Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neurology
Published in: Journal of Neurology 2/2021

Open Access 01-02-2021 | Magnetic Resonance Imaging | Original Communication

Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis

Authors: Christoph Helmstaedter, Niels Hansen, Pitshaporn Leelaarporn, Kerstin Schwing, Demet Oender, Guido Widman, Attila Racz, Rainer Surges, Albert Becker, Juri-Alexander Witt

Published in: Journal of Neurology | Issue 2/2021

Login to get access

Abstract

Objective

Neuropsychological impairments are major symptoms of autoimmune limbic encephalitis (LE) epilepsy patients. In LE epilepsy patients with an autoimmune response against intracellular antigens as well as in antibody-negative patients, the antibody findings and magnetic resonance imaging pathology correspond poorly to the clinical features. Here, we evaluated whether T- and B-cells are linked to cognitive impairment in these groups.

Methods

In this cross-sectional, observational, case–controlled study, we evaluated 106 patients with adult-onset epilepsies with a suspected autoimmune etiology. We assessed verbal and visual memory, executive function, and mood in relation to the presence or absence of known auto-antibodies, and regarding T- and B-cell activity as indicated by flow cytometry (fluorescence-activated cell sorting = FACS, peripheral blood = PB and cerebrospinal fluid = CSF).

Results

56% of the patients were antibody-negative. In the other patients, auto-antibodies were directed against intracellular antigens (GAD65, paraneoplastic: 38%), or cellular surface antigens (LGI1/CASPR2/NMDA-R: 6%). Excluding LGI1/CASPR2/NMDA-R, the groups with and without antibodies did not differ in disease features, cognition, or mood. CD4+ T-cells and CD8+ T-cells in blood and CD4+ T-cells in CSF were prominent in the auto-antibody positive group. Regression analyses indicated the role education, drug load, amygdala and/or hippocampal pathology, and CD4+ T-cells play in verbal memory and executive function. Depressed mood revealed no relation to flow cytometry results.

