this study provides class iv evidence that immunoadsorption combined with immunosuppression therapy is effective in patients with autoimmune encephalitis with surface antibodies .
the purpose of our study was to investigate whether addition of antibody - removing therapy to immunosuppression ( ia - is therapy ) accelerates recovery of patients with proven autoimmune encephalitis and surface antibodies or antibodies to intracellular antigens . from june 2011
to may 2015 , 30 patients were treated with ia because of definite or suspected autoimmune encephalitis .
eleven patients were excluded due to incomplete data or doubts about the validity of the diagnosis .
the remaining 19 patients were either immunotherapy - naive ( n = 5 ) or had received immunotherapeutic interventions before without effect ( n = 14 ) .
fifteen patients were treated in the epilepsy centre bielefeld - bethel , germany , a tertiary referral center , and 4 in the department of neurology , university of mnster , germany .
data were recorded for 3 time points : baseline ( before ia treatment ) , early follow - up ( directly after ia ) , and late follow - up several months after ia .
patients had limbic encephalitis ( with lgi1 or caspr2 antibodies , n = 7 ) , anti - nmdar encephalitis ( n = 7 ) , or immune - mediated temporal lobe epilepsy with gad antibodies ( n = 5 ) .
one patient had a neoplasm ( nmdar - f , small cell lung cancer ) .
individual patients ' characteristics at baseline modified rankin scale ( mrs ) scores were determined retrospectively and independently by 2 investigators per patient ; one knew the patient , the other one rated from the records . in cases of divergent ratings ( maximum difference was 1 mrs point ) , the mean was noted .
values 2 indicate independent living of the patient , values > 2 increasing degrees of dependency .
seizure frequencies are expressed as per week and relate to following time periods : baseline , preceding 4 months or ( if this was shorter ) time from symptom onset ; at early follow - up , the previous week ; at late follow - up , time since last ia session . for memory assessment , the verbal learning and memory test , the german adaptation of the rey auditory verbal learning test , and the diagnostikum fr cerebralschdigung , revised version ( dcs - r ) for figural memory were used . in mnster patients ,
eight values out of the potential 57 ( 19 patients  3 time points [ 14% ] ) are missing . five patients received 2 ia sequences because of an assumedly incomplete effect of the first one .
this study provides class iv evidence because of a lacking control group and masked outcome assessment .
all patients underwent ia based on an individual informed written consent of the patient or his or her representatives ( compassionate use ) .
antibody specificities and titers for all patients were determined in the bethel antibody laboratory using cell - based assays in the form of commercially available biochips ( euroimmun , lbeck , germany ) .
forty - eight hours after transfection , cells are fixed with paraformaldehyde ( lgi1 , caspr2 , and other antigens , not relevant for this study ) or acetone ( nmdar with nr1 subunits only and gad65 ) .
coated cover glasses are cut into 1  1 mm fragments and assembled to mosaics in defined orders . for titration purposes , slides containing 5 double fields ( 1 with hek cells transfected with the antigen of interest and 1 with nontransfected control cells )
we followed the manufacturer 's instructions with modifications . for detection of antibodies , serum at 1:15 and undiluted csf
the secondary system consists of a goat - anti - human immunoglobulin g ( igg ) ( heavy and light chain ) antibody conjugated with alexa fluor 594 produced by jackson immunoresearch ( west grove , pa , code 109 - 585 - 088 ) at a dilution of 1:100 .
both incubate at room temperature ( anti - igg : 30 minutes , hoechst 33342 : 10 minutes ) .
finally , cover glasses are put on antifading mounting medium 11,4-diazabicyclo ( 2.2.2 ) octane ( 1% ) .
stained biochips are examined using a fluorescence microscope ( leica dm 2000 ; wetzlar , germany ) with excitation at 592 nm and emission filter at 616 nm for bound antibody and 350/462 nm for nuclear counterstain .
the decision if an antibody is present in the tested material is done by 1 of 3 investigators ( c.g.b .
two persons rate titration stainings independently . in cases of divergent ratings , the mean is recorded . in 16 out of a potential 114 samples , no material for titration was available ( 14% ) . in bielefeld - bethel ,
sera were stored and titrated , having been obtained directly prior to an ia session and directly afterwards .
