J Neurol DOI 10.1007/s00415-014-7408-6
ORIGINAL COMMUNICATION
Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity M. P. Malter • C. Frisch • J. C. Schoene-Bake • C. Helmstaedter • K. P. Wandinger • W. Stoecker • H. Urbach • R. Surges • C. E. Elger A. V. Vincent • C. G. Bien
•
Received: 11 March 2014 / Revised: 5 June 2014 / Accepted: 6 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab-). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab? patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7408-6) contains supplementary material, which is available to authorized users. M. P. Malter C. Frisch J. C. Schoene-Bake C. Helmstaedter R. Surges C. E. Elger C. G. Bien Department of Epileptology, University of Bonn Medical Center, Bonn, Germany M. P. Malter (&) Department of Neurology, Marien-Krankenhaus Bergisch Gladbach, Dr.-Robert-Koch-Straße 18, 51465 Bergisch Gladbach, Germany e-mail: [email protected] J. C. Schoene-Bake Department of Pediatrics, Braunschweig City Hospitals, Brunswick, Germany
(72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab? patients, but in none of the CASPR-2-Ab? or LGI/CASPR-2-Ab- patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab? patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab?-LE. Keywords Limbic encephalitis VGKC LGI1 Autoimmune epilepsy
Introduction Antibodies (Abs) to voltage-gated potassium channel complex (VGKC) have been found in patients with K. P. Wandinger W. Stoecker Institute of Experimental Immunology, Affiliated to Euroimmun AG Luebeck, Luebeck, Germany H. Urbach Department of Neuroradiology, University of Freiburg Medical Center, Freiburg, Germany A. V. Vincent Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK C. G. Bien Epilepsy Centre Bethel, Krankenhaus Mara, Bielefeld, Germany
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acquired myotonia [10], Morvan’s syndrome [18], epilepsy [1, 16, 25] and limbic encephalitis [2, 14, 15, 23]. The Abs are detected by radioimmunoprecipitation (RIA) of Kv1 shaker-type VGKC channel complexes, labelled with 125 I-a-dendrotoxin, from mammalian brain extracts [30]. Recently, leucine-rich, glioma inactivated 1 protein (LGI1) and contactin-associated protein-like 2 (CASPR-2), both of which are present in the VGKC-complexes, were shown to be the main targets of these Abs [14, 21]. Limbic encephalitis (LE) is a clinicopathological entity with inflammatory lesions in the limbic structures of the medial temporal lobes. Temporal lobe epilepsy (TLE), memory deficits and affective disorders are the main clinical features. Although initially described in the 1960s as a paraneoplastic condition [5, 6], non-paraneoplastic forms have also been described, particularly with VGKC-complex-Abs (VGKC-LE) [3, 32, 34]. VGKC-LE is mostly non-paraneoplastic [9, 23] and thought to be responsive to immunotherapies [29, 35]. In a recent study [14], 77 % of the 64 patients with LE and VGKC-complex-Abs [400 pmol/l were positive for LGI1-Abs (LGI1-Ab?), 11 % were positive for CASPR2-Abs (CASPR-2-Ab?), and the remaining 12 % were negative for both LGI1 and CASPR-2-Abs (LGI1/CASPR2-Ab-). The aim of the present study was to describe the phenotypes and outcomes in the VGKC-LE patients divided into these three groups.
Patients’ characteristics, treatment and follow up The first inpatient assessment (visit 1) included brain MRI, neuropsychological assessment, serum and CSF collection, and the same test modalities were applied at the most recent visit (termed visit 2). Age at disease onset, first signs and symptoms, disease duration and follow up period, seizure frequency, MRI features, memory function, antiepileptic drug therapy and immunotherapy were obtained from the patient records. The cumulative corticosteroid dose was expressed as methylprednisolone-equivalent doses (prednisone/prednisolone doses were multiplied by 0.8) [22]. Antiepileptic drug (AED) therapy was converted into defined daily drug dose (ddd), defined by the World Health Organisation (WHO) (www.whocc.no/atc_ddd_index/), to standardize comparison between individual treatment regimens. A disease relapse was defined as deterioration in seizure control or memory function after stabilization for at least 2 months. Tumour searches were performed, adapted to the risk profile of the individual patient (see Supplemental Table 1). Seizure outcome Seizure freedom was defined as the absence of all seizures including auras over a minimum period of 1 month at visit 2 with or without antiepileptic drugs.
Methods Neuropsychological assessment Patients All 18 LE patients positive for VGKC-complex-, LGI1or CASPR-2-Abs, identified at the University of Bonn, Department of Epileptology between 01-01-2003 and 06-31-2011 (8.5 years), were included and evaluated retrospectively. Serum of these patients had been stored for potential further Ab studies at -20 °C with informed consent and local ethics committee approval. All patients were diagnosed with LE based on the features of limbic signs and symptoms (C1 of the following: seizures of temporal semiology, disturbance of episodic memory, affective disturbances with prominent mood lability or disinhibition) and brain MRI revealing medial temporal encephalitis (T2/FLAIR hyperintensity) manifesting in adulthood B5 years previously [4, 23]. Eleven of these patients were reported before, either in a case study [3] or as a comparison group to patients with glutamatedecarboxylase Ab positive LE [8, 23]. The LGI1- and CASPR-2-Ab reactivity has not been reported previously, and the follow up period has been extended in 9/16 patients.
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The neuropsychological evaluation focused on memory tests for temporal lobe functions. The Verbal Learning and Memory Test (a German adaptation of the Rey Auditory Verbal Learning Test, VLMT) [11] and the Diagnostikum fu¨r Cerebralscha¨digung, revised version (DCS-R) [12], a design learning test, were used. The VLMT includes a distraction trial, immediate free recall after distraction, and a delayed free recall before patients are asked to recognize the learned items out of a list of alternatives; the DCS-R only asks for immediate and delayed recognition. To condense the information from these tests, three parameters of verbal learning (immediate recall over five learning trials), verbal memory (loss of learned words in half an hour delayed free recall), and recognition (correctly recognized words out of alternatives minus errors) as well as three parameters of figural memory, figural learning (immediate recall over five learning trials), figural supraspan learning (immediate recall after the last learning trial), and figural recognition (correctly recognized designs out of alternatives minus errors) were transformed into age-corrected standard values according to clinical normative data
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and then transformed into a single summary score representative for the respective memory domain. Performances below mean -1 SD of age-matched controls were rated as impaired. MRI Brain MRIs were obtained according to a dedicated epilepsy protocol [33] using a 3 Tesla scanner, Philips, The Netherlands (Department of Neuroradiology) or a 3 T ‘‘Trio’’ scanner from Siemens, Erlangen, Germany (Life & Brain Institute). Previous brain MRIs from other institutions were assessed if available. All images were re-evaluated for this study. Hippocampal signal on T2-weighted or FLAIR images was classified as ‘‘hyperintense’’ or ‘‘normal’’ and hippocampal volume as ‘‘normal/enlarged’’ or ‘‘atrophic’’ visually by an experienced neuroradiologist (HU). HU was not blinded for VGKC-Ab-positivity but for subtype specificity. Antibody tests Sera of the patients were tested both at visit 1 and 2 for VGKC-Abs by RIA (normal values\100 pmol/, performed at Oxford as described before [10]) and LGI1 and CASPR-2 by indirect immunofluorescence. This was first performed at the Institute of Experimental Immunology, Luebeck, using formalin-fixed HEK293 cells containing membrane bound LGI1 or CASPR-2 and confirmed at Oxford using live-cells. Endpoint titrations were performed at Oxford on all available samples. Furthermore all sera were tested for Abs against glutamate-decarboxylase, N-methyl-D-aspartate-receptors, NR1a/NR2b, GABA-b, AMPA-receptors, aquaporin-4 and glycine-receptor and onconeural Abs. CSF studies were obtained from the patient records at visit 1. Statistics For numerical data, t test (dependent and independent data), Kruskal–Wallis test (independent data), univariate analysis of variance and bivariate correlation (dependent and independent data) were used. For categorical data the v2 test (independent data) and the McNemar test (dependent data) were used. All tests were two-tailed. Due to multiple comparisons, p values were adjusted according to the Holm-Bonferroni stepwise correction procedure, global p value was considered \0.05.
