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Autoimmune Encephalitis

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Immunoglobulins

Cohort of patients with a CASPR2 antibody-associated auto-immune encephalitis.

Defining the initial clinical symptoms and those leading to the diagnosis of CASPR2 antibody associated encephalitis. For that, we will investigate the initial cognitive status, the initial neuropsychological investigations the clinical presentation of the first seizures, and the prodromes assessed by patients at the beginning of their disease. We will also look at the initial EEG records, in order to acknowledge whether the initial cognitive symptoms may be due to unseen seizures.

CASPR2 encephalitis

Jérôme HONNORAT, Pr

Auto-immune encephalitides involve auto-antibodies targeting the central nervous system, and particularly the synapse and its structure, such as protein CASPR2.

CASPR2 antibody-associated auto-immune encephalitides lead to an inflammation of the limbic system and generate focal temporal seizures and cognitive impairment. Most patients are initially hospitalized because of the temporal seizures (Joubert et al., JAMA Neurology 2016). However, many already show at that time cognitive impairment, which has failed to elicit the appropriate investigations, therefore delaying the diagnosis.

The study will hence investigate precisely the initial, sometimes neglected, clinical symptoms and those leading to the diagnosis, in the cohort of patients suffering from a CASPR2 antibody-associated encephalitis, from the French reference center on paraneoplastic neurological diseases and autoimmune encephalitis.

This way, the study aims to delineate the symptoms that should trigger suspicions of a CASPR2 antibody-associated encephalitis

CASPR2 Encephalitis Initial Symptoms

Defining the Initial Clinical Symptoms and Characterizing Those Leading to the Discovery of CASPR2

The retained information will depend on the very first declared symptom: if the patient first showed focal seizures, we will precise the clinical presentation of this seizure. On the other hand, if the patient first showed cognitive symptoms, we will best define this impairment.

Hospices Civils de Lyon

Amino Acids

Antibodies, Antinuclear

N-Methylaspartate

gamma-Aminobutyric Acid

Aspartic Acid

Glutamic Acid

Cancer patients with Paraneoplastic neurological syndromes presenting various autoimmune anomalies:

* Anti-Hu also known as anti-Neuron specific cell Nuclear Antibodies (anti-ANNA1) (350 patients), uncommon form of brain inflammation associated with an underlying cancer
* anti-Yo (130 patients), antibody associated with paraneoplastic cerebellar degeneration
* anti-Ma2 (50 patients), antibody associated with paraneoplastic encephalitis
* anti-N-methyl-d-aspartate (NMDA) Receptor (350 patients), autoimmune disorder in which antibodies attack N-methyl-D-aspartate-type glutamate receptors
* anti-gamma-aminobutyric acid-B (GABAb) receptor (35 patients), autoimmune disorder in which antibodies attack gamma-aminobutyric acid-B receptors
* anti-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor (15 patients), autoimmune disorder in which antibodies attack alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors
* without antibodies (50 patients).

Jerome HONNORAT, PhD

Paraneoplastic neurological syndromes (PNS) are immune-mediated complications of cancer that can affect any part of the central or peripheral nervous system.

PNS occurs at the intersection between immune system and the tumor, where a combination of genetical and environmental factors may play a role.

Mechanisms leading to immune tolerance breakdown and autoimmunity in PNS remain largely unknown, and this reflects in an unsatisfactory repertoire of treatments available. Moreover, a better understanding of the biological mechanisms underlying PNS would allow a more precise identification of the modalities that permit PNS patients to have a better oncological prognosis than cancer patient without PNS, with obvious repercussions in clinical oncology.

To this effect, an extremely innovative approach involves directly exploring the tumoral tissue of patients suffering from specific PNS via genomic and transcriptomic analysis.

The study team hypothesizes that antigen ectopic expression by tumour cells may contribute to the generation of PNS.

In the present study, the investigators will analyze the salient features of tumors associated with PNS, namely the histological and immune cells infiltrate characteristics, their transcriptomic profile, and mutational status of involved antigens.

Tumor Characteristics in Patients With Paraneoplastic Neurological Syndromes (PNS)

Genomic Profile and Tumor Immune Attack in Paraneoplastic Neurological Syndromes (PNS)

Genetic alterations in tumors associated with Paraneoplastic neurological syndromes (PNS)

Histological immune infiltrate characteristics

Anti-Inflammatory Agents

Antineoplastic Agents

Prednisone

Immunomodulating Agents

Tacrolimus

Immunosuppressive Agents

Immunologic Factors

Calcineurin Inhibitors

Enzyme Inhibitors

Tacrolimus at doses of 0.15- 0.3mg/kg/day in two divided oral doses, in conjunction with, initially, up to 60mg/day of oral prednisone

Robert Darnell, MD, PhD

We treat a subset of patients with paraneoplastic neurologic disorders, including those with Yo-mediated paraneoplastic cerebellar degeneration (PCD), the Hu syndrome, which is most commonly associated with small cell lung cancer (SCLC) - paraneoplastic subacute sensory neuropathy, encephalomyelitis, limbic encephalopathy, autonomic neuropathy - and the Ri Syndrome (a.k.a. Paraneoplastic Opsoclonus-Myoclonus Ataxia), as well as those patients suspected to have a paraneoplastic neurologic disorder but in whom a characteristic antibody has not yet been identified. Our treatment protocol consists of immune suppression therapy using tacrolimus (FK506), a potent inhibitor of lymphocyte proliferation that is commonly used to prevent organ transplant rejection.