orienting suggestions for applications , dosages , treatment durations , and follow - up schedules were agreed upon among the physicians in the participating neurologic and nephrologic departments ( figure 1a ) .
the scheme was modified individually according to patients ' properties , preferences , or organizational circumstances .
for immunoadsorption , vascular access was obtained by an indwelling shaldon catheter inserted into the internal jugular vein .
plasma filtrate passes through either a regenerative double column system ( immunosorba fresenius medical care , bad homburg , germany ) with 1.52 plasma volumes ( mnster , n = 4 ) or 2 to 2.2 plasma volumes ( bielefeld - bethel , n = 4 ) processed or a disposable tryptophan column ( immunosorba tr-350 , octonova technology , diamed medizintechnik gmbh , cologne , germany ; 2 l plasma per session , n = 11 , all done in bielefeld - bethel ) . at onset , 2 to 3 sessions were done on consecutive days .
one ia sequence consisted of 10 sessions in bielefeld - bethel ( except for patient nmdar - e with 9 sessions and lgi1-c with 8 sessions ) and 5 in mnster ( nmdar - d received 8 sessions ) .
all patients except one ( nmdar - d ) received prednisolone in parallel ( median dose 4.9 g , range 1.416 g ) . before ia , 5 patients had been treated with other immunotherapies ( plasma exchange : n = 2 , nmdar - e and lgi1-c ; ivig : n = 2 , nmdar - a and lgi1-c ; azathioprine : n = 1 , gad - c ; and cyclophosphamide : n = 1 , caspr2-a ; for further details , see table 1 ) .
( b  d ) changes of antibody titers in serum ( b ) and csf ( c ) at early and late follow - up in relation to the antibody targets ( means with standard errors of the means ) .
( d ) antibody titers of all patients ( pooled ) from bielefeld - bethel ( n = 15 , means and standard errors of the means ) on the immunoadsorption days directly prior to ( dark purple bars ) and after the immunoadsorptions ( light purple bars ) .
this shows the known sawtooth configuration that reflects the antibody redistribution between the vascular and extravascular compartments . even after the fifth session ,
caspr2 = contactin - associated protein-2 ; gad = glutamic acid decarboxylase ; ia = immunoadsorption ; lgi1 = leucine - rich glioma inactivated protein 1 ; nmdar = nmda receptor .
all patients underwent ia based on an individual informed written consent of the patient or his or her representatives ( compassionate use ) .
antibody specificities and titers for all patients were determined in the bethel antibody laboratory using cell - based assays in the form of commercially available biochips ( euroimmun , lbeck , germany ) .
forty - eight hours after transfection , cells are fixed with paraformaldehyde ( lgi1 , caspr2 , and other antigens , not relevant for this study ) or acetone ( nmdar with nr1 subunits only and gad65 ) .
coated cover glasses are cut into 1  1 mm fragments and assembled to mosaics in defined orders . for titration purposes , slides containing 5 double fields ( 1 with hek cells transfected with the antigen of interest and 1 with nontransfected control cells )
we followed the manufacturer 's instructions with modifications . for detection of antibodies , serum at 1:15 and undiluted csf are incubated with biochips for 30 minutes at room temperature .
the secondary system consists of a goat - anti - human immunoglobulin g ( igg ) ( heavy and light chain ) antibody conjugated with alexa fluor 594 produced by jackson immunoresearch ( west grove , pa , code 109 - 585 - 088 ) at a dilution of 1:100 .
both incubate at room temperature ( anti - igg : 30 minutes , hoechst 33342 : 10 minutes ) .
finally , cover glasses are put on antifading mounting medium 11,4-diazabicyclo ( 2.2.2 ) octane ( 1% ) .
stained biochips are examined using a fluorescence microscope ( leica dm 2000 ; wetzlar , germany ) with excitation at 592 nm and emission filter at 616 nm for bound antibody and 350/462 nm for nuclear counterstain .
the decision if an antibody is present in the tested material is done by 1 of 3 investigators ( c.g.b .
two persons rate titration stainings independently . in cases of divergent ratings , the mean is recorded . in 16 out of a potential 114 samples , no material for titration was available ( 14% ) . in bielefeld - bethel ,
sera were stored and titrated , having been obtained directly prior to an ia session and directly afterwards .