Results Eighteen LE patients (median age at onset 55 years, range 20–73; 12 males), with elevated VGKC-Abs on RIA were
identified at visit 1. The duration of disease at this time was 8 months (range 0–23). Nine (50 %) patients had LGI1Abs, three (17 %) had CASPR-2-Abs and the remaining six (33 %) were negative for both antigens. CSF studies at visit 1 (17/18 patients), were mostly normal only 13 % of VGKC-LE patients had elevated cell counts and none of the patients had unmatched oligoclonal bands. Details are given in Tables 1 and 2. Clinical presentation at visit 1 Demographical data (Table 1) in the three subgroups (LGI1-Ab?, CASPR-2-Ab?, LGI1/CASPR-2-Ab-) were not different. No dual Ab positivity was found in any of the included patients. None of the patients had tumours identified. Initial features were seizures only in 7/18, both seizures and non-seizure limbic disturbances (depression, anxiety, memory loss, concentration difficulties, confusion) in 5/18, and non-seizure limbic disturbances only in 6/18. By the time of visit 1, however, all but one patient had experienced seizures. This patient (no. 18 in Table 1, VGKC-complex-Abs 691 pM, LGI1/CASPR-2-Ab-) had a history of epilepsy from age 8 years, developing into pharmacoresistant TLE, and had undergone left-sided amygdalohippocampectomy for hippocampal sclerosis 38 months before onset of LE. He had been seizure-free since this operation (Engel IA) [7], and his LE presented as acute onset of severe memory disturbances only. Hyponatremia was found in two LGI1-Ab? patients. We did not find myoclonus in LGI1-Ab? patients nor symptoms of peripheral nerve hyperexcitability in CASPR-2-Ab? patients currently or in the past. Treatments given and clinical follow up at visit 2 All patients received immunotherapy with corticosteroids as inpatient treatment at visit 1. Standard therapy was monthly intravenous methylprednisolone (MP) pulses (500–1,000 mg/day on 3–5 consecutive days) without (N = 13) or with (N = 4) subsequent oral continuation at descending doses for a median of 7 months (range 1–43 months). One LGI1-Ab? patient only received oral prednisolone therapy (MP-equivalent dose [22] 4.8 g/ 4 months). All VGKC-LE patients received comparable MP-equivalent doses [22] without differences in the subgroups (median 27 g; range 4.5–66). At the time of visit 2, MP had already been terminated or was to be terminated after this visit in all patients. For further details see Table 1. Only two patients remained on long-term immunotherapy with mycophenolat-mofetil (MMF) at visit 2. One of these patients was a LGI1/CASPR-2-Ab- patient (no. 17 in Table 1) who had experienced acute liver failure, treated
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123
M, 61
M, 55
F, 43
F, 52
M, 54
F, 61
M, 67
M, 32
Pat. 2
Pat. 3
Pat. 4
Pat. 5
Pat. 6
Pat. 7
Pat. 8
Pat.9
Pat. 10
M, 69
CASPR-2-Ab?
M, 59
Pat. 1
LGI1-Ab?
Gender, age at onset (year)
5.6
9.2
7.4
0.6
7.8
13.2
5.7
6.4
3.5
2.8
Disease duration (months) at V1
31
8
49
16
64
33
42
6
20
37
FU period from visit 1 (months)
Table 1 Individual patient characteristics at visit 1 and 2
48
4.8
12
19.1
29
50
29.3
5
37.5
66
MP doses (g)
1,419
440
4,511
844
761
907
2,766
4,362
3,020
7,655
169
245
407
67
25
-56
7
617
-12
805
1,620
180
1,620
1,620
540
540
1,620
1,620
1,620
n.a.
n.a.
60
20
60
20
20
0
540
60
1,620
at V2
at V1
at V1
at V2
LGI1/ CASPR-2 (RC-IFT, titer 1)
VGKC conc (RIA, mmol/ l)
12
60
0.2
2
4
24
5
70
60
16
Szfrequency/ month at V1
sz-free, (28)
sz-free, (4)
sz-free, (13)
sz-free, (4)
sz-free, (8)
not sz-free
sz-free, (1)
sz-free, (11)
sz-free, (4)
sz-free, (2)
Sz-outcome (months from onset to szfreedom) at V2
none
none
bl
bl
none
l
l
bl
bl
bl
MRI features of HA at V2
VM,
FM
VM,
FM
VM,
FM
FM
n.d.b
FM
FM
FM VM,
VM,
none
VM
VM,
none
FM
none
FM
FM VM
VM,
FM VM,
VM,
VM,
FM
at V2
FM
FM
VM,
at V1
Memory deficits
0.6
0.33
2.47
0.67
0.67
0.00
1.33
2.17
0.80
0.98
at V1
0.67
0.50
0.00
1.33
1.33
1.33
0.75
2.17
2.53
1.33
at V2
AED (ddd)
off IT
on AED,
off IT
on AED,
off IT
on AED,
off IT
on AED,
on AED, off IT
off IT
on AED,
off IT
on AED,
off IT
on AED,
off IT
on AED,
on AED, off IT
AED, IT at V2
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M, 38
Pat. 12
F, 19
M, 72
M, 68
F, 47
M, 35
Pat. 14
Pat. 15
Pat. 16
Pat. 17
Pat. 18
0.2
22.7
12.0
11.5
9.7
13.9
21.4
3.9
Disease duration (months) at V1
5
51
8
26
22
70
11
58
FU period from visit 1 (months)
25
11.3
30
4.5
35
13.4
45
13
MP doses (g)
691
1,156
320
265
539
107
509
2,061
229
1,139
193
-47
859
0
1,929
6,793
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4,800
4,800
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4,800
4,800
at V2
at V1
at V1
at V2
LGI1/ CASPR-2 (RC-IFT, titer 1)
VGKC conc (RIA, mmol/ l)
0
3
12
2
10
90
6
0.3
Szfrequency/ month at V1
none
bla
sz-free, (0a)
none
none
none
none
none
none
MRI features of HA at V2
sz-free, (28)
not sz-free
not sz-free
sz-free, (13)
not sz-free
sz-free, (27)
not sz-free
Sz-outcome (months from onset to szfreedom) at V2
VM, FM
FM
FM
none
none
none
none
none
FM
at V2
VM,
FM
VM
VM
none
VM
VM
FM
VM,
at V1
Memory deficits
2.60
0.83
0.20
0.50
0.83
0.0
2.17
0.0
at V1
2.00
0.0
1.80
0.67
1.53
0.67
1.0
0.2
at V2
AED (ddd)
off IT
on AED,
off AED, MMF
off IT
on AED,
off IT
on AED,
off IT
on AED,
off IT
on AED,
MMF
on AED,
off IT
on AED,
AED, IT at V2
b
Patient refused complete neuropsychological assessment without complaining deficits in daily living
V1 visit 1, V2 visit 2, conc concentration, HA hippocampal atrophy, MP methylprednisolone, sz seizure, AED antiepileptic drugs, ddd defined daily dose, M male, F female, pos positive, neg negative, n.d. not done, n.a. not available, bl bilateral ammon’s horn sclerosis, l left-sided hippocampal atrophy, VM verbal memory, FM figural memory, MMF mycophenylat-mofetil a Patient with preexisting bilateral HA and amygdalohippocampectomy before onset of LE and memory deficits only in LE
F, 57
Pat. 13
LGI1/CASPR-2-Ab-
M, 47
Pat. 11
Gender, age at onset (year)
Table 1 continued
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J Neurol Table 2 Serum and CSF of VGKC-patients and their subforms and Ab titers at visit 1
Visit 1 Standard CSF studies Elevated cell count ([5/ll)
VGKC all
LGI1 Ab?
