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HOT TOPIC

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Antibody Prevalence in Epilepsy and Encephalopathy (APE2) Score:A PRACTICAL APPROACH TO IMPROVING UTILIZATION OF ANTIBODY PROFILES

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Presenter:

Divyanshu Dubey, M.B.B.S. Assistant Professor of Laboratory Medicine and Pathology and Neurology

Department of Laboratory Medicine and Pathology at Mayo Clinic, Rochester, Minnesota

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Disclosures• I receive research support from Grifols,

CMSAN, CCATS• I have patent applications for Kelch-11 as a

marker of neurological disease and cancer

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12

34

567

89

10111213

1415161718

192021

222324

0

5

10

15

20

25

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1960 1970 1980 1990 2000 2010 2020 2030

ANNA1 IgG

Ma2 IgG

NMDA-R IgG

LGI1 IgG

Year

Antib

odie

s d

isco

vere

d Incidence rates of autoimmune encephalitis 0.4 per 100,000 (1995-2005) 1.2 per 100,000 (2005-2015)

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©MFMER | slide-7Date of download: 8/8/2019 Copyright © 2017 American Medical Association. All rights reserved.

From: Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology

JAMA Neurol. 2017;74(4):397-402. doi:10.1001/jamaneurol.2016.5429

Distribution of Autoantibody Specificity by New-Onset Epilepsy and Established Epilepsy

Abs detected in 23 (20%) cases

Good clinical outcome

associated with neural specific Abs

(p<0.01)

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Predictive Models in the Diagnosis and Treatment of Autoimmune Epilepsy4

• Mayo Clinic (Rochester, Jacksonville, Scottsdale)• Retrospective design (06/30/2014-06/30/2016)• Adult & pediatric cases• 387 patients had a diagnosis of epilepsy

• Serum: 321patients• CSF: 20 patients • Both: 46 patients

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Variables Antibody Positive Cases (n=44) Antibody Negative Cases (n=343) P value

New onset seizures (%) 31 (72.1) 114 ( 33.1) <0.01Neuropsychiatric changes (%) 32 ( 72.7) 88 ( 25.7) <0.01

Autonomic dysfunction (%) 8 (18.2) 5 (1.5) <0.01Viral Prodrome (%) 9 (20.5) 9 (2.6) <0.01

FBDS orOrofacial dyskinesias (%)

13(29.5) 2 (0.6) <0.01

Refractory Seizure (%) 35 (79.5) 172 (50.5) <0.01CSF protein >50 mg/dl (%) 15 (40.5) 31 (16.4) <0.01

CSF cell count >5 cells/dl (%) 13 (35.1) 9 (10.3) <0.01

Specific oligoclonal bands in CSF >4 (%) 5 (14.3) 7 (4.2) <0.05

Medial temporal FLAIR/T2 hyperintensity (%) 14 (31.8) 58 (16.9) <0.05

Systemic malignancy detected (%) 6 (13.6) 34 (9.9) NS

Temporal lobe onset seizures (%) 25 (67.9) 20 (47.6) NS

Cognitive dysfunction (%) 31 (81.6) 122 (38.6) <0.01Pilo-erection (%) 2 (5.3%) 0 <0.01

Other Autoimmune conditions (%) 6 (15.8) 39 (12.1) NS

Mesial temporal sclerosis (%) 3 (7.7) 21 (9.1) NS

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Antibody Prevalence in Epilepsy & Encephalopathy Score (APE2 score)5,6New onset, rapidly progressive mental status changes developed over 1-6 weeks or new onset seizure activity (within one year of evaluation)

(+1)

Neuropsychiatric changes; agitation, aggressiveness, emotional labiality (+1)Autonomic dysfunction (+1)Viral prodrome (rhinorrhea, sore throat, low grade fever) only to be scored in the absence of underlying malignancy within 5 years of neurological symptom onset

(+2)

Faciobrachial dystonic movements (+3)Facial dyskinesias, to be scored in the absence of faciobrachial dystonic seizures (+2)

Seizure refractory to at least to two anti-seizure medications (+2)CSF findings consistent with inflammation (+2)Brain MRI suggesting encephalitis (T2/FLAIR hyperintensity restricted to one or both medial temporal lobes, or multifocal in grey matter, white matter, or both compatible with demyelination or inflammation)c

(+2)