orienting suggestions for applications , dosages , treatment durations , and follow - up schedules were agreed upon among the physicians in the participating neurologic and nephrologic departments ( figure 1a ) .
the scheme was modified individually according to patients ' properties , preferences , or organizational circumstances .
for immunoadsorption , vascular access was obtained by an indwelling shaldon catheter inserted into the internal jugular vein .
plasma filtrate passes through either a regenerative double column system ( immunosorba fresenius medical care , bad homburg , germany ) with 1.52 plasma volumes ( mnster , n = 4 ) or 2 to 2.2 plasma volumes ( bielefeld - bethel , n = 4 ) processed or a disposable tryptophan column ( immunosorba tr-350 , octonova technology , diamed medizintechnik gmbh , cologne , germany ; 2 l plasma per session , n = 11 , all done in bielefeld - bethel ) . at onset , 2 to 3 sessions were done on consecutive days .
one ia sequence consisted of 10 sessions in bielefeld - bethel ( except for patient nmdar - e with 9 sessions and lgi1-c with 8 sessions ) and 5 in mnster ( nmdar - d received 8 sessions ) .
all patients except one ( nmdar - d ) received prednisolone in parallel ( median dose 4.9 g , range 1.416 g ) . before ia , 5 patients had been treated with other immunotherapies ( plasma exchange : n = 2 , nmdar - e and lgi1-c ; ivig : n = 2 , nmdar - a and lgi1-c ; azathioprine : n = 1 , gad - c ; and cyclophosphamide : n = 1 , caspr2-a ; for further details , see table 1 ) .
( b  d ) changes of antibody titers in serum ( b ) and csf ( c ) at early and late follow - up in relation to the antibody targets ( means with standard errors of the means ) .
( d ) antibody titers of all patients ( pooled ) from bielefeld - bethel ( n = 15 , means and standard errors of the means ) on the immunoadsorption days directly prior to ( dark purple bars ) and after the immunoadsorptions ( light purple bars ) .
this shows the known sawtooth configuration that reflects the antibody redistribution between the vascular and extravascular compartments . even after the fifth session
caspr2 = contactin - associated protein-2 ; gad = glutamic acid decarboxylase ; ia = immunoadsorption ; lgi1 = leucine - rich glioma inactivated protein 1 ; nmdar = nmda receptor .
patients had antibodies against lgi1 ( n = 3 ; disease duration 13 [ range 9.541 ] months ) , caspr2 ( n = 4 ; 4.8 [ range 0.916 ] months ) , nmdar ( n = 7 , all had csf antibodies ; disease duration 1.2 [ range 0.336 ] months ) , or gad ( n = 5 , all with high serum titers 1:1,500 and csf antibodies ; 8 years [ range 4 months28 years ] ) . individual data on all patients at baseline and follow - up time points are given in tables 1 and 2 . at early follow - up ( median 5 days after the last ia , range 043 days ) , serum and csf titers decreased by a median of 97% and 64% , respectively , in the whole group . at late follow - up ( median lag :
3.9 months , range 2.48.7 months ) , median decrease rates were 97% ( serum ) and 88% ( csf ) .
individual patient titer changes are given in figure 1 , b and c. course of serum titers during the sequence of ia is depicted in figure 1d .
individual patients ' characteristics at early and late follow - up at early follow - up , 9 of 14 patients with antibodies against surface antigens had improved by 1 mrs point : 2 of 3 with lgi1 antibodies , 3 of 4 with caspr2 antibodies , and 4 of 7 with nmdar antibodies . whereas at baseline all patients with antibodies to surface antigens were dependent ( mrs > 2 ) ,
6 of 14 patients were independent ( mrs 2 , 43% ) at early follow - up ( figure 2 ) .
rapid improvement is particularly evident by looking at seizure frequencies in patients with lgi1 and caspr2 antibodies : 5 became immediately seizure - free .
the lgi1 patients and caspr2-b received no antiepileptic medication at all until early follow - up .
caspr2-c was on the same dose until late follow - up , and caspr2-a had even been reduced ( figure 3 , a and b ) .
this is similar with memory performance of patients with nmdar antibodies : 2 of 7 improved rapidly by more than 1 sd ( figure 3c ) .
remarkably , 4 of 5 gad - antibody - positive patients had disease durations of > 3 years prior to ia .
modified rankin scale ( mrs ) values of the present series that lie in between whole numbers ( because of the averaging procedure in case of divergent ratings ) are rounded up to be as conservative as possible .
the line in between mrs 2 and 3 separates patients who can look after themselves ( mrs  2 ) from those who can not live independently ( mrs > 2 ) .
( e  h ) individual mrs changes are given ( reduction indicates clinical improvement ) .
responder patients are those with mrs change of at least 1 ( red lines ) .
the dark green parts of the columns are changes from baseline to early follow - up ; the light green parts are those that evolved in addition to that until late follow - up . above each bar ,
patient nmdar - f improved between early and late follow - up while she underwent radio - chemotherapy of her small cell lung cancer .
caspr2 = contactin - associated protein-2 ; gad = glutamic acid decarboxylase ; lgi1 = leucine - rich glioma inactivated protein 1 .
seizures in patients with ( a ) leucine - rich glioma inactivated protein 1 ( lgi1 ) antibodies and ( b ) contactin - associated protein-2 ( caspr2 ) antibodies .
the antiepileptic drug defined daily dose ( aed ddd ) figures show that this was not due to anticonvulsive therapy .
nmda receptor ( nmdar ) patients with 2 patients improving by > 1 sd already at early follow - up ( red arrows ) .
note the preservation of hippocampal volume in patient lgi1-b in contrast to the hippocampal sclerosis that was present from the beginning of ia in patient lgi1-c .
aed ddd according to who ( http://www.whocc.no/atc_ddd_index/ ; accessed september 2 , 2015 ) . at late follow - up , 12 of 14 patients ( 86% ) with surface antibodies were responders on the mrs compared to baseline .
all but 1 patient with nmdar and 2 with caspr2 antibodies had improved even beyond the performance at early follow - up , at least by 0.5 mrs scores ( figure 2 , e  g ) .
only 1 man with limbic encephalitis and lgi1 antibodies ( lgi1-c ) but already fixed hippocampal sclerosis and 1 woman with nmdar antibodies ( nmdar - g ) did not improve by 1 mrs point ( figure 2 , e and g ) .
however , despite a good early overall recovery , there was no recovery of memory performance in patients with lgi1 or casrp2 antibodies within the observational period .
no patient with gad antibodies , 4 of 5 with long time lags until ia , improved at any point in time .
the only patient with a small - cell lung cancer ( nmdar - f ) showed no improvement at early follow - up but only after radio - chemotherapy between early and late follow - up .
a median of 4.5 ( 3.610.0 ) months after the last ia of the first series , 6 patients started a second ia series due to assumed incomplete effect of the first series : nmdar - g , lgi1-c ( with hippocampal sclerosis ) , caspr2-d , caspr2-b , gad - a , and gad - d .
five had a follow - up ( median 4.6 months , range 2.96.0 months ) .
none of these patients improved by 1 mrs point compared to first late follow - up .
adverse effects of ia were associated with the venous catheter : colonization of catheter tip with coagulase - negative staphylococcus requiring antibiotic therapy ( lgi-2 ) and venous air embolism ( gad65 - 1 ) .
glucocorticoid therapy led to elevated blood glucose levels ( caspr2-d ) , acne ( nmdar - e ) , upper respiratory infection ( lgi1-a ) , weight gain , and skin dryness and fungal infections ( gad65 - 3 ) .
tachycardia and lip herpes were related to rituximab and cyclophosphamide in 1 patient ( nmdar - c ) and depressive mood disturbance to mycophenolate mofetil ( gad65 - 1 ) .
a 19-year - old woman ( nmdar - b ) had encephalopathy with predominant psychiatric / cognitive impairment .
six days after symptom onset , she was treated at another hospital with 4  1,000 mg iv methylprednisolone without any effect .
one day after last ia , mrs was found to have gone down from 4.5 ( baseline ) to 1.0 .
her memory returned almost into the normal range ( from z score 1.3 to 1.0 ) .
three months later , she was back to school without memory impairment ( mrs 0 , memory z score : + 0.4 ) ( figure 3c ) .
a 65-year - old woman ( lgi1-b ) started having multiple dyscognitive seizures per day .
diagnosis of limbic encephalitis with lgi1 antibodies and left hippocampal hyperintense lesion without atrophy was made 13 months after disease onset when she was not on antiepileptic drugs and had 5 seizures per day .
she became seizure - free within 35 days after start of ia and 80 mg oral prednisolone ( figure 3a ) .
an mri 3 months after ia showed normalization of the hippocampus ( figure 3a ) .
two years after disease onset , immunosuppressive and antiepileptic therapy had been terminated , with total remission of symptoms .
one year later , she had a relapse with 3 seizures per day . after starting prednisolone 80 mg / d ( but neither ia nor antiepileptic drugs ) , seizures stopped within 10 days
. a 60-year - old man ( lgi1-c ) developed le due to lgi1 antibodies with frequent pilomotor seizures , hyperhidrosis , and memory and mood problems . at disease onset , iv methylprednisolone , oral prednisolone , and immunoglobulins had been administered with transient improvement of memory deficits and hyperhidrosis . upon presentation to our center
( 41 months after symptom onset ) and prior to ia - is , he had mri evidence of left - sided hippocampal sclerosis and right - sided amygdalar hyperintense signal ( figure 3a ) .
ia was followed by seizure reduction at early follow - up ( figure 3a ) .
a second ia course was performed about 6 months later because depression and seizures continued and lgi1 antibodies increased .
a 30-year - old man ( gad65-b ) had pharmacoresistant temporal lobe seizures but normal memory performance and normal mri .
levetiracetam was increased from 2 g to 3 g per day without effect on mrs or seizures .
a median of 4.5 ( 3.610.0 ) months after the last ia of the first series , 6 patients started a second ia series due to assumed incomplete effect of the first series : nmdar - g , lgi1-c ( with hippocampal sclerosis ) , caspr2-d , caspr2-b , gad - a , and gad - d .
five had a follow - up ( median 4.6 months , range 2.96.0 months ) .
none of these patients improved by 1 mrs point compared to first late follow - up .
adverse effects of ia were associated with the venous catheter : colonization of catheter tip with coagulase - negative staphylococcus requiring antibiotic therapy ( lgi-2 ) and venous air embolism ( gad65 - 1 ) .
glucocorticoid therapy led to elevated blood glucose levels ( caspr2-d ) , acne ( nmdar - e ) , upper respiratory infection ( lgi1-a ) , weight gain , and skin dryness and fungal infections ( gad65 - 3 ) .
tachycardia and lip herpes were related to rituximab and cyclophosphamide in 1 patient ( nmdar - c ) and depressive mood disturbance to mycophenolate mofetil ( gad65 - 1 ) .
a 19-year - old woman ( nmdar - b ) had encephalopathy with predominant psychiatric / cognitive impairment .
six days after symptom onset , she was treated at another hospital with 4  1,000 mg iv methylprednisolone without any effect .
one day after last ia , mrs was found to have gone down from 4.5 ( baseline ) to 1.0 .
her memory returned almost into the normal range ( from z score 1.3 to 1.0 ) .
three months later , she was back to school without memory impairment ( mrs 0 , memory z score : + 0.4 ) ( figure 3c ) .
a 65-year - old woman ( lgi1-b ) started having multiple dyscognitive seizures per day .
diagnosis of limbic encephalitis with lgi1 antibodies and left hippocampal hyperintense lesion without atrophy was made 13 months after disease onset when she was not on antiepileptic drugs and had 5 seizures per day .
she became seizure - free within 35 days after start of ia and 80 mg oral prednisolone ( figure 3a ) .
an mri 3 months after ia showed normalization of the hippocampus ( figure 3a ) .
two years after disease onset , immunosuppressive and antiepileptic therapy had been terminated , with total remission of symptoms .
one year later , she had a relapse with 3 seizures per day . after starting prednisolone 80 mg / d ( but neither ia nor antiepileptic drugs ) , seizures stopped within 10 days
. a 60-year - old man ( lgi1-c ) developed le due to lgi1 antibodies with frequent pilomotor seizures , hyperhidrosis , and memory and mood problems . at disease onset , iv methylprednisolone , oral prednisolone , and immunoglobulins had been administered with transient improvement of memory deficits and hyperhidrosis . upon presentation to our center
( 41 months after symptom onset ) and prior to ia - is , he had mri evidence of left - sided hippocampal sclerosis and right - sided amygdalar hyperintense signal ( figure 3a ) .
ia was followed by seizure reduction at early follow - up ( figure 3a ) .
a second ia course was performed about 6 months later because depression and seizures continued and lgi1 antibodies increased .
we traced back this incomplete response to the fixed hippocampal sclerosis . a 30-year - old man ( gad65-b ) had pharmacoresistant temporal lobe seizures but normal memory performance and normal mri .
levetiracetam was increased from 2 g to 3 g per day without effect on mrs or seizures .
two - thirds of patients with igg antibodies to the surface antigens lgi1 , caspr2 , and nmdar responded within days to ia - is therapy .
the rapid achievement of seizure freedom in 5 of 7 lgi1/caspr2-antibody - positive patients and the fast memory improvement in 2 of 7 patients with anti - nmdar encephalitis are particularly impressive . in this retrospective , uncontrolled design
, it is challenging to disentangle the effect of ia from ( 1 ) the natural course of autoimmune encephalitis , ( 2 ) the effect of previous immunologic interventions , and ( 3 ) the concomitant prednisolone therapy .
option 1 probably did not contribute to the rapid improvements during ia as documented at early follow - up .
the relapse in patient lgi1-b ( see case description ) was successfully treated with steroids alone , but this was a different disease episode . on the other hand , 2 patients had been treated with corticosteroids alone for 1 month ( nmdar - b ) or with a combination of corticosteroids and cyclophosphamide for 6 months ( caspr2-a ) . only after ia - is therapy did the patients improve .
this means that in these 2 patients a specific effect of ia can be uncoupled from a steroid effect in the same disease episode .
other reports have also described patients with surface antibodies benefiting from plasmapheresis in combination with immunosuppression .
incomplete improvement in patients lgi1-c and caspr2-d is best explained by either preexisting or developing hippocampal atrophy that may result from complement activation with subsequent irreversible neuronal death .
our data do not argue in favor of ia in patients with temporal lobe epilepsy and gad antibodies .
poor responses of patients with gad antibodies have also been reported in other cohorts including recent onset patients .
this suggests that gad antibodies per se predict limited therapeutic effects of ia - is .
other authors , however , describe a more positive influence of apheresis therapy in patients with antibodies against intracellular antigens . however , improvement was not stringently defined , short - lived , or absent .
poor response to antibody removal in these patients accounts for a primarily t - cell - based cytotoxicity and supports the idea of lack of antibody pathogenicity . in line with previous studies , our study data show that ia brought down antibody concentration in the periphery .
interestingly , csf titers were also strongly reduced ( by 66% at early follow - up ) . in a previous plasma exchange study , however , only a mean drop of 23% of csf antibody titers was observed .
this is probably due to weaker reduction of peripheral igg levels ( mean 75% ) with reduced igg redistribution from csf across the blood 
this shift from csf to the bloodstream may contribute to the sawtooth - like kinetics of antibody concentrations in serum ( figure 1d).long - term reduction of antibodies is probably due to the ongoing suppression of antibody secretion by corticosteroids .
apart from the in part rapid effect of ia , evaluation of clinical usefulness of ia needs to take into account tolerability and costs .
addition of ia to corticosteroids at first glance increases costs and risks . in 2 of 19 patients , there were side effects that would have been serious adverse events in prospective trials , all related to the venous catheter . however , accelerated clinical recovery of patients treated with ia with reduced neurologic impairment , reduced or absent seizures , and possibly shorter periods of time spent in the hospital may outweigh risks and costs introduced by ia treatment .
. long disease duration until ia - is in some patients may have contributed to an unfavorable outcome .
late diagnosis or failures of first therapeutic interventions were the reasons for the long time lag until ia - is therapy .
we did not study control patients , including patients with steroid therapy alone . on the basis of our data
, the effect of ia can not be clearly separated from that of concomitantly given steroids , ivig , or other immunosuppressive therapies in some patients .
the only patient with a tumor ( nmdar - f ) did not improve during ia - is therapy .
rapid improvement of patients with surface antibodies upon ia further supports the idea of a pathogenic effect of these antibodies .
one might tentatively suggest that addition of ia to corticosteroids can speed up recovery by quick reduction of antibody titers .
this might be an advantage in severely affected patients . in the absence of a control group and a masked outcome assessment ,
prospective controlled studies are needed to gain further data for the specific benefit of ia .
. , and c.g.b . antibody determination was done by c.g.b . , c.b . ,
c.g.b . wrote the manuscript draft , which was reviewed and refined by all authors for important intellectual content .
diamed medizintechnik gmbh , cologne , germany , and fresenius medical care , bad homburg , germany , supported this evaluation .
m. dogan onugoren received travel funding and/or speaker honoraria from fresenius medical care and eisai .
d. munstermann runs a commercial laboratory , which performed the detection of vgkc antibodies described in the study .
h. wiendl serves on the scientific advisory boards for bayer healthcare , biogen idec , sanofi - genzyme , merck serono , novartis , roche , and teva ; received travel funding and/or speaker honoraria from bayer vital gmbh , bayer schering ag , biogen , csl behring , emd serono , fresenius medical care , sanofi - genzyme , merck serono , omniamed , novartis , and teva ; is on the editorial board for journal of clinical practice , journal of neuroinflammation , and plos one ; has consulted for biogen idec , merck serono , novartis , omniamed , roche , and sanofi - genzyme ; and received research support from bayer healthcare , bayer vital , biogen idec , merck serono , novartis , sanofi - genzyme , teva pharma , german ministry for education and research , deutsche forschungsgesellchaft , european union , else kroner fresenius foundation , fresenius foundation , hertie foundation , nrw ministry of education and research , interdisciplinary center for clinical studies muenster , re children 's foundation , sanofi - aventis , and novonordisk .
n. melzer received travel funding and/or speaker honoraria from biogen idec , glaxosmithkline , teva , and fresenius medical care ; performs immunoabsorption ; and received research support from fresenius medical care .
bien serves on the scientific advisory board for eisai and ucb ; received travel funding and/or speaker honoraria from grifols , ucb , eisai , glaxosmithkline , destin honoraria , fresenius , diamed , and rasmussen encephalitis children project ; received research support from fresenius medical care , diamed , university of bonn , hagedorn foundation bielefeld , and the krankenhaus mara ; and receives payment for antibody tests ( antineural antibodies ) performed in the antibody laboratory ( as those described in this study ) .
 objective : it was hypothesized that in encephalitides with autoantibodies directed to cns surface antigens an antibody - removing intervention might speed up recovery.methods:the outcome of autoimmune encephalitis in 19 patients with antibodies against surface antigens ( leucine - rich , glioma inactivated 1 [ lgi1 ] , n = 3 ; contactin - associated protein-2 [ caspr2 ] , n = 4 ; nmda receptor [ nmdar ] , n = 7 ) and intracellular antigens ( glutamic acid decarboxylase [ gad ] , n = 5 ) after immunoadsorption in addition to corticosteroid therapy was evaluated retrospectively . modified rankin scale ( mrs ) scores and data on seizures , memory , and antibody titers directly after immunoadsorption ( early follow - up ) and after a median of 4 months ( late follow - up ) were compiled.results:immediately after immunoadsorption , 9 of 14 patients with antibodies against lgi1 , caspr2 , or nmdar ( 64% ) , but none with gad antibodies , 
 had improved by at least one mrs point . 
 five of the 7 patients with lgi1 or casrp2 antibodies had become seizure - free , and 2 patients with nmdar antibodies had a memory improvement of more than 1 sd of a normal control population . at late follow - up , 
 12 of 14 patients with surface antibodies had improved ( 86% ) , and none of the patients with gad antibodies.conclusions:it is suggested that addition of immunoadsorption to immunosuppression therapy in patients with surface antibodies may accelerate recovery . 
 this supports the pathogenic role of surface antibodies.classification of evidence : this study provides class iv evidence that immunoadsorption combined with immunosuppression therapy is effective in patients with autoimmune encephalitis with surface antibodies . 
Classification of evidence:
METHODS
Standard protocol approvals, registrations, and patient consents.
Antibody determination.
Therapeutic intervention.
RESULTS
Second IA series.
Adverse events.
Four representative case descriptions.
DISCUSSION
AUTHOR CONTRIBUTIONS
STUDY FUNDING
DISCLOSURE