CASPR-2 Ab?
LGI1/CASPR-2 Ab-
N = 18
N=9
N=3
N=6
N = 17
N=8
N=3
N=6
2 (both 6/ll)
1 (6/ll)
1 (6/ll)
0
Elevated protein content ([500 mg/l)
5 (B828 mg/l)
1 (696 mg/l)
3 (B783 mg/l)
1 (828 mg/l)
Blood brain barrier disturbance (determined according to ref [28])
7
3
2
2
Unmatched oligoclonal bands
0
0
0
0
N = 18
N=9
N=3
N=6
Median VGKC-ab concentration (RIA) pmol/l
876 (107–7,655)
2,766 (440–7,655)
1,419 (509–2,061)
430 (107–1,156)
Sodium values below normal ranges (normal 135–150 mmol/l)
2 (130, 133)
2 (130, 133)
0
0
Serum antibody studies
Ab antibodies, RIA radio-immuno-assay
Fig. 1 Antibody titers in serum in the course of the disease for LGI1-ab? patients. x-axis timepoints of first assessment (visit 1 and 2). y-axis indirect immunofluorescence using recombinantly transfected HEK293 cells (RC-IFT, 1:n)
by liver transplantation, while treated with MP and lamotrigine in the acute stage of LE. The liver failure was thought to be related to the steroid therapy. The patient recovered and had been seizure-free at visit 2 for 46 months without AED treatment but under long-term immunotherapy with MMF post-transplantation. The other patient receiving MMF was a 41-year-old with CASPR-2Abs (no. 12 in Table 1). Causes for MMF in this patient were persistent seizures and positive VGKC-Abs based on individual physician’s decision. In addition to MMF, he received AED therapy with levetiracetam and eslicarbazepin-acetate. Concomitant hypertension and smoking were thought to have been the cause of his subsequent death from myocardial infarction (no autopsy done). None of the patients developed a tumour during
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follow up. No relapses were seen and there were no other deaths. Comparison between visit 1 and visit 2 Antibody levels VGKC-complex-Abs at visit 1 ranged from 107 to 7,655 pM and by visit 2 had decreased substantially, becoming negative (\100 pm//l) in 12/17 (71 %) patients. However, this was most evident in the LGI1-Ab? patients (Fig. 1) whereas the VGKC-complex-Abs in the three CASPR-2-Ab? patients were variable, did not necessarily fall following treatments, and did not correlate with the CASPR-2-Ab titres (Table 1).
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Seizures At visit 1, seizures occurred at a median frequency of 6 months (range 0–90) with no apparent differences between the three subgroups (Kruskal–Wallis test n.s.). Two LGI1-Ab? patients had faciobrachial dystonic seizures (FBDS) at visit 1 together with limbic features. By visit 2, 13 patients (72 %) were seizure-free 89 % with LGI-Abs, 67 % with CASPR-2-Abs, and 50 % with neither antigen (v2 test, p = n.s.). Duration from onset until seizure freedom, if achieved, was a median of 10 months (range 1–28) without differences between the subgroups, and by visit 2 the seizure-free patients had been in this state
for a median period of 19 months (range 2–63 months). For details see Table 1. Memory outcome At visit 1, 16/18 of the VGKC-LE patients had memory deficits in either verbal or figural memory or in both (see Table 1). Whereas most of the LGI1-Ab? (7/9) and CASPR-2-Ab? patients (2/3) were affected in both domains, the LGI1/CASPR-2-Ab- patients were affected in only one domain (p = 0.006, n.s. due to BonferroniHolm correction procedure). Three patients had incomplete neuropsychological testing: one LGI1-Ab? patient was too
Fig. 2 Neuropsychological verbal (a) and figural (b) memory parameters at visit 1 and 2 (x-axis). Performances (y-axis) below -1 SD are rated as impaired. Asterisk significant improvement (t test vs. visit 1, p \ 0.01)
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encephalopathic to complete testing at visit 1, a CASPR-2Ab? patient was judged impaired in verbal and figural memory only using a computerized screening test [13]. At visit 2, 11/17 patients still showed deficits in at least one memory domain (McNemar test vs. visit 1, p = n.s.), without differences between the three subgroups (p = 0.623), but four patients (three in the LGI1-Ab? group, one in the LGI1/CASPR-2-Ab- group, p = n.s.) still showed impaired scores in both domains (McNemar test vs. visit 1, p = n.s.). One LGI1-Ab? patient refused memory testing after substantial clinical recovery. Overall, significant improvements between visit 1 and 2 were seen in both domains (t test, all patients; verbal memory p = 0.004; figural memory p = 0.002), but 6/8 of the LGI1-Ab? patients remained impaired (see Table 1; Fig. 2). Detailed neuropsychological parameters in the course are given for all patients with complete assessment in Fig. 2. MRI outcome At visit 1, all patients had encephalitic MRI FLAIR and T2 hyperintense mesiotemporal structures (see ‘‘Methods’’) 61 % VGKC-LE were affected bilaterally, 28 % left-sided and 11 % right-sided. Only the LGI1/CASPR-2-Abpatient (no. 18 in Table 1) who had had left-sided amygdalohippocampectomy before onset of LE had pre-existing MRI features of hippocampal atrophy with T2/FLAIR signal increase (i.e., hippocampal sclerosis). At visit 2, by contrast, MRI features differed between the groups: seven (39 %) patients, all with LGI1-Abs, had developed hippocampal atrophy with increased signal (five bilateral, two unilateral left-sided; v2 test, p = 0.003). Six of these patients were seizure-free, but six were persistently impaired in memory (verbal 4/6; figural 5/6; both 3/6), consistent with the hippocampal atrophy seen. Individual MRI outcomes are given in Table 1. Potential outcome determinants To evaluate potential outcome determinants we explored the seizure and memory outcome at visit 2 of patients with high VGKC-Ab-concentrations ([400 pmol/l) versus those with low VGKC-Ab-concentrations (B400 pmol/l) at visit 1. Unfavourable memory outcome was diagnosed if one of the two domains (VM or FM) was \-1 SD of controls. Fifteen from eighteen included patients had high Ab-concentrations and three low-Ab-concentrations, all lowVGKC-Ab-concentration-patients belonged to LGI1/CASPR-2-Ab- group. High-VGKC-Ab-concentration-patients were more often seizure-free (13/15) at visit 2 than lowAb-concentration-patients (0/3, v2 test, p = 0.002), but memory outcome was not different between both groups
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(v2 test, p = n.s.). Furthermore we tested for the correlation between time interval between onset of disease and onset of immunotherapy, immunotherapy duration and MP doses on dichotomous seizure and memory outcomes at visit 2. There was no such correlation. At visit 1, 15/18 patients were already under AED treatment. Patients without AED treatment at first presentation had a worse seizure outcome (t test 0.006, not significant due to Holms-Bonferroni-corrections). At visit 2 no differences in AED treatment and seizure outcome could be observed (t test p = n.s.).
