3rd Congress of the European Academy of Neurology
Amsterdam, The Netherlands, June 24 – 27, 2017
Teaching Course 2
Autoimmune causes of epilepsy - Level 3
Treatment of autoimmune epilepsies
Andrea Rossetti Lausanne, Switzerland
Email: [email protected]
1
08.03.2017
1
EAN, Amsterdam, June 24th 2017
The treatment of autoimmune epilepsies
1
Andrea O. RossettiServcice de neurologieLausanneSwitzerland
Disclosures
None
2
08.03.2017
1
EAN, Amsterdam, June 24th 2017
The treatment of autoimmune epilepsies
1
Andrea O. RossettiServcice de neurologieLausanneSwitzerland
Disclosures
None
2
2
08.03.2017
2
Aim
To learn the principles of
pharmacological management
of epilepsy and status epilepticus
in patients with autoimmune etiologies
3
Case study 1: Mrs. CF, 25 yoSubacute onset of-drowsiness-congitive impairment (teacher)-unusual behavior, irritability.
After admission-stuporous, episodes of blank staring-dysautonomic features, athetotic movements
4
08.03.2017
2
Aim
To learn the principles of
pharmacological management
of epilepsy and status epilepticus
in patients with autoimmune etiologies
3
Case study 1: Mrs. CF, 25 yoSubacute onset of-drowsiness-congitive impairment (teacher)-unusual behavior, irritability.
After admission-stuporous, episodes of blank staring-dysautonomic features, athetotic movements
4
3
08.03.2017
3
5
Case study 1: Mrs. CF, 25 yo
Case study 2: Mr. MP, 47 yo
2 nocturnal GTC within 3 weeks
Slight, subacute-emotional changes (wife)-memory impairment (work)
6
08.03.2017
3
5
Case study 1: Mrs. CF, 25 yo
Case study 2: Mr. MP, 47 yo
2 nocturnal GTC within 3 weeks
Slight, subacute-emotional changes (wife)-memory impairment (work)
6
4
08.03.2017
4
7
Case study 2: Mr. MP, 47 yo
Case study 2: Mr. MP, 47 yo
8
08.03.2017
4
7
Case study 2: Mr. MP, 47 yo
Case study 2: Mr. MP, 47 yo
8
5
08.03.2017
5
Case study 3: Mrs GR, 49 yo
At 28 yo:-L arm convulsions, then throat constrictions
Evolution over 20 years:-several episodes of L focal Status epilepticus, progressive L corticospinal signs, then dystonia-cognitive slowing, tilt to the R
9
Case study 3: Mrs GR, 49 yo
10
08.03.2017
5
Case study 3: Mrs GR, 49 yo
At 28 yo:-L arm convulsions, then throat constrictions
Evolution over 20 years:-several episodes of L focal Status epilepticus, progressive L corticospinal signs, then dystonia-cognitive slowing, tilt to the R
9
Case study 3: Mrs GR, 49 yo
10
6
08.03.2017
6
12/2002
10/2007
11
Case study 3: Mrs GR, 49 yo
Operational epilepsy definitionFisher Epilepsia 2014
• ≥ 2 seizures not due to reversible factors, or
• 1 seizure and >60% recurrence risk /10yrs, or
• one defined epileptic syndrome
08.03.2017
6
12/2002
10/2007
11
Case study 3: Mrs GR, 49 yo
Operational epilepsy definitionFisher Epilepsia 2014
• ≥ 2 seizures not due to reversible factors, or
• 1 seizure and >60% recurrence risk /10yrs, or
• one defined epileptic syndrome
7
08.03.2017
7
Operational epilepsy definitionFisher Epilepsia 2014
• ≥ 2 seizures not due to reversible factors, or
• 1 seizure and >60% recurrence risk /10yrs, or
• one defined epileptic syndrome
Epilepsies: treatment approach
14
NO
1st monotherapy
Efficacious treatment
2nd monotherapy Polytherapy (2 AEDs)
Efficacious treatment
Efficacious treatment"in extremis"
Surgery,Palliative treatments
Polytherapy (2-3 AEDs)
Is it epilepsy ?
08.03.2017
7
Operational epilepsy definitionFisher Epilepsia 2014
• ≥ 2 seizures not due to reversible factors, or
• 1 seizure and >60% recurrence risk /10yrs, or
• one defined epileptic syndrome
Epilepsies: treatment approach
14
NO
1st monotherapy
Efficacious treatment
2nd monotherapy Polytherapy (2 AEDs)
Efficacious treatment
Efficacious treatment"in extremis"
Surgery,Palliative treatments
Polytherapy (2-3 AEDs)
Is it epilepsy ?