Patients may stay either in-hospital while being treated with Tacrolimus, receive treatment as an outpatient, or a combination of the two. Additionally, patients who are too sick to be treated at Rockefeller University (RU) (eg. patients actively seizing), but are in need of urgent treatment, may be treated at either Memorial Sloan-Kettering Cancer Center or New York-Presbyterian Hospital. During treatment, patients will undergo blood draws, at set intervals (see section g below), clinical evaluation, possibly repeat leukapheresis or large volume blood draw, and lumbar puncture (see below). Since many patients live far away from New York, some of these procedures may be performed by RU staff or in conjunction with their local MDs.

Patients who are terminated from Tacrolimus treatment after 7-21 days will be followed up as outpatients for evaluation of their neurologic and medical status. Wherever possible, these patients will be seen on days 3 and 10 post treatment termination, and then on a biweekly basis for two months. Since many patients live far away from New York, they may instead be monitored in conjunction with their local MDs. Patients who show a definite clinical response to Tacrolimus may be maintained on a therapeutic dose for up to one year, and will be followed as outpatients. For patients receiving retreatment, they may be treated as inpatients or on an outpatient basis, at the discretion of the PI, on the same schedule as patients being treated initially. Long term improvement or decline in neurologic function will be objectively assessed by neurologic exam, which will be quantified by use of the Karnofsky scale (a measure of functional neurologic status). Since the vast majority of Hu patients decline over a 6-12 month period following diagnosis, a stable or improved Karnofsky score over such a time period will be taken as a measure of successful treatment. Repeat lumbar puncture (up to eight per year) and leukapheresis or large volume blood draw (approx. 100 cc) may be performed (up to four of each per year), especially in the setting of neurologic change, to assess the immune responses to the medications.

Immunotherapy of the Paraneoplastic Syndromes

Survival in patients with paraneoplastic disease who are treated with Tacrolimus, from time of tacrolimus treatment

Rockefeller University

All Patients

Age, Continuous

Sex: Female, Male

Robert B. Darnell, MD, PhD

White blood cell (WBC) count in CSF pre-treatment

Pre-treatment

White blood cell (WBC) count in CSF post-treatment

Post-treatment

19 treatment events in 16 patients at which both pre- and post-treatment CSF samples available.

The data are reported below, separately for pre-treatment samples and post-treatment samples.

Cerebrospinal Fluid (CSF) Pleocytosis

Tacrolimus at doses of 0.15-0.3mg/kg/day in two divided oral doses, in conjunction with, initially, up to 60mg/day of oral prednisone

Survival of Patients With Paraneoplastic Disease Who Are Treated With Tacrolimus

Overall Study

Substance Related Disorders

Neurotoxicity Syndromes

Poisoning

Chemically-Induced Disorders

Immune Checkpoint Inhibitors

Patients treated with ICIs who developed neurologic syndromes consistent with NirAEs, of grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE)

This is a non-interventional study. We will collect clinical data exclusively, and will do so by reviewing all available patients clinical records.

Immune-checkpoint inhibitors (ICIs) have radically changed the therapy of cancer in recent years. ICIs promote antitumor immune response inhibiting one of the following immune checkpoints: cytotoxic T-lymphocyte antigen-4 (CTLA-4; ipilimumab), programmed death-1 (PD-1: pembrolizumab, nivolumab, and cemiplimab), and programmed death ligand-1 (PD-L1: atezolizumab, durvalumab, and avelumab). Despite the desired effect as cancer treatment, ICIs can break immune tolerance to self-antigens and induce specific toxicities known as immune-related adverse events (irAEs), that may affect both peripheral and central nervous system (Neurological immune mediated adverse events, NirAEs). The pathogenic mechanisms underlying NirAEs are probably heterogeneous, as reflected by the variety of clinical phenotypes and severity.

NirAEs are rare, but there is some concern that the incidence may increase in the next future, in particular because ICIs are being used more and more for cancers commonly associated with paraneoplastic neurological syndromes (e.g. small-cell lung cancer). Moreover, NirAEs are usually severe, and often fatal. Indeed, irAEs-related complications are the most common cause of death among these patients. On the other hand, these patients usually have a good tumor response to immunotherapy. There is some evidence that irAEs may predict ICIs efficacy and consequently NirAE surivors are likely to have longer life expectancy than non-NirAE patients.

Therefore, it is of utmost importance to better characterize the long-term outcomes of NirAE patients in terms of neurologic disability and mortality, and to identify predictors of severe NirAEs. So far, only few studies with sufficient follow-up have been published on the topic, and they included only small number of patients.

The aims of our study is to characterize the main clinical and paraclinical features of NirAEs in a large cohort of NirAE patients, to assess long-term outcomes and to identify prognostic factors. This study will help define new guidelines regarding NirAE prediction and management.

CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.

Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.

Evaluation of residual neurological disability as assessed by the modified Rankin scale (mRS)

0 - No symptoms.

1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
3. - Moderate disability. Requires some help, but able to walk unassisted.
4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
6. - Dead.

Paraneoplastic Syndromes, Nervous System

Nervous System Neoplasms

Neurodegenerative Diseases

Robert Darnell, MD, PHD

The investigators believe that T cells, cells that are a part of the immune system, are what are causing the neurological problems while also attacking tumor cells. This protocol studies the clinical status of patients with paraneoplastic neurological disorder (PND) as well as their blood to understand the relationship between their neurological disease, their cancer, and their immune system.

Patients with paraneoplastic neurological disorders (PNDs) provide a unique model for studying tumor immunity and neuronal autoimmunity. We hypothesize that T lymphocyte autoimmune dysfunction is involved in the pathogenesis of the paraneoplastic neurological syndromes, and that killer T cells are involved in the targeting and successful killing of tumor cells in these cancer patients. Furthermore, we postulate that this activity may provide a model for autoimmune brain disease. We will assess the immune responses in PND patients, correlate these with the clinical data (time course of disease, symptoms and signs, disability), and collect and archive clinical data, serum and cells from PND patients for current and future studies into the basic immune system phenomenon present in PND patients.

The Study of Immune Cell (T Cell) Activity in Patients With Paraneoplastic Neurologic Syndromes

Killer T Cell Activity in the Paraneoplastic Neurologic Syndromes

Immune System Diseases

Autoimmune Diseases

Autoimmune Diseases of the Nervous System

This is a non-interventional study involving biological samples. Samples are already stored in biobank repositories and collected as part of "good clinical practice" in the diagnostic process of patients with suspected autoimmune encephalitis, meaning that the standard diagnostic and therapeutic approaches will not be altered in the selected study population. Patients have already gave explicit written consent for biological specimens sampling and storage at the "Centre de Ressources Biologiques des Hospices Civils de Lyon" (CRB-HCL) (including tissue, cells or biological fluids).

Tests can be used: immunofluorescence, immunodot, western blot, tests CBA on sera or CSF.

Diagnosis test

Paraneoplastic neurological syndromes (PNS) are rare complications of cancer occurring in 0.01% of cases. Their clinical, biological and radiological presentation is heterogeneous and may constitute a diagnostic challenge. Anti-Ma2 PNS are rare diseases with a guarded prognosis. They are most often associated with a seminoma-like testicular tumor but can also be associated with lung cancer. Classically, they present as limbic, diencephalic and/or brainstem encephalitis. Anti-Ma2 antibodies target intracellular receptors and are characteristic of a particular form of encephalitis. Atypical manifestations including narcolepsy-cataplexy, weight gain, sexual dysfunction and motor neuron syndrome have been described and explain the difficulty in diagnosing anti-Ma2 associated PNS. It seems interesting to better characterize the phenotypes of Ma2 patients in order to optimize the diagnosis and follow-up.

Sera, blood, DNA, CSF collected at diagnosis time

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CASPR2 Encephalitis Initial Symptoms	NCT04653571	CASPR2-Antibody Encephalitis Au... Paraneoplastic ...	CASPR2 encephal...	18 Years -	Hospices Civils de Lyon
Tumor Characteristics in Patients With Paraneoplastic Neurological Syndromes (PNS)	NCT03963700	Cancer Paraneoplastic ... Neurologic Diso... Immune System a... Tumor Genetics		18 Years - 100 Years	Hospices Civils de Lyon
Immunotherapy of the Paraneoplastic Syndromes	NCT00378326	Paraneoplastic ...	Tacrolimus	14 Years -	Rockefeller University
CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.	NCT05942872	Paraneoplastic ...	This is a non-i...	18 Years -	Hospices Civils de Lyon
The Study of Immune Cell (T Cell) Activity in Patients With Paraneoplastic Neurologic Syndromes	NCT00327236	Paraneoplastic ...		1 Year -	Rockefeller University
CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.	NCT05942872	Paraneoplastic ...	This is a non-i...	18 Years -	Hospices Civils de Lyon
CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.	NCT05942872	Paraneoplastic ...	This is a non-i...	18 Years -	Hospices Civils de Lyon
The Study of Immune Cell (T Cell) Activity in Patients With Paraneoplastic Neurologic Syndromes	NCT00327236	Paraneoplastic ...		1 Year -	Rockefeller University
Characterisation of Clinical Phenotypes and Outcomes of Ma2 Patient	NCT05645185	Autoimmune Ence... Paraneoplastic ...	Diagnosis test	18 Years -	Hospices Civils de Lyon

Spots Global Cancer Trial Database for paraneoplastic syndromes