Conclusion

Our results indicate a link between T- and B-cell activity and cognition in epilepsy patients with suspected limbic encephalitis, thus suggesting that flow cytometry results can provide an understanding of cognitive impairment in LE patients with autoantibodies against intracellular antigens.
Literature
1.
Adam VN, Budincevic H, Mrsic V, Stojcic EG, Matolic M, Markic A (2013) Paraneoplastic limbic encephalitis in a patient with adenocarcinoma of the colon: a case report. J Clin Anesth 25:491–495PubMed
2.
Argyropoulos GPD, Moore L, Loane C, Roca-Fernandez A, Lage-Martinez C, Gurau O, Irani SR, Zeman A, Butler CR (2020) Pathologic tearfulness after limbic encephalitis: a novel disorder and its neural basis. Neurology 20:20
3.
Beck A, Steer R (1987) Beck depression inventory manual. Psychological Corporation, San Antonio
4.
Britton JW, Dalmau J (2019) Recognizing autoimmune encephalitis as a cause of seizures: treating cause and not effect. Neurology 92:877–878PubMed
5.
Butler CR, Miller TD, Kaur MS, Baker IW, Boothroyd GD, Illman NA, Rosenthal CR, Vincent A, Buckley CJ (2014) Persistent anterograde amnesia following limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex. J Neurol Neurosurg Psychiatry 85:387–391PubMed
6.
Doelken MT, Mennecke A, Huppertz HJ, Rampp S, Lukacs E, Kasper BS, Kuwert T, Ritt P, Doerfler A, Stefan H, Hammen T (2012) Multimodality approach in cryptogenic epilepsy with focus on morphometric 3T MRI. J Neuroradiol 39:87–96PubMed
7.
Elger CE, Helmstaedter C, Kurthen M (2004) Chronic epilepsy and cognition. Lancet Neurol 3:663–672PubMed
8.
9.
Finke C, Kopp UA, Pajkert A, Behrens JR, Leypoldt F, Wuerfel JT, Ploner CJ, Pruss H, Paul F (2016) Structural hippocampal damage following anti-N-methyl-d-aspartate receptor encephalitis. Biol Psychiatry 79:727–734PubMed
10.
Frisch C, Hanke J, Kleineruschkamp S, Roske S, Kaaden S, Elger CE, Schramm J, Yilmazer-Hanke DM, Helmstaedter C (2009) Positive correlation between the density of neuropeptide y positive neurons in the amygdala and parameters of self-reported anxiety and depression in mesiotemporal lobe epilepsy patients. Biol Psychiatry 66:433–440PubMed
11.
Frisch C, Malter MP, Elger CE, Helmstaedter C (2013) Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis. Eur J Neurol 20:1297–1304PubMed
12.
13.
Golombeck KS, Bonte K, Monig C, van Loo KM, Hartwig M, Schwindt W, Widman G, Lindenau M, Becker AJ, Glatzel M, Elger CE, Wiendl H, Meuth SG, Lohmann H, Gross CC, Melzer N (2016) Evidence of a pathogenic role for CD8(+) T cells in anti-GABAB receptor limbic encephalitis. Neurol Neuroimmunol Neuroinflamm 3:e232PubMedPubMedCentral
14.
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404PubMedPubMedCentral
15.
Hansen N, Ernst L, Ruber T, Widman G, Becker AJ, Elger CE, Helmstaedter C (2018) Pre- and long-term postoperative courses of hippocampus-associated memory impairment in epilepsy patients with antibody-associated limbic encephalitis and selective amygdalohippocampectomy. Epilepsy Behav 79:93–99PubMed
16.
Hansen N, Schwing K, Onder D, Widman G, Leelaarporn P, Prusseit I, Surges R, Melzer N, Gross C, Becker AJ, Witt JA, Elger CE, Helmstaedter C (2020) Low CSF CD4/CD8+ T-cell proportions are associated with blood-CSF barrier dysfunction in limbic encephalitis. Epilepsy Behav 102:106682PubMed
17.
Hansen N, Widman G, Schwing K, Leelaarporn P, Onder D, Prusseit I, Surges R, Becker AJ, Witt JA, Helmstaedter C, Elger CE (2020) CD19+B-cells contribute to auto-antibody-negative limbic encephalitis. Epilepsy Behav 20:20
18.
Hansen N, Widman G, Stuff S, Becker AJ, Witt JA, Ahmadzadehfar H, Helmstaedter C, Elger CE (2018) Cancer frequency detected by positron emission tomography-computed tomography in limbic encephalitis. Epilepsy Behav 89:105–111PubMed
19.
Hansen N, Widman G, Witt JA, Wagner J, Becker AJ, Elger CE, Helmstaedter C (2016) Seizure control and cognitive improvement via immunotherapy in late onset epilepsy patients with paraneoplastic versus GAD65 autoantibody-associated limbic encephalitis. Epilepsy Behav 65:18–24PubMed
20.
Helmstaedter C (2002) Effects of chronic epilepsy on declarative memory systems. Prog Brain Res 135:439–453PubMed
21.
Helmstaedter C, Lendt M, Lux S (2001) VLMT Verbaler Lern- und Merkfähigkeitstest. Beltz Test GmbH, Göttingen
22.
Helmstaedter C, Pohl C, Hufnagel A, Elger CE (1991) Visual learning deficits in nonresected patients with right temporal lobe epilepsy. Cortex 27:547–555PubMed
23.
Helmstaedter C, Winter B, Melzer N, Lohmann H, Witt JA (2019) Accelerated long-term forgetting in focal epilepsies with special consideration given to patients with diagnosed and suspected limbic encephalitis. Cortex 110:58–68PubMed
24.
Helmstaedter C, Witt JA (2012) Clinical neuropsychology in epilepsy: theoretical and practical issues. Handb Clin Neurol 107:437–459PubMed
25.
Heming M, Lohmann L, Schulte-Mecklenbeck A, Brix T, Gross CC, Wiendl H, Klotz L, Meyer Z, Horste G (2020) Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis. J Neuroimmunol 341:577171PubMed
26.
Heming M, Schulte-Mecklenbeck A, Brix T, Wolbert J, Ruland T, Klotz L, Meuth SG, Gross CC, Wiendl H, Meyer Z, Horste G (2019) Immune cell profiling of the cerebrospinal fluid provides pathogenetic insights into inflammatory neuropathies. Front Immunol 10:515PubMedPubMedCentral
27.
Hermetter C, Fazekas F, Hochmeister S (2018) Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis. Front Neurol 9:706PubMedPubMedCentral
28.
Kay L, Bauer S, Koczulla AR, Librizzi D, Vadasz D, Knake S, Rosenow F, Strzelczyk A (2018) Ondine's curse and temporal lobe seizures: anti-Hu- and Zic4-associated paraneoplastic brainstem and limbic encephalitis. Eur J Neurol 25:e59–e60PubMed
29.
Kunstreich M, Kreth JH, Oommen PT, Schaper J, Karenfort M, Aktas O, Tibussek D, Distelmaier F, Borkhardt A, Kuhlen M (2017) Paraneoplastic limbic encephalitis with SOX1 and PCA2 antibodies and relapsing neurological symptoms in an adolescent with Hodgkin lymphoma. Eur J Paediatr Neurol 21:661–665PubMed
30.
Lamberti G, Weidlich S (1999) DCS: a visual learning and memory test for neuropsychological assessment. Hogrefe and Huber Publishers, Göttingen
31.
Lutz MT, Helmstaedter C (2005) EpiTrack: tracking cognitive side effects of medication on attention and executive functions in patients with epilepsy. Epilepsy Behav 7:708–714PubMed
32.
Lux S, Helmstaedter C, Elger CE (1999) Normative study on the "Verbaler Lern- und Merkfahigkeitstest" (VLMT). Diagnostica 45:205–211
33.
Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470–478PubMed
34.
Malter MP, Widman G, Galldiks N, Stoecker W, Helmstaedter C, Elger CE, Wagner J (2016) Suspected new-onset autoimmune temporal lobe epilepsy with amygdala enlargement. Epilepsia 57:1485–1494PubMed
35.
Miller TD, Chong TT, Aimola Davies AM, Ng TWC, Johnson MR, Irani SR, Vincent A, Husain M, Jacob S, Maddison P, Kennard C, Gowland PA, Rosenthal CR (2017) Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis. Brain 140:1212–1219PubMedPubMedCentral
36.
Mitchell AN, Bakhos CT, Zimmerman EA (2015) Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma. J Clin Neurosci 22:421–423PubMed
37.
Monstad SE, Nostbakken JK, Vedeler CA (2009) CRMP5 antibodies found in a patient with limbic encephalitis and myasthenia gravis. J Neurol Neurosurg Psychiatry 80:241–242PubMed
38.
Ortega Suero G, Sola-Valls N, Escudero D, Saiz A, Graus F (2018) Anti-Ma and anti-Ma2-associated paraneoplastic neurological syndromes. Neurologia 33:18–27PubMed
39.
Pitsch J, Kamalizade D, Braun A, Kuehn JC, Gulakova PE, Rueber T, Lubec G, Dietrich D, von Wrede R, Helmstaedter C, Surges R, Elger CE, Hattingen E, Vatter H, Schoch S, Becker AJ (2020) Drebrin autoantibodies in patients with seizures and suspected encephalitis. Ann Neurol 20:20
40.
Scharf M, Miske R, Heidenreich F, Giess R, Landwehr P, Blocker IM, Begemann N, Denno Y, Tiede S, Dahnrich C, Schlumberger W, Unger M, Teegen B, Stocker W, Probst C, Komorowski L (2015) Neuronal Na+/K+ ATPase is an autoantibody target in paraneoplastic neurologic syndrome. Neurology 84:1673–1679PubMed
41.
Schroder O, Schriewer E, Golombeck KS, Kurten J, Lohmann H, Schwindt W, Wiendl H, Bruchmann M, Melzer N, Straube T (2015) Impaired autonomic responses to emotional stimuli in autoimmune limbic encephalitis. Front Neurol 6:250PubMedPubMedCentral
42.
Steriade C, Britton J, Dale RC, Gadoth A, Irani SR, Linnoila J, McKeon A, Shao XQ, Venegas V, Bien CG (2020) Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 20:20
43.
Tuzun E, Dalmau J (2007) Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist 13:261–271PubMed
44.
Urbach H, Rauer S, Mader I, Paus S, Wagner J, Malter MP, Pruss H, Lewerenz J, Kassubek J, Hegen H, Auer M, Deisenhammer F, Ufer F, Bien CG, Baumgartner A (2015) Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis. Neuroradiology 57:1203–1209PubMed
45.
von Rhein B, Wagner J, Widman G, Malter MP, Elger CE, Helmstaedter C (2017) Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy. Acta Neurol Scand 135:134–141
46.
Wagner-Altendorf TA, Wandinger KP, Frydrychowicz A, Merseburger AS, Munte TF (2019) Anti-Amphiphysin-associated limbic encephalitis in a 72-year-old patient with aortic angiosarcoma. BMJ Case Rep 12:20
47.
Wagner J, Schoene-Bake JC, Malter MP, Urbach H, Huppertz HJ, Elger CE, Weber B (2013) Quantitative FLAIR analysis indicates predominant affection of the amygdala in antibody-associated limbic encephalitis. Epilepsia 54:1679–1687PubMed
48.
Wagner J, Schoene-Bake JC, Witt JA, Helmstaedter C, Malter MP, Stoecker W, Probst C, Weber B, Elger CE (2016) Distinct white matter integrity in glutamic acid decarboxylase and voltage-gated potassium channel-complex antibody-associated limbic encephalitis. Epilepsia 57:475–483PubMed
49.
Wagner J, Witt JA, Helmstaedter C, Malter MP, Weber B, Elger CE (2015) Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis. J Neurol Neurosurg Psychiatry 86:735–742PubMed
50.
Widman G, Golombeck K, Hautzel H, Gross CC, Quesada CM, Witt JA, Rota-Kops E, Ermert J, Greschus S, Surges R, Helmstaedter C, Wiendl H, Melzer N, Elger CE (2015) Treating a GAD65 antibody-associated limbic encephalitis with basiliximab: a case study. Front Neurol 6:167PubMedPubMedCentral
51.
Widman G, Schulte-Mecklenbeck A, Witt J, Dik A, Pitsch J, Golembeck KS, Wagner J, Moenig C, Strippel C, Johnen A, Kuhlmann T, Wiendl H, Elger CE, Meuth SG, Helmstaedter C, Gross C, Becker AJ, Melzer N (2018) CD8+ T cell-mediated epileptic neurodegeneration in limbic encephalitis associated with glutamic acid decarboxylase autoantibodies
52.
Witt JA, Coras R, Becker AJ, Elger CE, Blumcke I, Helmstaedter C (2019) When does conscious memory become dependent on the hippocampus? The role of memory load and the differential relevance of left hippocampal integrity for short- and long-term aspects of verbal memory performance. Brain Struct Funct 224:1599–1607PubMed
53.
Witt JA, Coras R, Schramm J, Becker AJ, Elger CE, Blumcke I, Helmstaedter C (2014) The overall pathological status of the left hippocampus determines preoperative verbal memory performance in left mesial temporal lobe epilepsy. Hippocampus 24:446–454PubMed
54.
Witt JA, Helmstaedter C (2017) Cognition in epilepsy: current clinical issues of interest. Curr Opin Neurol 30:174–179PubMed
55.
Witt JA, Helmstaedter C (2013) Monitoring the cognitive effects of antiepileptic pharmacotherapy–approaching the individual patient. Epilepsy Behav 26:450–456PubMed
56.
Witt JA, Helmstaedter C (2012) Should cognition be screened in new-onset epilepsies? A study in 247 untreated patients. J Neurol 259:1727–1731PubMed
57.
Witt JA, Vogt VL, Widman G, Langen KJ, Elger CE, Helmstaedter C (2015) Loss of autonoetic awareness of recent autobiographical episodes and accelerated long-term forgetting in a patient with previously unrecognized glutamic acid decarboxylase antibody related limbic encephalitis. Front Neurol 6:130PubMedPubMedCentral
58.
Witt JA, Werhahn KJ, Kramer G, Ruckes C, Trinka E, Helmstaedter C (2014) Cognitive-behavioral screening in elderly patients with new-onset epilepsy before treatment. Acta Neurol Scand 130:172–177PubMed
Metadata
Title
Specific B- and T-cell populations are associated with cognition in patients with epilepsy and antibody positive and negative suspected limbic encephalitis
Authors
Christoph Helmstaedter
Niels Hansen
Pitshaporn Leelaarporn
Kerstin Schwing
Demet Oender
Guido Widman
Attila Racz
Rainer Surges
Albert Becker
Juri-Alexander Witt
Publication date
01-02-2021
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 2/2021
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-020-10158-1

Other articles of this Issue 2/2021

Journal of Neurology 2/2021 Go to the issue

Original Communication

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis

Original Communication

Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension

Original Communication

Does pallidal neuromodulation influence cognitive decline in Huntington’s disease?

Correction

Correction to: Utility of the Parkinson’s disease-Cognitive Rating Scale for the screening of global cognitive status in Huntington’s disease

Original Communication

Estimating the relative contribution of comorbidities in predicting health-related quality of life of people with multiple sclerosis

Original Communication

Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation