuations.
Dissociative responses to stimuli.
9. phase 4 “hyperkinetic phase”
Oro-facial dyskinesias, bruxism, lip and tongue
biting, dystonia, complex stereotyped movements,
ophisthotonus, oculogyric crises and choreiform
movements.
phase 5 “recovery phase”
gradual return of awareness & responsiveness. Some
patients are left with cognitive deficits- memory
dysfunction, frontal lobe signs, behavioral and
attention deficit disorders.
10. Anti-NMDA Receptor Encephalitis
Pathogenesis-
NMDAR - ligand-gated cation channel involved in
synaptic transmission.
two heteromers, Glu N1 and Glu N2.
NMDAR Ab binding to NMDAR --- internalization of
the receptors by the cell, decreasing the synaptic
transmission of NMDA clusters.
magnitude of changes directly proportional to the
antibody titer.
11. NMDAR abs block GABAergic neurons, leading to a
disinhibition of the excitatory pathways and ↑
extracellular glutamate.
Hence, hyperkinetic movement disorders.
Ovarian teratomas express Glu N1.
12. Diagnosis-
1. Imaging
CT brain usually normal.
MRI brain normal (50%)or may show nonspecific
abnormalities in T2 or FLAIR sequences in the mesial
TL, cerebral cortex (esp frontobasal), cerebellum, basal
ganglia.
MRI cortical-----> subcortical progression
Transient meningeal/ cortical enhancement can be seen.
Serial MRIs can show cerebral atrophy (reversible).
13.
14. 2. Lumbar puncture
Lymphocytic pleocytosis; mean count of 26 cells on presentation (5 to
200 cells).
Protein levels elevated.
Glucose often normal.
CSF IgG index elevated, indicating intrathecal ab synthesis
CSF oligoclonal bands seen in about 50%.
CSF anti-NMDAR antibodies are highly positive and titers correlate
with the disease severity.
Few patients show positive mycoplasma serology- significance unclear.
15. 3. EEG
Electrographic sz (10%)
Generalized/ frontotemporal polymorphic delta
Extreme delta brush pattern : Rhythmic delta (1–3 Hz) activity with bursts of
beta (20–30 Hz) superimposed on the delta waves - seen in 30% - relatively
specific
Some abnormal movements can be misinterpreted as seizures & have no EEG
correlate.
4. Search for ovarian teratoma.
In ~ 60% of the women, an ovarian teratoma is found by abdominal USG, CT or
MRI of pelvis.
5. Brain biopsy non-diagnostic
17. Clinical features vary depending on distributions
of the target antigens.
LGI1 protein expressed mainly in hippocampus.
CASPR2 expressed strongly in both PNS & CNS
neurons.
18. Clinical features in LGI1 related LE-
short-term memory impairment
psychiatric symptoms- personality change,
depression, anxiety, hallucinations, confusion
seizures - complex partial— temporal or classical
faciobrachial tonic seizures
myoclonus (40%)
19. Clinical features in CASPR2 related encephalitis-
psychiatric symptoms & hallucinations,
sleep dysfunction,
autonomic dysfunction,
peripheral nerve hyperexcitability (Morvan disease).
Allodynia
Neuropathic pain
21. Other investigations-
CSF- pleocytosis, lymphocytic predominance, raised
protein & oligoclonal bands.
Hyponatremia (50%)
EEG- focal or generalized epileptiform discharges or
slow wave activity.
Search for tumor (In contrast to NMDAR encephalitis,
associated tumour found in only 11%).
22. GABA- B receptor encephalitis:
Mean Age – 62 yrs, M=F
Malignancy- 50%; Majority SCLC
Presentation- LE, seizures early & prominent
Most seizures appear to have a temporal-lobe onset with
secondary generalization,
some - status epilepticus or subclinical seizures demonstrated on
EEG.
