Edited by: Stephan Schuele, Northwestern University, United States
Reviewed by: George Culler, Dartmouth University, United States; Stephen VanHaerents, Northwestern Medicine, United States
This article was submitted to Epilepsy, a section of the journal Frontiers in Neurology
†These authors have contributed equally to this work
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Epilepsy and new onset seizures in elderly patients are an important health issue of the aging population (
The presence of neural antibodies (AB) in serum and/or CSF can be suggestive of an autoimmune origin, but their absence does not exclude autoimmunity (
Therefore, the aim of this study was to investigate the prevalence of AE in a large cohort of patients with late-onset seizures and to find predictors of when to suspect AE in late-onset seizures. We furthermore aimed to characterize the long-term outcomes and provide clinicians with recommendations for an adequate treatment in this challenging group of patients.
In this prospective single-institution cohort study, patients from the general neurology department, the neurological intensive care unit, and the epilepsy monitoring unit who underwent diagnostic workup after epileptic seizures including CSF analysis between 2012 and 2019 were studied at the University Hospital of Greifswald, Germany (serving a population of about 500,000 people).
Patients ≥50 years of age with status epilepticus, repetitive seizures for ≤6 months, or one single seizure (further referred to as seizure disorder) and CSF analysis were included. Cerebrospinal fluid analysis was performed in all patients with a first manifestation of a seizure disorder. Cerebrospinal fluid analysis after a first seizure disorder is a clinical standard in our institution, especially in patients aged 50 years or older, with certain exceptions, such as clear evidence of a generalized genetic epilepsy syndrome. All patients without CSF analysis regardless of the reason (for example, those who have refused consent or have oral anticoagulation) were excluded from the study. Patients with suspected infectious etiology of the seizure disorder based on CSF analysis (cell count, lactate, and protein elevation in CSF analysis and/or evidence of viral or bacterial infection in microbiological analysis) without further evidence of a comorbid autoimmune encephalitis were also excluded from the study. Seizures were classified according to the International League Against Epilepsy (ILAE) classification of seizure types (
Immunosuppressive therapy (IT) and/or anti-seizure drug (ASD) treatment was started at the discretion of the treating physician. First-line IT included prednisolone (per os/intravenous), plasma exchange (PEX), immunoabsorption (IA), or intravenous immunoglobulins, second-line IT included further immunosuppressive therapy (rituximab, methotrexate, cyclophosphamide, azathioprine). Tumor screening, including CT scan of the thorax/abdomen and gynecological/urological investigations, was performed in cases of suspected paraneoplastic AE in 6-month intervals for at least 2 years.
Patients were categorized in three cohorts and defined as follows: (1) definite autoimmune encephalitis (dAE): neural AB positivity and/or bilateral hyperintense signals in T2-FLAIR MRI sequences either restricted to the medial temporal lobes or in multifocal areas compatible with demyelination or inflammation (
Follow-up (FU) investigation was not part of the initial study protocol and was carried out in 2019 after the end of the intended observation period. Follow-up included clinical and seizure outcomes in cohorts 1 and 2 (dAE/sAE) if available and was assessed with a structured telephone interview or data evaluation from the available medical charts. Minimum follow-up time was 6 months.
Standardized neuropsychological assessment was feasible in 11 out of 17 (65%) dAE/sAE patients (
Laboratory analyses were performed in the Interdisciplinary CSF laboratory of the University Medicine Greifswald. Laboratory analyses were performed as described previously (
The determination of neural AB in CSF and serum was performed by the MVZ Labor Krone GbR, Siemensstraße 40, 32105 Bad Salzuflen, Germany (for details see
Statistical analysis was performed using SPSS 23.0 (IBM Co., Armonk, New York, USA). Kolmogorov-Smirnov analysis was used to test for Gaussian distribution of the data. Statistical significance of nominal data was assessed using chi-square tests and Fisher's exact test with a significance defined as a probability, (
The study has been approved by the institutional review board (IRB). Patient consent was not obtained prospectively, as the diagnostic pathway for this study was integrated into the clinical routine diagnostic procedure and was required only for patients who were contacted for follow-up investigations.