Systemic cancer diagnosed within 5 years of neurological symptom onsetc (excluding cutaneous squamous cell carcinoma, basal cell carcinoma, brain tumor, cancer with brain metastasis)

(+2)

Total (max: 19)

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Medial Temporal T2/FLAIR hyperintensity

LGI1 Ma2 ANNA1

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Multifocal MRI brain lesions

GABAA R IgG

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APE2 score5,6

• APE2 ≥4 • 98% sensitive • 84% specific

• APE2 ≥7: increased specificity (>95%)

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APE2: Cognitive dysfunction5

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Epilepsy of unknown etiologyExclusion of alternative etiology

APE2 score (based on clinical features, MRI, CSF)

APE2 score ≥4

Neural specific antibody evaluation not available

Neural specific antibody negative

Immunotherapy trial

Lack of favorable outcomee

APE2 score 4 to 6

Possible autoimmune epilepsy

APE2 score <4Autoimmune epilepsy unlikely

Neural specific antibody evaluation

Neural specific antibody positivec

Definiteautoimmune epilepsy

Favorable outcomee

APE2 score ≥7

Probable autoimmune epilepsy

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New onset seizure 0Neuropsychiatric changes 0Autonomic dysfunction 0Viral prodrome 0Facial dyskinesias 2Seizures refractory to at least 2 AEDs 2CSF inflammatory(TNC 2 cells/μL, CSF protein : 58 mg/dl)

2

Medial temporal lobe or multifocal T2/FLAIR hyperintensities compatible with demyelination or inflammation

2

Underlying malignancy 0

APE2 scorePatient 1: 58 year old woman presented to outside hospital with electrical shock-like sensations on the right side of her body and speech arrests (30-60 sec), along with few episodes of secondarily generalized tonic clonic seizures. Three years later she continued to have refractory seizures, along with orolingual dyskinesias and stridor.

APE2 score: 8Antibody testing: ANNA2 (Ri) IgG

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Patient 2:60 yo male, long time smoker presents with 3 weeks of new onset seizures, refractory to 2 antiepileptic medications. Since last week started with behavioral problems and short term memory loss. MRI brain was reported normal. CSF showed 10 WBC and 8 OCB. APE2 score: 6

Antibody testing: GABAB-R IgG

New onset seizure 1

Neuropsychiatric changes 1

Autonomic dysfunction 0

Viral prodrome 0

Facial dyskinesias or FBDS 0

Seizures refractory to at least 2 AEDs 2

CSF inflammatory(TNC 10 cells/μL)

2

Medial temporal lobe or multifocal T2/FLAIR hyperintensities compatible with demyelination or inflammation

0

Underlying malignancy 0

APE2 score

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Patient 3:72 year old man with progressive cognitive decline with memory deficit over 6 years. MRI showed global brain atrophy, CSF showed elevated protein of 65mg/dl.

APE2 score: 2Antibody testing: negative

New onset seizure 0

Neuropsychiatric changes 0

Autonomic dysfunction 0

Viral prodrome 0

Facial dyskinesias or FBDS 0

Seizures refractory to at least 2 AEDs 0

CSF inflammatory(CSF protein : 65 mg/dl)

2

Medial temporal lobe or multifocal T2/FLAIR hyperintensities compatible with demyelination or inflammation

0

Underlying malignancy 0

APE2 score

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Patient 471 yo woman presented with a 6-week history of frequent involuntary jerking movements involving the right face and arm, along with significant memory loss. MRI brain showed bilateral medial temporal T2 hyperintensities.

APE2 score: 6Antibody testing: LGI1 IgG

Video

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Conclusion• APE2 scores can aid diagnosis, treatment, &

prognostication of autoimmune epilepsy or autoimmune encephalopathy.

• Very low APE2 score is most helpful in clinical practice.

• Early treatment critical

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References1. Mitoma, H. and Manto, M. (2019). NEUROIMMUNE DISEASES. [S.l.]: SPRINGER NATURE.

2. Dubey D, Pittock S, Kelly C, et al: Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018 Jan;83(1):166-177.

3. Dubey D, Algallaf A, Hays R, et al: Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017 Apr; 74(4):397-402.

4. Dubey D, Singh J, Britton J, et al: Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia 2017 Jul;58(7):1181-1189.

5. Dubey D, Kothapalli N, McKeon A, et al: Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018 Oct;323:62-72.

6. Dubey D, Pittock S, McKeon A: Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia 2019 Feb;60(2):367-369.

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Thank you!