The brain MRI - abnormal in 2/3, showing unilateral or bilateral
medial temporal lobe FLAIR/T2 signal – s/o LE
CSF - lymphocytic pleocytosis.
GABAB receptor antibodies
other autoantibodies (e.g., TPO, ANA, GAD65), reflecting a
tendency to autoimmunity
23. Other less common forms
AMPA receptor encephalitis:
Typical patient- female , median age 60 yrs
Presentation- limbic encephalitis
Syndrome lacks movement disorders,
autonomic dysfunction & hypoventilation
Malignancy (70%)- lung, breast, thymus
Pathogenesis- ↓ no of receptors at synapse alter
function
24.
25.
26.
27.
28.
29. Chronic treatment-
Steroids are mainstay of maintenance Rx
Alternate day schedules are preferred
Daily Calcium + Vit D, GI ulcer prophylaxis, glucose &
BP monitoring
Steroid sparing agents – Azathioprine, MMF to
overlap with steroids for months
Duration – 2- 3 years, No RCT available
30. Other aspects of management
Symptomatic Rx
AEDs for seizures (usually requires > 1 AED in view of
refractoriness)
antipsychotics, antidepressants and medications for sleep
disorders.
Intubation & mechanical ventilation for airway protection and
hypoventilation
Movement disorders resistant to medications require sedation,
including propofol, IV benzodiazepine, NM blockade to prevent
lip and tongue injury and loss of dentition.
31. Pacemaker to prevent severe symptomatic brady/
tachyarrhythmias.
Tumor removal can improve response to
immunotherapy.
32. Serial CBC, RFT, LFT
Latent TB screening
Pregnancy test
IgA level
Mesna in Cyclophosphamide
S-methyltransferase enzyme in AZT
Pneumocystis prophylaxis with TMP-SMZ
Hepatitis screen in Rituximab
33. Prognosis
Response rate – 75 to 80% with tumor removal & immunosuppression.
Time to full recovery : 1–14 months
In NMDA-R encephalitis, Ab titres, esp CSF correlate with disease
severity.
Long term (> 1 yr) maintenance immunosuppression is required in
80%.
Recovery more favorable in patients with an underlying tumor than in
idiopathic cases.
Relapse can be associated with reappearance of 2nd teratoma. USG or
MRI of pelvis - yearly for at least 2 yrs after recovery.
34. Neurologic sequalae
Hemi/ quadriparesis
aphasia
signs of frontal lobe disturbance (apathy,
disinhibition, lack of planning and poor judgment)
sleep disturbance
35. Conclusion
AE should always be considered in evaluation of rapidly
progressive dementia esp in young patients.
Combination of psychiatric illness, hyperkinetic movement
disorders (especially oro-facial dyskinesias), dysautonomia and
central hypoventilation should arouse the suspicion of NMDAR-E.
Similarity of NMDAR-E to Japanese encephalitis is striking, so,
presumed JE cases with negative serology should be
further investigated to rule out NMDARE.
Early initiation of immunotherapy is likely to improve
outcome.
36. References
Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL. Bradley's neurology in clinical practice. Elsevier
Health Sciences; 2015 Oct 25.
FLANAGAN EP, DRUBACH DA, BOEVE BF. Autoimmune dementia and encephalopathy.
Handbook of clinical neurology. 2016 Mar 11;133:247.
Autoimmune encephalopathy. Flanagan et al., Semin Neurol, April 2011.
Immune mediated encephalopathies with an emphasis on paraneoplastic encephalopathies. Pruitt.,
Semin Neurol, April 2011.
Update on paraneoplastic & autoimmune disorders of CNS. Rosenfeld et al., Semin Neurol, March
2010.
Steroid responsive encephalopathy associated with autoimmune thyroiditis. Castillo et al., Arch
Neurol, 2006, 63, 197-202.
Clinical experience and laboratory investigations in patients with anti-NMDAR
encephalitis. Dalmau et al., Lancet Neurol 10(1):63-74, 2011.