In all, 225 patients (53.8% female) with a mean age of 73 years (range: 51–94) were prospectively enrolled in the study. Seventeen (8%) of them were classified as definite or suspected AE, the remaining 208 (92%) as AE negative (cohort III).
A total of nine patients (
Patients with definite AE.
No. 1 | 87 | normal | generalized continuous slow activity | methylprednisolone 1,000 mg per day i.v. for 5 days | no | lost to follow-up |
No. 2 | 71 | normal | normal | methylprednisolone 1,000 mg per day i.v., followed by prednisolone 1 mg/kg per day p.o. |
Levetiracetam 1,000 mg per day | 21 months, seizure free, |
No. 3 | 67 | T2/FLAIR hyperintensity right insula, mesial temporal, temporopolar | intermittent regional slow right temporal | prednisolone 1 mg/kg per day p.o. |
Lamotrigine 200 mg per day | 37 months, seizure free, |
No. 4 | 59 | normal | normal | prednisolone 1 mg/kg per day p.o. |
Levetiracetam 2,000 mg per day | 62 months, seizure free |
No. 5 | 66 | T2/FLAIR hyperintensity right temporal | normal | methylprednisolone 500 mg per day i.v. for 5 days, plasma exchange, followed by prednisolone 1 mg/kg per day p.o. |
Levetiracetam 2,000 mg per day | 102 months, seizure free |
No. 6 | 80 | contrast enhancement left parietal | intermittent generalized slow with isolated ß-bursts | methylprednisolone 1,000 mg per day i.v., followed by prednisolone 1 mg/kg per day p.o. |
valproate (dosage unknown) | lost to follow-up |
No. 7 | 67 | normal | normal | methylprednisolone 1,000 mg per day i.v. for 5 days, plasma exchange (5 cycles), prednisolone 1 mg/kg per day p.o. |
no | 3 months |
No. 8 | 61 | T2/FLAIR hyperintensity right mesial temporal | normal | methylprednisolone 1,000 mg per day i.v. for 5 days, followed by prednisolone 1 mg/kg per day p.o. |
no | lost to follow-up |
No. 9 | 67 | normal | intermittent regional slow left hemisphere with isolated epileptic discharges | methylprednisolone 1,000 mg per day i.v. for 5 days, followed by prednisolone 1 mg/kg per day p.o. |
Levetiracetam 4,000 mg per day | 23 months, seizure free |
Neural antibody and CSF results of patients with definite and suspected AE.
No. 1 anti-GAD65 AB (serum: 1:1280, CSF 1:8) | 1 | 2.7 | 14.9 | Negative | 92% monocytes |
7% lymphocytes | |||||
1% other cells | |||||
No. 2 anti-LGI1 AB [serum: 1:640, CSF 1:4 (+ anti-titin ab + unspecific neuropil ab in serum + CSF)] | 2 | 1.7 | 9.6 | Negative | 44% monocytes 56% lymphocytes |
No. 3 anti-CASPR2 AB (serum 1:2,560, CSF 1:32) | 9 | 1.7 | 14.2 | Negative | 90% lymphocytes |
9% monocytes | |||||
1% other cells | |||||
No. 4 anti-CASPR2 AB (serum 1:1,500,000, CSF 1:100,000) | 12 | 2.2 | 7 | Negative | 74% monocytes |
26% lymphocytes | |||||
No. 5 anti-CASPR2 AB (serum 1:1,000, CSF 1:100) | 1 | 1.7 | 5.5 | Negative | 65% monocytes |
32% lymphocytes | |||||
3% other cells | |||||
No. 6 anti-NMDAR AB (serum 1:80, CSF 1:256) | 11 | 1.5 | 4.4 | Positive | 83% lymphocytes, 16% monocytes |
1% other cells | |||||
No. 7 Amphiphysin + Neuropil AB CSF and serum | 2 | 2 | 8.5 | Positive | 86% lymphocytes |
12% monocytes | |||||
2% other cells | |||||
No. 8 anti-GABAbR AB serum 1:640, CSF 1:8/Hu CSF and serum; Sox/Zic CSF and serum | 2 | 2.4 | 3.3 | Positive | 92% lymphocytes, 7% monocytes, 1% other cells |
No. 9 Hu AB CSF and serum/Zic4 AB serum | 14 | 1.7 | 9.2 | Positive | 92% lymphocytes |
3% other cells | |||||
5% monocytes | |||||
No. 10 anti-GABABR AB serum 1:200; CSF negative | 1 | 1.6 | 3.3 | Negative | 55% lymphocytes |