Discussion Although there have been no formal trials, it is generally accepted that VGKC-LE patients improve when treated with steroids and other immunotherapies; most become seizure-free and improve in memory performance. Steroid therapy regimen in VGKC-LE as treatment option is widely accepted and adopted from patients with relapsing remitting multiple sclerosis [19, 27, 35]. However, in this study, only 41 % of the patients had normal memory function at visit 2. Interestingly, the worst outcomes, involving defects in both verbal and figural memory, occurred in those patients who had LGI1-Abs and had developed hippocampal atrophy, whereas those with CASPR-2 or neither Ab fared better in both memory tests and had all normal hippocampal volumes (and also otherwise unremarkable brain MRIs) following treatment. These results could have important implications for the recognition and treatment of patients with LGI1-Abs. In this LE cohort, the proportion of patients with LGI1, CASPR-2 or neither Abs was similar to those described in the LE patients studied early in Oxford [14]. Although we found a higher proportion, 33 %, with neither antigen, this may be because we included patients with VGKC-complex-Abs \400 pmol/l. Of possible significance, these three patients with lower VGKC-Ab-concentrations did not become seizure-free following treatment, whereas 13/15 of those patients with VGKC-complex-Abs [400 pmol/l did become seizure-free. This raises the possibility that patients with VGKC-Abs in the low range (100–400 pmol/l) may not have an immunotherapy responsive disease, and these lower levels of VGKC-complex-Abs should be interpreted with caution [26], indeed, levels \400 pmol/l were found in up to 5 % of a series of older subjects in the community [34]. On the other hand, a group from the Mayo Clinic recently found in a large patient series that 61 % of patients seropositive for Abs against LGI1, CASPR-2 or both would have been missed according to this cut-off above 400 pmol/l [20], but the clinical details of these patients were diverse and not divided into distinct syndromes. The
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same group reported seizure response to immunotherapy in 32 patients with autoimmune epilepsies, wherein 17 positive for VGKC-Abs (14 for LGI1-Abs, 1 CASPR-2-Abs, 2 for both) were included [27]. Immunotherapies applied were MP pulses, intravenous immunoglobulines (IVIG), plasma exchange and immunosuppressive treatment with MMF or rituximab, in most cases several therapies were used. All of these patients improved and 82 % became seizure-free. Interestingly, 7/14 of these patients were reported as MRI-negative (unlike our patients); MRI follow up data were not given. Recent prospective data from the University of Oxford documented favourable therapeutic outcome of ten patients with LGI-Abs and FBDS without full-blown LE [19]. Shin et al. [31] reported recently the therapeutic outcome of 14 patients with LGI1-Ab?-encephalitis. In contrast to our group, the majority of them (10/14, 71.4 %) had FBDS, 12/14 patients (85.7 %) presented with cognitive dysfunction but no formal neuropsychological tests were outlined in this report. In 10/14 patients, MRI exhibited pathological increased signals on MRI FLAIR or T2 in medial temporal structures. However, it was not differentiated whether these findings reflected acute inflammation or residual hippocampal atrophy and no follow up data on MRI were given. They attempted to figure out differences in clinical outcome according to the initial immunotherapeutic regimen (steroids only vs. combined therapy with steroids, plasma exchange, cyclophosphamid, rituximab) but there was no evidence for that. Duration and doses of steroids were not given in detail to compare ‘‘therapeutic intensity’’ with the present group. Wong et al. [35] proposed an aggressive immunotherapeutic regimen in patients with VGKC-LE combining plasma exchange, IVIG and intravenous MP pulses followed by long-term immunosuppression with oral prednisolone or MMF. They reported of nine patients with VGKC-LE with rapid decline of VGKC-Ab serum concentrations and clinical improvement in all patients under therapy. On the other hand severe adverse events related to aggressive immunosuppression occurred in 3/9 patients (33 %) two patients had septicaemia, one of them died consecutively and one had thrombosis of the affected leg with pulmonal embolism. An advantage of this study is the dedicated longitudinal study of memory performance reflecting Ab-subtypes, reflecting the facilities for presurgical evaluation at an active epilepsy centre. However, there are limitations. Firstly, since all patients were studied in a tertiary referral epilepsy centre, there may be a bias towards patients with difficult-to-treat seizures and long durations of disease at the time of starting immunotherapies. Secondly, the MRIpositivity was a defining feature whereas not all patients with VGKC-Abs and LE have typical MRI features [14, 21,
27]. Diagnosis of hippocampal atrophy was made by visual analysis without using further imaging tools such as MRI volumetry or relaxometry. Thirdly, it is a retrospective study with all inherent limitations, all patients were treated with AEDs with individual choice of substance and dosage according to common clinical practice. Influence of AED treatment in clinical outcome can be assumed. But there was no correlation between AED load and seizure outcome at visit 2. Nevertheless, it is possible that immunotherapy with monthly MP pulses is not sufficient in the LGI1-Ab? group and more intense immunological treatment could improve outcomes. The combination of high-dose oral corticosteroids for some months, with several cycles of plasma exchange or immunoadsorption, followed by IVIG, may be more effective in preserving the structure and function of the medial temporal tissue, and avoiding possible intractable seizures in the future. However, potential treatment benefits must be weighted against potential severe adverse effects of intense immunotherapies as illustrated by two recent reports of clinical outcomes in patients with VGKC-LE [29, 35]. Patients with LGI1-Abs had similar rates of seizures at onset and good outcomes in terms of seizure control, but the frequent development of hippocampal atrophy and association with continuing defects in verbal and figural memory function suggests that this is a particularly important group of patients to recognize and treat effectively as soon as possible. Moreover, it is possible that the current patients have entered a ‘‘silent period’’ with ‘‘ripening’’ of an epileptogenic focus [24] which could cause further difficulties in the future. Clearly one would like to identify and treat these patients promptly. This may be helped by the increasing number of LE patients identified with FBDS [17, 19] that frequently precede the onset of a typical LE. More aggressive and sustained immunotherapies may be important not just to decrease the seizures, which they do very effectively, but to prevent the longterm consequences in terms of hippocampal atrophy and persistent memory impairment. Acknowledgments The authors would like to thank Dr. Bethan Lang and Ms. Linda Clover, Nuffield Department of Clinical Neurosciences, for Ab determinations. Conflicts of interest MPM received payments for congress participation, travel expenses, lecture and manuscript preparation from UCB and EISAI. CF reports no disclosure. JCSB was funded by grants from Transregio SFB TR3 (Projects A1 and A8) and as part of the Gerok programme (BONFOR commission, University of Bonn). He received payments for travel expenses from Desitin. CH was funded by grants from Transregio SFB TR3 A1, BMBF and DFG, he received payments for board membership, consultancy, lectures, manuscript preparation and royalties from UCB Pharma, Desitin, VIAMED GmbH, EISAI, Glaxo Smith Kline.
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J Neurol KPW is a full-time employee of and hold stock in EUROIMMUN AG. WS is a full-time employee of and hold stock in EUROIMMUN AG. HU reports no disclosure. RS has received support for congress participation and speaker fees from EISAI and had a consultancy agreement with UCB. CEE received honoraria for consultancy, expert testimony and lectures from UCB Pharma, Desitin and Pfizer. He is an employee of the Life and Brain Institute Bonn. AV and the University of Oxford hold patents and receive royalties and payments for antibody testing. AV receives funding from Euroimmun AG and has consultancy agreement with Athena Diagnostics. CGB served on a scientific advisory board of UCB and EISAI, Germany, undertook industry-funded travel with support of Eisai, UCB, Desitin and Grifols (all Germany), and obtained honoraria for speaking engagements from Eisai, UCB, GlaxoSmithKline and Desitin (all Germany). As part of his present position, he performs serum and cerebrospinal fluid tests for antibodies as those described in the text; for this, his employer charges fees from external senders. Ethical standard Studies have been approved by the ethics committee and have, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.