8
08.03.2017
8
AED: pearls and pitfalls
15
Situation to favour to avoid
Depression LTG, VPA, CBZ, OXC LEV, TPM, VGV, PER
Anxiety PGB, GBP LEV
Overweight TPM, ZNS VPA, CBZ, PGB
Elderly / polymedicated LTG, LEV, PGB, GBP PB, PHT, PRM, CBZ, OXC
Childbearing age VPA, PB, TPM
After Rossetti Rev Med Suisse 2010
Mostly for chronic treatment, CAVE:• PHT and steroids
• LEV and hallucinosis / irritability
16
Operational Status epilepticus definitionTrinka Epilepsia 2015
guides treatment start guides treatmentaggressiveness
08.03.2017
8
AED: pearls and pitfalls
15
Situation to favour to avoid
Depression LTG, VPA, CBZ, OXC LEV, TPM, VGV, PER
Anxiety PGB, GBP LEV
Overweight TPM, ZNS VPA, CBZ, PGB
Elderly / polymedicated LTG, LEV, PGB, GBP PB, PHT, PRM, CBZ, OXC
Childbearing age VPA, PB, TPM
After Rossetti Rev Med Suisse 2010
Mostly for chronic treatment, CAVE:• PHT and steroids
• LEV and hallucinosis / irritability
16
Operational Status epilepticus definitionTrinka Epilepsia 2015
guides treatment start guides treatmentaggressiveness
9
08.03.2017
9
Status epilepticus: tt approachRossetti & Bleck Int Care Med 2014
17
ImmunosuppressantsTitulaer Lancet Neurol 2013
First line:• corticosteroids; IVIG, PEX
Second line•cyclophosphamide, rituximab, methotrexate, tacrolimus, alemtezumab,
adalimumab, K
18
08.03.2017
9
Status epilepticus: tt approachRossetti & Bleck Int Care Med 2014
17
ImmunosuppressantsTitulaer Lancet Neurol 2013
First line:• corticosteroids; IVIG, PEX
Second line•cyclophosphamide, rituximab, methotrexate, tacrolimus, alemtezumab,
adalimumab, K
18
10
08.03.2017
10
19
Immunosuppressants: targetsCompound Humoral (AB) Cellular
Corticosteroids √√√√ √√√√
IV Immunoglobulins √√√√
Plasma exchange √√√√
Cyclophosphamide √√√√
Methotrexate √√√√
Rituximab (anti CD20) √√√√
Alemtezumab (anti CD52) √√√√
Adalimumab (anti TNα) √√√√
• Immunologic treatment !!!! good prognosis! Bien Epilepsia 2013
20
AB vs surface AG (NMDA-R, LGI-1, AMPA-R)
Not all abnormal movements are epileptic !! (continuous)EEG
Dericioglu Epil Disord 2013
Treatment with MP ± IVIG, PEX correlates withexcellent prognosis in 60-90%
Titulaer Lancet Neurol 2013
08.03.2017
10
19
Immunosuppressants: targetsCompound Humoral (AB) Cellular
Corticosteroids √√√√ √√√√
IV Immunoglobulins √√√√
Plasma exchange √√√√
Cyclophosphamide √√√√
Methotrexate √√√√
Rituximab (anti CD20) √√√√
Alemtezumab (anti CD52) √√√√
Adalimumab (anti TNα) √√√√
• Immunologic treatment !!!! good prognosis! Bien Epilepsia 2013
20
AB vs surface AG (NMDA-R, LGI-1, AMPA-R)
Not all abnormal movements are epileptic !! (continuous)EEG
Dericioglu Epil Disord 2013
Treatment with MP ± IVIG, PEX correlates withexcellent prognosis in 60-90%
Titulaer Lancet Neurol 2013
11
08.03.2017
11
• Immunologic treatment !!!! good prognosis!
21
AB vs surface AG (NMDA-R, LGI-1, AMPA-R)
MP ± IVIG, PEX Irani Brain 2013
Outcome better for seizures than memoryMalter J Neurol 2014
• Immunologic treatment !!!! moderate prognosis!
22
AB vs surface AG (NMDA-R, LGI-1, AMPA-R)
Survival better for pts w/o associated onconeural AB Höftberger Neurology 2015
PET to disentangle inflammation vs. seizures ?Spatola J Neuroimmunol 2014
08.03.2017
11
• Immunologic treatment !!!! good prognosis!
21
AB vs surface AG (NMDA-R, LGI-1, AMPA-R)
MP ± IVIG, PEX Irani Brain 2013
Outcome better for seizures than memoryMalter J Neurol 2014
• Immunologic treatment !!!! moderate prognosis!
22
AB vs surface AG (NMDA-R, LGI-1, AMPA-R)
Survival better for pts w/o associated onconeural AB Höftberger Neurology 2015
PET to disentangle inflammation vs. seizures ?Spatola J Neuroimmunol 2014
12
08.03.2017
12
AB vs intracellular AG (Hu/ANNA, Ma2/Ta, Yo, GAD65)
Attempt tumor removal! Dalmau & Rosenfeld Lancet Neurol 2008
RituximabSeizures controlled in few patients (Hu) Shams’ili J Neurol 2006
MP ± IVIG, rituximab, cyclophosphamideBetter seizure response in Ma2, Yo; (55%) than GAD65 (18%) Hansen Epilepsy Behav 2016
MP, IVIG, PEX, surgerySeizure response: fair (MP: 45% - surgery: 66%) to poor (IVIG: 20%, PEX: 13%) in GAD65 Malter Seizure 2015
23
24
Varadkar Lancet Neurol 2014
Rasmussen encephalitis
Bien Epilepsy Res 2009
08.03.2017
12
AB vs intracellular AG (Hu/ANNA, Ma2/Ta, Yo, GAD65)
Attempt tumor removal! Dalmau & Rosenfeld Lancet Neurol 2008
RituximabSeizures controlled in few patients (Hu) Shams’ili J Neurol 2006
MP ± IVIG, rituximab, cyclophosphamideBetter seizure response in Ma2, Yo; (55%) than GAD65 (18%) Hansen Epilepsy Behav 2016
MP, IVIG, PEX, surgerySeizure response: fair (MP: 45% - surgery: 66%) to poor (IVIG: 20%, PEX: 13%) in GAD65 Malter Seizure 2015
23
24
Varadkar Lancet Neurol 2014
Rasmussen encephalitis
Bien Epilepsy Res 2009
13
08.03.2017
13
Tacrolimus/IVIGFunctional « survival »No definite effect on seizuresBien Epilepsia 2013
25
Rasmussen encephalitis
Anti TNFα (adalimumab) 5/11 with 12-mo effect on sz frequency (<<50%) 3/5 with functional deficit stabilizationCAVE: infections, hepatotoxicity, neutropenia, skin reactionsLagarde Epilepsia 2016
Presumed autoimmune, intractable epilepsy29pts.; tt with MP, IVIG, PEX; response:
•62%; seizure free in 34%
•surface AG: 88%, intracellular AG or no AB: 33%
•More often in subacute onset; median epilepsy duration 9 months (88%)Toledano Neurology 2014
26
42pts.; tt with MP, IVIG, PEX; •neural AB in 15 (36%); with surface AG in 8
•response in 9 (60%), seizure free in 6 (40%); mostly with surface AG and
disease duration < 6 monthsIorio Eur Neurol 2014
08.03.2017
13
Tacrolimus/IVIGFunctional « survival »No definite effect on seizuresBien Epilepsia 2013
25
Rasmussen encephalitis
Anti TNFα (adalimumab) 5/11 with 12-mo effect on sz frequency (<<50%) 3/5 with functional deficit stabilizationCAVE: infections, hepatotoxicity, neutropenia, skin reactionsLagarde Epilepsia 2016
Presumed autoimmune, intractable epilepsy29pts.; tt with MP, IVIG, PEX; response:
•62%; seizure free in 34%
•surface AG: 88%, intracellular AG or no AB: 33%
•More often in subacute onset; median epilepsy duration 9 months (88%)Toledano Neurology 2014
26
42pts.; tt with MP, IVIG, PEX; •neural AB in 15 (36%); with surface AG in 8
•response in 9 (60%), seizure free in 6 (40%); mostly with surface AG and
disease duration < 6 monthsIorio Eur Neurol 2014
14
08.03.2017
14
570 adult episodes
•14 (2.5%) with autoimmune etiology
•Younger pts, more refractory to treatment than infectious causes
•Mortality in 1, more often restitutio than infectious causesSpatola Neurology 2015
27
Autoimmune Status epilepticus
28
Suspected autoimmune epilepsy!clinic, serum, CSF, MRI
AEDs +IV MP 1g, x 5d
IVIG 0.4 g/kg, x 5d, orPEX 5-7d
If response: Wait and seeIf response: Wait and see
Rituximab 1g, 2x over 14dor
Cyclophosphamide 500mg, every 2w for 4 mo
Supportive care, until delayed response(consider experimentally: alemtezumab,
intrathecal methotrexateU)
Modified afterBakpa Seizure 2016
Flow chart of treatmentno definite AB / syndrome, illness > 2-3 years : STOPno definite AB / syndrome, illness > 2-3 years : STOP
No definite AB / syndrome, illness <2-3 years
No definite AB / syndrome, illness <2-3 yearsDefinite AB / syndromeDefinite AB / syndrome
If no response: STOPIf no response: STOP
If no response: continueIf no response: continue
08.03.2017
14
570 adult episodes
•14 (2.5%) with autoimmune etiology
•Younger pts, more refractory to treatment than infectious causes
•Mortality in 1, more often restitutio than infectious causesSpatola Neurology 2015
27
Autoimmune Status epilepticus
28
Suspected autoimmune epilepsy!clinic, serum, CSF, MRI
AEDs +IV MP 1g, x 5d
IVIG 0.4 g/kg, x 5d, orPEX 5-7d
If response: Wait and seeIf response: Wait and see
Rituximab 1g, 2x over 14dor
Cyclophosphamide 500mg, every 2w for 4 mo
Supportive care, until delayed response(consider experimentally: alemtezumab,
intrathecal methotrexateU)
Modified afterBakpa Seizure 2016
Flow chart of treatmentno definite AB / syndrome, illness > 2-3 years : STOPno definite AB / syndrome, illness > 2-3 years : STOP
No definite AB / syndrome, illness <2-3 years
No definite AB / syndrome, illness <2-3 yearsDefinite AB / syndromeDefinite AB / syndrome
If no response: STOPIf no response: STOP
If no response: continueIf no response: continue
15
08.03.2017
15
29
Case study 1: Mrs. CF, 25 yo
30
Case study 1: Mrs. CF, 25 yo
St. epilepticus in NMDA-R encephalitis
Which antiepileptic strategy do you prefer, after a benzo. ?
A. Levetiracetam
B. Phenytoin
C. Valproate
D. Ketamine
08.03.2017
15
29
Case study 1: Mrs. CF, 25 yo
30
Case study 1: Mrs. CF, 25 yo
St. epilepticus in NMDA-R encephalitis
Which antiepileptic strategy do you prefer, after a benzo. ?
A. Levetiracetam
B. Phenytoin
C. Valproate
D. Ketamine
16
08.03.2017
16
31
Case study 1: Mrs. CF, 25 yoSt. epilepticus in NMDA-R encephalitis:
• ICU
• IV load with CLZ, LEV, then PO PGB, under cEEG
• After ruling out infections: IV MP, tightly followed by IVIG
• Slow improvement (EEG, clinical) over 8 weeks
Follow-up at 6 years:
• restitutio ad integrum
• no AED, no imunosuppression
32
Case study 2: Mr. MP, 47 yo
08.03.2017
16
31
Case study 1: Mrs. CF, 25 yoSt. epilepticus in NMDA-R encephalitis:
• ICU
• IV load with CLZ, LEV, then PO PGB, under cEEG
• After ruling out infections: IV MP, tightly followed by IVIG
• Slow improvement (EEG, clinical) over 8 weeks
Follow-up at 6 years:
• restitutio ad integrum
• no AED, no imunosuppression
32
Case study 2: Mr. MP, 47 yo
17
08.03.2017
17
33
Case study 2: Mr. MP, 47 yoGTC seizures in LGI-1 encephalitis
Which therapeutic strategy do you prefer ?
A. Antiepileptic prescription only
B. Left temporal lobectomy
C. Immunosuppression only
D. Antiepileptic and imunosuppression
34
Case study 2: Mr. MP, 47 yoGTC seizures in LGI-1 encephalitis :
• In-patient work-up
• VPA 2x500mg
• After ruling out infections: IV MP, then IVIG and 2x rituximab
Follow-up at 2 years:
• Slight memory impairment
• no seizures, no AED, no imunosuppression
08.03.2017
17
33
Case study 2: Mr. MP, 47 yoGTC seizures in LGI-1 encephalitis
Which therapeutic strategy do you prefer ?
A. Antiepileptic prescription only
B. Left temporal lobectomy
C. Immunosuppression only
D. Antiepileptic and imunosuppression
34
Case study 2: Mr. MP, 47 yoGTC seizures in LGI-1 encephalitis :
• In-patient work-up
• VPA 2x500mg
• After ruling out infections: IV MP, then IVIG and 2x rituximab
Follow-up at 2 years:
• Slight memory impairment
• no seizures, no AED, no imunosuppression
18
08.03.2017
18
Case study 3: Mrs GR, 49 yo
35
36
Case study 3: Mrs. GR, 49 yoSeizures and St. epilepticus in Rasmussen encephalitis
Which therapeutic strategy do you prefer ?
A. Long-term antiepileptic prescription
B. Elective hemispherotomy
C. Short-term immunosuppression
D. Long-term immunosuppression
08.03.2017
18
Case study 3: Mrs GR, 49 yo
35
36
Case study 3: Mrs. GR, 49 yoSeizures and St. epilepticus in Rasmussen encephalitis
Which therapeutic strategy do you prefer ?
A. Long-term antiepileptic prescription
B. Elective hemispherotomy
C. Short-term immunosuppression
D. Long-term immunosuppression
19
08.03.2017
19
37
Case study 3: Mrs. GR, 49 yoSeizures and St. epilepticus in Rasmussen encephalitis:
AED(CBZ, BDZ, VPA, VGV, TPM, GBP, LEV, LTG, LCM, PER)PHT (tight blood level follow-up); PB; PGB; CLBZ
ImmunologicalAZT; MP; PEX; IVIG; mycophenolate-mofetil ! no improvement
Follow-up at 21 years:
• Rel. stable neurological and neuropsychological deficits
• Dependent on PHT levels (target: 20-25 mg/l)
Conclusion: autoimmune epilepsies•Look for neuronal antibodies !
•Target the cause ! immunosuppression
•Surface antigens: generally good prognosis
•No definite syndrome, long illness: do not tt aggressively
38
08.03.2017
19
37
Case study 3: Mrs. GR, 49 yoSeizures and St. epilepticus in Rasmussen encephalitis:
AED(CBZ, BDZ, VPA, VGV, TPM, GBP, LEV, LTG, LCM, PER)PHT (tight blood level follow-up); PB; PGB; CLBZ
ImmunologicalAZT; MP; PEX; IVIG; mycophenolate-mofetil ! no improvement
Follow-up at 21 years:
• Rel. stable neurological and neuropsychological deficits
• Dependent on PHT levels (target: 20-25 mg/l)
Conclusion: autoimmune epilepsies•Look for neuronal antibodies !
•Target the cause ! immunosuppression
•Surface antigens: generally good prognosis
•No definite syndrome, long illness: do not tt aggressively
38
20
08.03.2017
20
Literature•Bakpa OD et al. Antibody-associated epilepsies: Clinical features, evidence for immunotherapies and future research questions. Seizure2016;41:26-41.•Bien CG & Schramm J. Treatment of Rasmussen encephalitis half a century after its initial description: promising prospects and a dilemma.Epilepsy Res 2009;86:101-12.•Bien CG. Value of autoantibodies for prediction of treatment response in patients with autoimmune epilepsy: review of the literature andsuggestions for clinical management. Epilepsia 2013; 45 Suppl 2:48-55.•Bien CG et al. Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins.Epilepsia 2013;54:543-50.•Dericioglu N et al. Antiepileptic treatment for anti-NMDA receptor encephalitis: the need for video-EEG monitoring. Epil Disord2013;15:166-70.•Fisher RS et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475-82.•Hansen N et al. Seizure control and cognitive improvement via immunotherapy in late onset epilepsy patients with paraneoplastic versusGAD65 autoantibody-associated limbic encephalitis. Epilepsy Behav 2016;65:18-24.•Höftberger R et al. Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology 2015;84:2403-2412.•Iorio R et al. The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response toimmunotherapy. Eur Neurol 2015;22:70-8.•Irani SE et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment ina broadening phenotype. Brain 2013;136:3151-62.•Lagarde S et al. Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen's encephalitis: An open pilot study. Epilepsia2016;57:956-66.•Malter MP et al. Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity. J Neurol 2014;261:1695-705.•Malter MP et al. Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies. Seizure 2015;30:57-63.•Rossetti AO & Bleck TP. What's new in status epilepticus? Int Care Med 2014;40:1359-62.•Rossetti AO & Seeck M. [Current drug treatment for epilepsy]. Rev Med Suiisse 2010;6:901-2.•Shams’ili s et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006;253:16-20.•Spatola M et al. Serial brain ¹⁸FDG-PET in anti-AMPA receptor limbic encephalitis. J Neuroimmunol 2014:271:53-55.•Spatola M et al. Status epilepticus of inflammatory etiology: a cohort study. Neurology 2015;85:464-70.•Titulaer MJ et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: anobservational cohort study. Lancet Neurol 2013;12:157-65.•ToledanoM et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 2014;82:1578-86.•Trinka E et al. A definition and classification of status epilepticus-Report of the ILAE Task Force on Classification of Status Epilepticus.Epilepsia 2015;56:1515-23.•Varadkar S et al. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 2014;13:195-205.
39