45% monocytes | |||||
No. 11 Unspecific neuropil AB in CSF and serum | 9 | 2.9 | 15.6 | Negative | 46% lymphocytes |
1% other cells | |||||
53% monocytes | |||||
No. 12 anti-CASPR2 AB serum 1 < 2,500, CSF negative, | 70 | 3.6 | 20.8 | Negative | 24% lymphocytes |
75% monocytes | |||||
No. 13 AB neg | 2 | 6.5 | 7.6 | Negative | 52% lymphocytes |
48% monocytes | |||||
No. 14 AB neg | 2 | 3.7 | 5.9 | Negative | 74% lymphocytes |
24% monocytes | |||||
No. 15 AB neg | 1 | 4.2 | 22.2 | Negative | 34% lymphocytes, 44% monocytes |
22% other cells | |||||
No. 16 AB neg | 1 | 2 | 5.5 | Negative | Not done |
No. 17 unspecific neuropil AB serum, AE following HSV encephalitis | 42 | 3.1 | 8.5 | Positive | Not done |
Eight patients (
Patients with suspicion of AE, not fulfilling the criteria for definite AE.
No. 1 | 75 | T2/FLAIR hyperintensity right temporal and left parietal | normal | plasma exchange (5 cycles) followed by prednisolone 1 mg/kg per day p.o. |
gabapentin 1,200 mg per day p.o. | 12 months, seizure free, progressive psychiatric and memory decline |
No. 2 | 61 | T2/FLAIR hyperintensity right mesial temporal | normal | prednisolone 1 mg/kg per day p.o. |
levetiracetam 2,000 mg per day | lost to follow-up |
No. 3 | 67 | contrast enhancement right cingulate gyrus and mesial temporal | intermittent generalized slow and intermittent regional slow right hemisphere | methylprednisolone 1,000 mg per day i.v. for 5 days followed by prednisolone 1 mg/kg per day per os |
phenytoin 200 mg per day, valproate 1,800 mg per day | 6 months, no information about seizure outcome available |
No. 4 | 79 | T2/FLAIR hyperintensity left temporal and insula | intermittent isolated epileptic discharges left frontal and temporal | prednisolone1 mg/kg per day p.o. |
brivaracetam 200 mg per day, phenobarbital 500 mg per day | lost to follow-up |
No. 5 | 41 | T2/FLAIR hyperintensity right insula | continuous generalized slow, continuous rhythmic pattern (sharp waves) over the right hemisphere | methylprednisolone 1,000 mg per day i.v. for 5 days followed by immunoadsorption, plasma exchange (5 cycles) | topiramate 150 mg per day, lacosamide 200 mg per day | 14 months, seizure free |
No. 6 | 61 | T2/FLAIR hyperintensity left mesiotemporal and medial thalamus | intermittent regional slow with left temporal continuous rhythmic pattern | methylprednisolone 1,000 mg per day i.v., followed by prednisolone 1 mg/kg per day p.o. |
phenytoin 350 mg per day, brivaracetam 200 mg per day, lacosamide 400 mg per day | 2 months, status epilepticus |
No. 7 | 80 | T2/FLAIR hyperintensity dorsal thalamus, mesial temporal and insula as well as bilateral occipital | continuous regional slow over the left hemisphere | Prednisolone 1mg/kg per day p.o. |
levetiracetam 3,000 mg per day, lacosamide 200 mg per day, valproate 1,800 mg per day | 48 months, seizure frequency >1/year |
No. 8 | 71 | atrophy left temporopolar and temporomesial | intermittent regional slow over the left hemisphere with continuous rhythmic pattern (sharp waves), generalized slow | prednisolone 1 mg/kg per day p.o. |
levetiracetam 1,000 mg per day, valproate 1,200 mg per day | 70 months, no information about seizure outcome available |
This cohort comprises 208 patients (
Compared with patients with no evidence of AE, those with definite and suspected AE
Intergroup comparison between
Comparison of clinical characteristics between AE cohorts and cohort III.
Age | 67 (61;75) | 75 (66;80) | 0.028 |
Female ( |
8;47 | 113;54 | 0.62 |
mRS | 2 (0;4) | 0 (0;3) | 0.162 |
Status epilepticus ( |
4;24 | 33;15.9 | 0.5 |
Semiology | 0.06 | ||
FIAS ( |
8;47 | 120;58 | |
FAS ( |
4;24 | 15;7.2 | |
GMS ( |
2;12 | 59;28 | |
≥2 ( |
1;6 | 9;4.3 | |
Onset (motor) ( |
5;29 | 114; 55 | 0.13 |
Malignancy (active or known) ( |
8;47 | 35; 16.9 | 0.006 |
EEG | |||
ED ( |
6; 35; | 51;25.4 | 0.393 |
Generalized slowing ( |
4; 24 | 63;31 | 0.594 |
Regional slowing and/or amplitude decrease ( |
6;35 | 44;22 | 0.2311 |
Neuropsychological impairment | |||
Mesial temporal‡ ( |
4; 36 | 3; 3 | 0.0012 |
No cognitive impairment ( |
3;27 | 27;25 | >0.999 |
CSF | |||
CC (> 4/μl) ( |
7; 41 | 13;6 | 0.0002 |
Lactate (> 2.5 mmol/l) ( |
8;47 (1.7;3.1) | 47;23 | 0.0374 |
Total protein (> 500 mg/dl) | 11;65 | 108;52 | 0.45 |
OCB pos ( |
5;29 | 8;4.5 | 0.0012 |
MRI† | <0.00001 |
||
No lesion ( |
5;56 | 134;86 | 0.0315 |
Unilateral lesion ( |
10;59 | 12; 8 | 0.0001 |
Bilateral lesion ( |
0;0 | 0;0 | |
Extratemporal lesion ( |
1; 6 | 9;6 | >0.99 |
A follow-up (FU) was carried out in 59% (
Data for an anti-CASPR2 AB positive patient. The patient had a first epileptic seizure (GMS) 3 months before the diagnosis and recurrent focal seizures until he received monotherapy with Lamotrigin, after which he became seizure-free. The first MRI showed unilateral swelling and T2-hyperintensity in the insula, the hippocampus, temporal mesial, and in the temporal lobe, compatible with possible AE, although not fulfilling the Graus criteria in the absence of neurocognitive or neuropsychiatric deficits. Immunotherapy was initialized after positive testing for anti-CASPR2 AB in serum and CSF. The patient had no clinical signs of AE until last FU; immunotherapy was reinitialized 2 years after diagnosis because of an increased titer of anti-CASPR2 AB in routine clinical FU and a recurrent pleocytosis in CSF. Anti-CASPR2 contactin-associated protein-like 2, GMS generalized motor seizure, MRI magnet resonance imaging, AE autoimmune encephalitis, CSF cerebrospinal fluid, FU follow-up, S Serum, NPS neuropsychological testing, OCB oligoclonal bands, LTG Lamotrigin, MP Methylprednisolon, AZA Azathioprin.
At hospital admission mRS was low (≤2) in the majority of
Modified Rankin scale score (mRS) of patients with definite AE and suspected AE at first hospital admission and FU in comparison with patients with late-onset seizures due to another etiology. Modified Rankin scale at hospital admission was low for patients with definite and suspected AE (71% with mRS ≤2), which decreased to 60% with mRS ≤2 at last FU [mean follow-up time of 40 months (range 6–102)]. Outcome was favorable for non-paraneoplastic and definite AE; outcome in paraneoplastic and suspected AE was worse. However, the generalizability of these study results is limited by the small number of patients. mRS, modified Rankin scale, AE, autoimmune encephalitis, FU, follow-up.
In our cohort, patients with definite and suspected AE comprised 8% of the study population. Definite AE was found in 4% of all patients: all of them had AB in serum and CSF. To our knowledge, this is the largest study aimed at investigating the prevalence and clinical features of AE with late-onset seizures as the first clinical symptom.