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ORIGINAL COMMUNICATION
Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity M. P. Malter • C. Frisch • J. C. Schoene-Bake • C. Helmstaedter • K. P. Wandinger • W. Stoecker • H. Urbach • R. Surges • C. E. Elger A. V. Vincent • C. G. Bien
•
Received: 11 March 2014 / Revised: 5 June 2014 / Accepted: 6 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab-). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab? patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7408-6) contains supplementary material, which is available to authorized users. M. P. Malter C. Frisch J. C. Schoene-Bake C. Helmstaedter R. Surges C. E. Elger C. G. Bien Department of Epileptology, University of Bonn Medical Center, Bonn, Germany M. P. Malter (&) Department of Neurology, Marien-Krankenhaus Bergisch Gladbach, Dr.-Robert-Koch-Straße 18, 51465 Bergisch Gladbach, Germany e-mail: [email protected] J. C. Schoene-Bake Department of Pediatrics, Braunschweig City Hospitals, Brunswick, Germany
(72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab? patients, but in none of the CASPR-2-Ab? or LGI/CASPR-2-Ab- patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab? patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab?-LE. Keywords Limbic encephalitis VGKC LGI1 Autoimmune epilepsy
Introduction Antibodies (Abs) to voltage-gated potassium channel complex (VGKC) have been found in patients with K. P. Wandinger W. Stoecker Institute of Experimental Immunology, Affiliated to Euroimmun AG Luebeck, Luebeck, Germany H. Urbach Department of Neuroradiology, University of Freiburg Medical Center, Freiburg, Germany A. V. Vincent Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK C. G. Bien Epilepsy Centre Bethel, Krankenhaus Mara, Bielefeld, Germany
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acquired myotonia [10], Morvan’s syndrome [18], epilepsy [1, 16, 25] and limbic encephalitis [2, 14, 15, 23]. The Abs are detected by radioimmunoprecipitation (RIA) of Kv1 shaker-type VGKC channel complexes, labelled with 125 I-a-dendrotoxin, from mammalian brain extracts [30]. Recently, leucine-rich, glioma inactivated 1 protein (LGI1) and contactin-associated protein-like 2 (CASPR-2), both of which are present in the VGKC-complexes, were shown to be the main targets of these Abs [14, 21]. Limbic encephalitis (LE) is a clinicopathological entity with inflammatory lesions in the limbic structures of the medial temporal lobes. Temporal lobe epilepsy (TLE), memory deficits and affective disorders are the main clinical features. Although initially described in the 1960s as a paraneoplastic condition [5, 6], non-paraneoplastic forms have also been described, particularly with VGKC-complex-Abs (VGKC-LE) [3, 32, 34]. VGKC-LE is mostly non-paraneoplastic [9, 23] and thought to be responsive to immunotherapies [29, 35]. In a recent study [14], 77 % of the 64 patients with LE and VGKC-complex-Abs [400 pmol/l were positive for LGI1-Abs (LGI1-Ab?), 11 % were positive for CASPR2-Abs (CASPR-2-Ab?), and the remaining 12 % were negative for both LGI1 and CASPR-2-Abs (LGI1/CASPR2-Ab-). The aim of the present study was to describe the phenotypes and outcomes in the VGKC-LE patients divided into these three groups.
Patients’ characteristics, treatment and follow up The first inpatient assessment (visit 1) included brain MRI, neuropsychological assessment, serum and CSF collection, and the same test modalities were applied at the most recent visit (termed visit 2). Age at disease onset, first signs and symptoms, disease duration and follow up period, seizure frequency, MRI features, memory function, antiepileptic drug therapy and immunotherapy were obtained from the patient records. The cumulative corticosteroid dose was expressed as methylprednisolone-equivalent doses (prednisone/prednisolone doses were multiplied by 0.8) [22]. Antiepileptic drug (AED) therapy was converted into defined daily drug dose (ddd), defined by the World Health Organisation (WHO) (www.whocc.no/atc_ddd_index/), to standardize comparison between individual treatment regimens. A disease relapse was defined as deterioration in seizure control or memory function after stabilization for at least 2 months. Tumour searches were performed, adapted to the risk profile of the individual patient (see Supplemental Table 1). Seizure outcome Seizure freedom was defined as the absence of all seizures including auras over a minimum period of 1 month at visit 2 with or without antiepileptic drugs.
Methods Neuropsychological assessment Patients All 18 LE patients positive for VGKC-complex-, LGI1or CASPR-2-Abs, identified at the University of Bonn, Department of Epileptology between 01-01-2003 and 06-31-2011 (8.5 years), were included and evaluated retrospectively. Serum of these patients had been stored for potential further Ab studies at -20 °C with informed consent and local ethics committee approval. All patients were diagnosed with LE based on the features of limbic signs and symptoms (C1 of the following: seizures of temporal semiology, disturbance of episodic memory, affective disturbances with prominent mood lability or disinhibition) and brain MRI revealing medial temporal encephalitis (T2/FLAIR hyperintensity) manifesting in adulthood B5 years previously [4, 23]. Eleven of these patients were reported before, either in a case study [3] or as a comparison group to patients with glutamatedecarboxylase Ab positive LE [8, 23]. The LGI1- and CASPR-2-Ab reactivity has not been reported previously, and the follow up period has been extended in 9/16 patients.
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The neuropsychological evaluation focused on memory tests for temporal lobe functions. The Verbal Learning and Memory Test (a German adaptation of the Rey Auditory Verbal Learning Test, VLMT) [11] and the Diagnostikum fu¨r Cerebralscha¨digung, revised version (DCS-R) [12], a design learning test, were used. The VLMT includes a distraction trial, immediate free recall after distraction, and a delayed free recall before patients are asked to recognize the learned items out of a list of alternatives; the DCS-R only asks for immediate and delayed recognition. To condense the information from these tests, three parameters of verbal learning (immediate recall over five learning trials), verbal memory (loss of learned words in half an hour delayed free recall), and recognition (correctly recognized words out of alternatives minus errors) as well as three parameters of figural memory, figural learning (immediate recall over five learning trials), figural supraspan learning (immediate recall after the last learning trial), and figural recognition (correctly recognized designs out of alternatives minus errors) were transformed into age-corrected standard values according to clinical normative data
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and then transformed into a single summary score representative for the respective memory domain. Performances below mean -1 SD of age-matched controls were rated as impaired. MRI Brain MRIs were obtained according to a dedicated epilepsy protocol [33] using a 3 Tesla scanner, Philips, The Netherlands (Department of Neuroradiology) or a 3 T ‘‘Trio’’ scanner from Siemens, Erlangen, Germany (Life & Brain Institute). Previous brain MRIs from other institutions were assessed if available. All images were re-evaluated for this study. Hippocampal signal on T2-weighted or FLAIR images was classified as ‘‘hyperintense’’ or ‘‘normal’’ and hippocampal volume as ‘‘normal/enlarged’’ or ‘‘atrophic’’ visually by an experienced neuroradiologist (HU). HU was not blinded for VGKC-Ab-positivity but for subtype specificity. Antibody tests Sera of the patients were tested both at visit 1 and 2 for VGKC-Abs by RIA (normal values\100 pmol/, performed at Oxford as described before [10]) and LGI1 and CASPR-2 by indirect immunofluorescence. This was first performed at the Institute of Experimental Immunology, Luebeck, using formalin-fixed HEK293 cells containing membrane bound LGI1 or CASPR-2 and confirmed at Oxford using live-cells. Endpoint titrations were performed at Oxford on all available samples. Furthermore all sera were tested for Abs against glutamate-decarboxylase, N-methyl-D-aspartate-receptors, NR1a/NR2b, GABA-b, AMPA-receptors, aquaporin-4 and glycine-receptor and onconeural Abs. CSF studies were obtained from the patient records at visit 1. Statistics For numerical data, t test (dependent and independent data), Kruskal–Wallis test (independent data), univariate analysis of variance and bivariate correlation (dependent and independent data) were used. For categorical data the v2 test (independent data) and the McNemar test (dependent data) were used. All tests were two-tailed. Due to multiple comparisons, p values were adjusted according to the Holm-Bonferroni stepwise correction procedure, global p value was considered \0.05.
Results Eighteen LE patients (median age at onset 55 years, range 20–73; 12 males), with elevated VGKC-Abs on RIA were
identified at visit 1. The duration of disease at this time was 8 months (range 0–23). Nine (50 %) patients had LGI1Abs, three (17 %) had CASPR-2-Abs and the remaining six (33 %) were negative for both antigens. CSF studies at visit 1 (17/18 patients), were mostly normal only 13 % of VGKC-LE patients had elevated cell counts and none of the patients had unmatched oligoclonal bands. Details are given in Tables 1 and 2. Clinical presentation at visit 1 Demographical data (Table 1) in the three subgroups (LGI1-Ab?, CASPR-2-Ab?, LGI1/CASPR-2-Ab-) were not different. No dual Ab positivity was found in any of the included patients. None of the patients had tumours identified. Initial features were seizures only in 7/18, both seizures and non-seizure limbic disturbances (depression, anxiety, memory loss, concentration difficulties, confusion) in 5/18, and non-seizure limbic disturbances only in 6/18. By the time of visit 1, however, all but one patient had experienced seizures. This patient (no. 18 in Table 1, VGKC-complex-Abs 691 pM, LGI1/CASPR-2-Ab-) had a history of epilepsy from age 8 years, developing into pharmacoresistant TLE, and had undergone left-sided amygdalohippocampectomy for hippocampal sclerosis 38 months before onset of LE. He had been seizure-free since this operation (Engel IA) [7], and his LE presented as acute onset of severe memory disturbances only. Hyponatremia was found in two LGI1-Ab? patients. We did not find myoclonus in LGI1-Ab? patients nor symptoms of peripheral nerve hyperexcitability in CASPR-2-Ab? patients currently or in the past. Treatments given and clinical follow up at visit 2 All patients received immunotherapy with corticosteroids as inpatient treatment at visit 1. Standard therapy was monthly intravenous methylprednisolone (MP) pulses (500–1,000 mg/day on 3–5 consecutive days) without (N = 13) or with (N = 4) subsequent oral continuation at descending doses for a median of 7 months (range 1–43 months). One LGI1-Ab? patient only received oral prednisolone therapy (MP-equivalent dose [22] 4.8 g/ 4 months). All VGKC-LE patients received comparable MP-equivalent doses [22] without differences in the subgroups (median 27 g; range 4.5–66). At the time of visit 2, MP had already been terminated or was to be terminated after this visit in all patients. For further details see Table 1. Only two patients remained on long-term immunotherapy with mycophenolat-mofetil (MMF) at visit 2. One of these patients was a LGI1/CASPR-2-Ab- patient (no. 17 in Table 1) who had experienced acute liver failure, treated
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123
M, 61
M, 55
F, 43
F, 52
M, 54
F, 61
M, 67
M, 32
Pat. 2
Pat. 3
Pat. 4
Pat. 5
Pat. 6
Pat. 7
Pat. 8
Pat.9
Pat. 10
M, 69
CASPR-2-Ab?
M, 59
Pat. 1
LGI1-Ab?
Gender, age at onset (year)
5.6
9.2
7.4
0.6
7.8
13.2
5.7
6.4
3.5
2.8
Disease duration (months) at V1
31
8
49
16
64
33
42
6
20
37
FU period from visit 1 (months)
Table 1 Individual patient characteristics at visit 1 and 2
48
4.8
12
19.1
29
50
29.3
5
37.5
66
MP doses (g)
1,419
440
4,511
844
761
907
2,766
4,362
3,020
7,655
169
245
407
67
25
-56
7
617
-12
805
1,620
180
1,620
1,620
540
540
1,620
1,620
1,620
n.a.
n.a.
60
20
60
20
20
0
540
60
1,620
at V2
at V1
at V1
at V2
LGI1/ CASPR-2 (RC-IFT, titer 1)
VGKC conc (RIA, mmol/ l)
12
60
0.2
2
4
24
5
70
60
16
Szfrequency/ month at V1
sz-free, (28)
sz-free, (4)
sz-free, (13)
sz-free, (4)
sz-free, (8)
not sz-free
sz-free, (1)
sz-free, (11)
sz-free, (4)
sz-free, (2)
Sz-outcome (months from onset to szfreedom) at V2
none
none
bl
bl
none
l
l
bl
bl
bl
MRI features of HA at V2
VM,
FM
VM,
FM
VM,
FM
FM
n.d.b
FM
FM
FM VM,
VM,
none
VM
VM,
none
FM
none
FM
FM VM
VM,
FM VM,
VM,
VM,
FM
at V2
FM
FM
VM,
at V1
Memory deficits
0.6
0.33
2.47
0.67
0.67
0.00
1.33
2.17
0.80
0.98
at V1
0.67
0.50
0.00
1.33
1.33
1.33
0.75
2.17
2.53
1.33
at V2
AED (ddd)
off IT
on AED,
off IT
on AED,
off IT
on AED,
off IT
on AED,
on AED, off IT
off IT
on AED,
off IT
on AED,
off IT
on AED,
off IT
on AED,
on AED, off IT
AED, IT at V2
J Neurol
M, 38
Pat. 12
F, 19
M, 72
M, 68
F, 47
M, 35
Pat. 14
Pat. 15
Pat. 16
Pat. 17
Pat. 18
0.2
22.7
12.0
11.5
9.7
13.9
21.4
3.9
Disease duration (months) at V1
5
51
8
26
22
70
11
58
FU period from visit 1 (months)
25
11.3
30
4.5
35
13.4
45
13
MP doses (g)
691
1,156
320
265
539
107
509
2,061
229
1,139
193
-47
859
0
1,929
6,793
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4,800
4,800
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4,800
4,800
at V2
at V1
at V1
at V2
LGI1/ CASPR-2 (RC-IFT, titer 1)
VGKC conc (RIA, mmol/ l)
0
3
12
2
10
90
6
0.3
Szfrequency/ month at V1
none
bla
sz-free, (0a)
none
none
none
none
none
none
MRI features of HA at V2
sz-free, (28)
not sz-free
not sz-free
sz-free, (13)
not sz-free
sz-free, (27)
not sz-free
Sz-outcome (months from onset to szfreedom) at V2
VM, FM
FM
FM
none
none
none
none
none
FM
at V2
VM,
FM
VM
VM
none
VM
VM
FM
VM,
at V1
Memory deficits
2.60
0.83
0.20
0.50
0.83
0.0
2.17
0.0
at V1
2.00
0.0
1.80
0.67
1.53
0.67
1.0
0.2
at V2
AED (ddd)
off IT
on AED,
off AED, MMF
off IT
on AED,
off IT
on AED,
off IT
on AED,
off IT
on AED,
MMF
on AED,
off IT
on AED,
AED, IT at V2
b
Patient refused complete neuropsychological assessment without complaining deficits in daily living
V1 visit 1, V2 visit 2, conc concentration, HA hippocampal atrophy, MP methylprednisolone, sz seizure, AED antiepileptic drugs, ddd defined daily dose, M male, F female, pos positive, neg negative, n.d. not done, n.a. not available, bl bilateral ammon’s horn sclerosis, l left-sided hippocampal atrophy, VM verbal memory, FM figural memory, MMF mycophenylat-mofetil a Patient with preexisting bilateral HA and amygdalohippocampectomy before onset of LE and memory deficits only in LE
F, 57
Pat. 13
LGI1/CASPR-2-Ab-
M, 47
Pat. 11
Gender, age at onset (year)
Table 1 continued
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123
J Neurol Table 2 Serum and CSF of VGKC-patients and their subforms and Ab titers at visit 1
Visit 1 Standard CSF studies Elevated cell count ([5/ll)
VGKC all
LGI1 Ab?
CASPR-2 Ab?
LGI1/CASPR-2 Ab-
N = 18
N=9
N=3
N=6
N = 17
N=8
N=3
N=6
2 (both 6/ll)
1 (6/ll)
1 (6/ll)
0
Elevated protein content ([500 mg/l)
5 (B828 mg/l)
1 (696 mg/l)
3 (B783 mg/l)
1 (828 mg/l)
Blood brain barrier disturbance (determined according to ref [28])
7
3
2
2
Unmatched oligoclonal bands
0
0
0
0
N = 18
N=9
N=3
N=6
Median VGKC-ab concentration (RIA) pmol/l
876 (107–7,655)
2,766 (440–7,655)
1,419 (509–2,061)
430 (107–1,156)
Sodium values below normal ranges (normal 135–150 mmol/l)
2 (130, 133)
2 (130, 133)
0
0
Serum antibody studies
Ab antibodies, RIA radio-immuno-assay
Fig. 1 Antibody titers in serum in the course of the disease for LGI1-ab? patients. x-axis timepoints of first assessment (visit 1 and 2). y-axis indirect immunofluorescence using recombinantly transfected HEK293 cells (RC-IFT, 1:n)
by liver transplantation, while treated with MP and lamotrigine in the acute stage of LE. The liver failure was thought to be related to the steroid therapy. The patient recovered and had been seizure-free at visit 2 for 46 months without AED treatment but under long-term immunotherapy with MMF post-transplantation. The other patient receiving MMF was a 41-year-old with CASPR-2Abs (no. 12 in Table 1). Causes for MMF in this patient were persistent seizures and positive VGKC-Abs based on individual physician’s decision. In addition to MMF, he received AED therapy with levetiracetam and eslicarbazepin-acetate. Concomitant hypertension and smoking were thought to have been the cause of his subsequent death from myocardial infarction (no autopsy done). None of the patients developed a tumour during
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follow up. No relapses were seen and there were no other deaths. Comparison between visit 1 and visit 2 Antibody levels VGKC-complex-Abs at visit 1 ranged from 107 to 7,655 pM and by visit 2 had decreased substantially, becoming negative (\100 pm//l) in 12/17 (71 %) patients. However, this was most evident in the LGI1-Ab? patients (Fig. 1) whereas the VGKC-complex-Abs in the three CASPR-2-Ab? patients were variable, did not necessarily fall following treatments, and did not correlate with the CASPR-2-Ab titres (Table 1).
J Neurol
Seizures At visit 1, seizures occurred at a median frequency of 6 months (range 0–90) with no apparent differences between the three subgroups (Kruskal–Wallis test n.s.). Two LGI1-Ab? patients had faciobrachial dystonic seizures (FBDS) at visit 1 together with limbic features. By visit 2, 13 patients (72 %) were seizure-free 89 % with LGI-Abs, 67 % with CASPR-2-Abs, and 50 % with neither antigen (v2 test, p = n.s.). Duration from onset until seizure freedom, if achieved, was a median of 10 months (range 1–28) without differences between the subgroups, and by visit 2 the seizure-free patients had been in this state
for a median period of 19 months (range 2–63 months). For details see Table 1. Memory outcome At visit 1, 16/18 of the VGKC-LE patients had memory deficits in either verbal or figural memory or in both (see Table 1). Whereas most of the LGI1-Ab? (7/9) and CASPR-2-Ab? patients (2/3) were affected in both domains, the LGI1/CASPR-2-Ab- patients were affected in only one domain (p = 0.006, n.s. due to BonferroniHolm correction procedure). Three patients had incomplete neuropsychological testing: one LGI1-Ab? patient was too
Fig. 2 Neuropsychological verbal (a) and figural (b) memory parameters at visit 1 and 2 (x-axis). Performances (y-axis) below -1 SD are rated as impaired. Asterisk significant improvement (t test vs. visit 1, p \ 0.01)
123
J Neurol
encephalopathic to complete testing at visit 1, a CASPR-2Ab? patient was judged impaired in verbal and figural memory only using a computerized screening test [13]. At visit 2, 11/17 patients still showed deficits in at least one memory domain (McNemar test vs. visit 1, p = n.s.), without differences between the three subgroups (p = 0.623), but four patients (three in the LGI1-Ab? group, one in the LGI1/CASPR-2-Ab- group, p = n.s.) still showed impaired scores in both domains (McNemar test vs. visit 1, p = n.s.). One LGI1-Ab? patient refused memory testing after substantial clinical recovery. Overall, significant improvements between visit 1 and 2 were seen in both domains (t test, all patients; verbal memory p = 0.004; figural memory p = 0.002), but 6/8 of the LGI1-Ab? patients remained impaired (see Table 1; Fig. 2). Detailed neuropsychological parameters in the course are given for all patients with complete assessment in Fig. 2. MRI outcome At visit 1, all patients had encephalitic MRI FLAIR and T2 hyperintense mesiotemporal structures (see ‘‘Methods’’) 61 % VGKC-LE were affected bilaterally, 28 % left-sided and 11 % right-sided. Only the LGI1/CASPR-2-Abpatient (no. 18 in Table 1) who had had left-sided amygdalohippocampectomy before onset of LE had pre-existing MRI features of hippocampal atrophy with T2/FLAIR signal increase (i.e., hippocampal sclerosis). At visit 2, by contrast, MRI features differed between the groups: seven (39 %) patients, all with LGI1-Abs, had developed hippocampal atrophy with increased signal (five bilateral, two unilateral left-sided; v2 test, p = 0.003). Six of these patients were seizure-free, but six were persistently impaired in memory (verbal 4/6; figural 5/6; both 3/6), consistent with the hippocampal atrophy seen. Individual MRI outcomes are given in Table 1. Potential outcome determinants To evaluate potential outcome determinants we explored the seizure and memory outcome at visit 2 of patients with high VGKC-Ab-concentrations ([400 pmol/l) versus those with low VGKC-Ab-concentrations (B400 pmol/l) at visit 1. Unfavourable memory outcome was diagnosed if one of the two domains (VM or FM) was \-1 SD of controls. Fifteen from eighteen included patients had high Ab-concentrations and three low-Ab-concentrations, all lowVGKC-Ab-concentration-patients belonged to LGI1/CASPR-2-Ab- group. High-VGKC-Ab-concentration-patients were more often seizure-free (13/15) at visit 2 than lowAb-concentration-patients (0/3, v2 test, p = 0.002), but memory outcome was not different between both groups
123
(v2 test, p = n.s.). Furthermore we tested for the correlation between time interval between onset of disease and onset of immunotherapy, immunotherapy duration and MP doses on dichotomous seizure and memory outcomes at visit 2. There was no such correlation. At visit 1, 15/18 patients were already under AED treatment. Patients without AED treatment at first presentation had a worse seizure outcome (t test 0.006, not significant due to Holms-Bonferroni-corrections). At visit 2 no differences in AED treatment and seizure outcome could be observed (t test p = n.s.).
Discussion Although there have been no formal trials, it is generally accepted that VGKC-LE patients improve when treated with steroids and other immunotherapies; most become seizure-free and improve in memory performance. Steroid therapy regimen in VGKC-LE as treatment option is widely accepted and adopted from patients with relapsing remitting multiple sclerosis [19, 27, 35]. However, in this study, only 41 % of the patients had normal memory function at visit 2. Interestingly, the worst outcomes, involving defects in both verbal and figural memory, occurred in those patients who had LGI1-Abs and had developed hippocampal atrophy, whereas those with CASPR-2 or neither Ab fared better in both memory tests and had all normal hippocampal volumes (and also otherwise unremarkable brain MRIs) following treatment. These results could have important implications for the recognition and treatment of patients with LGI1-Abs. In this LE cohort, the proportion of patients with LGI1, CASPR-2 or neither Abs was similar to those described in the LE patients studied early in Oxford [14]. Although we found a higher proportion, 33 %, with neither antigen, this may be because we included patients with VGKC-complex-Abs \400 pmol/l. Of possible significance, these three patients with lower VGKC-Ab-concentrations did not become seizure-free following treatment, whereas 13/15 of those patients with VGKC-complex-Abs [400 pmol/l did become seizure-free. This raises the possibility that patients with VGKC-Abs in the low range (100–400 pmol/l) may not have an immunotherapy responsive disease, and these lower levels of VGKC-complex-Abs should be interpreted with caution [26], indeed, levels \400 pmol/l were found in up to 5 % of a series of older subjects in the community [34]. On the other hand, a group from the Mayo Clinic recently found in a large patient series that 61 % of patients seropositive for Abs against LGI1, CASPR-2 or both would have been missed according to this cut-off above 400 pmol/l [20], but the clinical details of these patients were diverse and not divided into distinct syndromes. The
J Neurol
same group reported seizure response to immunotherapy in 32 patients with autoimmune epilepsies, wherein 17 positive for VGKC-Abs (14 for LGI1-Abs, 1 CASPR-2-Abs, 2 for both) were included [27]. Immunotherapies applied were MP pulses, intravenous immunoglobulines (IVIG), plasma exchange and immunosuppressive treatment with MMF or rituximab, in most cases several therapies were used. All of these patients improved and 82 % became seizure-free. Interestingly, 7/14 of these patients were reported as MRI-negative (unlike our patients); MRI follow up data were not given. Recent prospective data from the University of Oxford documented favourable therapeutic outcome of ten patients with LGI-Abs and FBDS without full-blown LE [19]. Shin et al. [31] reported recently the therapeutic outcome of 14 patients with LGI1-Ab?-encephalitis. In contrast to our group, the majority of them (10/14, 71.4 %) had FBDS, 12/14 patients (85.7 %) presented with cognitive dysfunction but no formal neuropsychological tests were outlined in this report. In 10/14 patients, MRI exhibited pathological increased signals on MRI FLAIR or T2 in medial temporal structures. However, it was not differentiated whether these findings reflected acute inflammation or residual hippocampal atrophy and no follow up data on MRI were given. They attempted to figure out differences in clinical outcome according to the initial immunotherapeutic regimen (steroids only vs. combined therapy with steroids, plasma exchange, cyclophosphamid, rituximab) but there was no evidence for that. Duration and doses of steroids were not given in detail to compare ‘‘therapeutic intensity’’ with the present group. Wong et al. [35] proposed an aggressive immunotherapeutic regimen in patients with VGKC-LE combining plasma exchange, IVIG and intravenous MP pulses followed by long-term immunosuppression with oral prednisolone or MMF. They reported of nine patients with VGKC-LE with rapid decline of VGKC-Ab serum concentrations and clinical improvement in all patients under therapy. On the other hand severe adverse events related to aggressive immunosuppression occurred in 3/9 patients (33 %) two patients had septicaemia, one of them died consecutively and one had thrombosis of the affected leg with pulmonal embolism. An advantage of this study is the dedicated longitudinal study of memory performance reflecting Ab-subtypes, reflecting the facilities for presurgical evaluation at an active epilepsy centre. However, there are limitations. Firstly, since all patients were studied in a tertiary referral epilepsy centre, there may be a bias towards patients with difficult-to-treat seizures and long durations of disease at the time of starting immunotherapies. Secondly, the MRIpositivity was a defining feature whereas not all patients with VGKC-Abs and LE have typical MRI features [14, 21,
27]. Diagnosis of hippocampal atrophy was made by visual analysis without using further imaging tools such as MRI volumetry or relaxometry. Thirdly, it is a retrospective study with all inherent limitations, all patients were treated with AEDs with individual choice of substance and dosage according to common clinical practice. Influence of AED treatment in clinical outcome can be assumed. But there was no correlation between AED load and seizure outcome at visit 2. Nevertheless, it is possible that immunotherapy with monthly MP pulses is not sufficient in the LGI1-Ab? group and more intense immunological treatment could improve outcomes. The combination of high-dose oral corticosteroids for some months, with several cycles of plasma exchange or immunoadsorption, followed by IVIG, may be more effective in preserving the structure and function of the medial temporal tissue, and avoiding possible intractable seizures in the future. However, potential treatment benefits must be weighted against potential severe adverse effects of intense immunotherapies as illustrated by two recent reports of clinical outcomes in patients with VGKC-LE [29, 35]. Patients with LGI1-Abs had similar rates of seizures at onset and good outcomes in terms of seizure control, but the frequent development of hippocampal atrophy and association with continuing defects in verbal and figural memory function suggests that this is a particularly important group of patients to recognize and treat effectively as soon as possible. Moreover, it is possible that the current patients have entered a ‘‘silent period’’ with ‘‘ripening’’ of an epileptogenic focus [24] which could cause further difficulties in the future. Clearly one would like to identify and treat these patients promptly. This may be helped by the increasing number of LE patients identified with FBDS [17, 19] that frequently precede the onset of a typical LE. More aggressive and sustained immunotherapies may be important not just to decrease the seizures, which they do very effectively, but to prevent the longterm consequences in terms of hippocampal atrophy and persistent memory impairment. Acknowledgments The authors would like to thank Dr. Bethan Lang and Ms. Linda Clover, Nuffield Department of Clinical Neurosciences, for Ab determinations. Conflicts of interest MPM received payments for congress participation, travel expenses, lecture and manuscript preparation from UCB and EISAI. CF reports no disclosure. JCSB was funded by grants from Transregio SFB TR3 (Projects A1 and A8) and as part of the Gerok programme (BONFOR commission, University of Bonn). He received payments for travel expenses from Desitin. CH was funded by grants from Transregio SFB TR3 A1, BMBF and DFG, he received payments for board membership, consultancy, lectures, manuscript preparation and royalties from UCB Pharma, Desitin, VIAMED GmbH, EISAI, Glaxo Smith Kline.
123
J Neurol KPW is a full-time employee of and hold stock in EUROIMMUN AG. WS is a full-time employee of and hold stock in EUROIMMUN AG. HU reports no disclosure. RS has received support for congress participation and speaker fees from EISAI and had a consultancy agreement with UCB. CEE received honoraria for consultancy, expert testimony and lectures from UCB Pharma, Desitin and Pfizer. He is an employee of the Life and Brain Institute Bonn. AV and the University of Oxford hold patents and receive royalties and payments for antibody testing. AV receives funding from Euroimmun AG and has consultancy agreement with Athena Diagnostics. CGB served on a scientific advisory board of UCB and EISAI, Germany, undertook industry-funded travel with support of Eisai, UCB, Desitin and Grifols (all Germany), and obtained honoraria for speaking engagements from Eisai, UCB, GlaxoSmithKline and Desitin (all Germany). As part of his present position, he performs serum and cerebrospinal fluid tests for antibodies as those described in the text; for this, his employer charges fees from external senders. Ethical standard Studies have been approved by the ethics committee and have, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.
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