Overall information about specific age-related differences of clinical features, treatment, and outcomes of AE is scarce and prospective studies to elucidate this topic are lacking. There is only limited information about AB prevalence in elderly patients. In a patient cohort >60 years of age with no signs of inflammation, the most common antibodies detected were anti-LGI1 AB (31.4%) and anti-IGLON5 AB (28.6%), whereas, anti-NMDAR AB and anti-CASPR2 AB are less common (
Consistent with a previous study showing that 23% of patients aged >60 years with positive AB had no signs of inflammation in their diagnostic work-up (
Magnetic resonance imaging shows that patients with AE as the cause of late-onset seizures often present with unilateral alterations in mesial temporal structures. In our cohort this was the case in 71% of patients. However, although unilateral MRI changes are common in AE, they are a limiting factor for fulfilling the diagnostic criteria proposed by Graus et al. (
Patients with dAE or sAE more frequently showed a pleocytosis and/or OCB in CSF than patients without AE, which is a frequent finding in patients with AE (
Except for faciobrachial dystonic seizures (FBDS) in anti-LGI1 AB encephalitis, no specific semiological features are known to be pathognomonic for AE, even in cases of status epilepticus.
Although not confirmed by our data, an EEG often provides important ways to suspect AE (
One of the most common neural AB detected in this elderly population was anti-CASPR2 AB. Only one of our patients (aged 80 years) presented with anti-NMDAR AB, which is usually found in young females with AE and only rarely (5–12%) in the elderly population (
Escudero et al. (
When we applied the clinical diagnostic criteria from Graus et al. (
Late-onset seizures in non-paraneoplastic AE are known to have a favorable prognosis (
Although randomized controlled trials on IT in AE are lacking, about 70% of AE patients respond to gradual IT escalation (
As most non-paraneoplastic AE patients have a favorable outcome, we suggest using second-line IT only in cases of recurrent disease attacks verified by MRI and/or CSF inflammation.
One major limitation of the study is the single-institutional design, which leads to a limited number of AE cases, further limiting statistical assertions and the possibility of comparing different subgroups (dAE and sAE). In addition, not all patients with AE received an FU investigation as this was not part of the initial study protocol.
To date, there are only limited data available concerning diagnostic strategies, clinical symptoms, treatment, and outcomes of autoimmune encephalitis in the elderly. The results of our study provide clinicians with additional information verified in a great cohort of 225 patients on the prevalence and outcomes of AE as well as predictors of when to suspect AE in patients with late-onset seizures. Although characteristic signs of inflammation in AE may be lacking especially in elderly patients, the presence of CSF and MRI signs of inflammation, mesial temporal neuropsychological alterations, younger age, a known malignancy and specific semiological features (such as FBDS) should suggest AE. An epileptic seizure may be the first symptom of AE. In short, AB testing in CSF and sera, cerebral MRI, lumbar puncture, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late onset seizures. First-line therapy comprises ASD as well as corticosteroids and/or PEX/IA; in view of the potential comorbidity and polypharmacy in the elderly, administration of second-line IT should be considered with caution.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by Institutional review board of the university medicine Greifswald, Germany. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
MS analyzed the data, interpreted the data, drafted the manuscript, and revised the manuscript for intellectual content. MZ had a major role in the acquisition and analysis of the data. VP revised the manuscript for intellectual content and interpreted the data. FP revised the manuscript for intellectual content and design and conceptualized the study. All authors contributed to the article and approved the submitted version.
MS reports personal fees and grants from Merck Healthcare Deutschland and Bayer Vital GmbH. FP obtained honoraria for speaking engagements from Desitin Pharma (Hamburg, Germany), EISAI Pharma (Frankfurt am Main, Germany), UCB Pharma (Monheim, Germany), BIAL (Mörfelden-Walldorf, Germany), and GW Pharma (München, Germany) and was part of the speakers bureau of Desitin Pharma (Hamburg, Germany), EISAI Pharma (Frankfurt am Main, Germany), UCB Pharma (Monheim, Germany), BIAL (Mörfelden-Walldorf, Germany), and GW Pharma (München, Germany). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We gratefully acknowledge the assistance of Dr. Michael Opolka for providing detailed neuropsychological test results as well as Roman Schimmer for proofreading and language revision. We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 393148499) and the Open Access Publication Fund of the University of Greifswald.
The Supplementary Material for this article can be found online at: