Auswahl der wissenschaftlichen Literatur zum Thema „Paraneoplastic cerebellar degeneration“

Introduction. Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated and rapidly progressive cerebellar syndrome that develops as a result of a cross-immune response to the common antigens for the tumor and cerebellar cells. Timely diagnosis and treatment of PCD improves the functional status and survival of these patients.Objective. To analyze the clinical, laboratory and neuroimaging characteristics of PCD case series in comparison with literature data.Material and methods. 16 patients with PCD (13 women, 3 men) were examined. An assessment of the clinical presentation, brain MRI study, blood and cerebrospinal fl uid laboratory tests were carried out, the data of cancer search and patients follow-up were analyzed.Results. The median age of PCD patients was 55 years, the duration of the disease was 8.5 months (range 4 to 16 months). In 12 patients, PCD was the fi rst manifestation of cancer. The clinical prentation was presented by rapidly progressive cerebellar ataxia, often in combination with oculomotor disturbances, pyramidal and bulbar syndrome, hand tremor and dystonia. An associated cancers were detected in 13 patients (81%). Antineuronal antibodies were found in 14 patients (88%): anti-Yo-1, antibodies to amphiphysin, anti-Hu, anti-CV2 and anti-GAD. Mild atrophic changes of the cerebellum were found in 6 patients, and in 2 cases cerebellar hemiatrophy was observed.Conclusion. PCD is a rare disabling but potentially curable disease. The basis of diagnosis is the analysis of the clinical presentation and neuroimaging data, the detection of antineuronal antibodies and in fl ammatory changes in the cerebrospinal fl uid, as well as a thorough cancer search.

ObjectiveInvestigate the value of including cerebellar degeneration-related protein 2-like (CDR2L) as a marker in commercial diagnostic tests for anti-Yo–associated paraneoplastic cerebellar degeneration (PCD).MethodsWe included sera and CSF samples from 24 patients with suspected PCD (6 of whom had PCD with underlying gynecologic or breast cancer), who were positive for Yo antibodies using the commercially available, paraneoplastic neurologic syndromes (PNS) 14 Line Assay from Ravo Diagnostika. The samples were further evaluated using the EUROLINE PNS 12 Ag Line Assay and a cell-based assay (CBA) from Euroimmun. For confirmation of positive lineblot results, we used indirect immunofluorescence of rat cerebellar sections. We also tested all samples in 2 assays developed in-house: a CBA for CDR2L and a Western blot analysis using recombinant cerebellar degeneration-related protein 2 (CDR2) and CDR2L proteins.ResultsIn PNS 14 and PNS 12 Ag Line Assays, anti-CDR2 reactivity was observed for 24 (100%) and 20 (83%) of the 24 samples, respectively. Thirteen of 24 subjects (54%) were also positive using the Euroimmun CBA. Rat cerebellar immunofluorescence was the best confirmatory test. In our in-house CBA for CDR2L and Western blot for CDR2 and CDR2L, only the 6 patients with confirmed PCD reacted with CDR2L.ConclusionsCommercially available tests for Yo antibody detection have low specificity for PCD because these assays use CDR2 as antigen. By adding a test for CDR2L, which is the major Yo antigen, the accuracy of PCD diagnosis greatly improved.Classification of EvidenceThis study provides Class III evidence that a CBA for CDR2L accurately identifies patients with PCD.

ABSTRACT:Paraneoplastic cerebellar degeneration is a rare complication of a number of cancers, particularly small cell lung cancer, gynecologic cancers and Hodgkin’s disease. The disorder is clinically characterized by rapid development of pancerebellar dysfunction, which usually does not improve, and pathologically characterized by loss of Purkinje cells with or without inflammatory infiltrates. In some but not all patients, an autoantibody that reacts with the tumor and Purkinje cells can be found in the serum and spinal fluid of patients with paraneoplastic cerebellar degeneration. The presence of the autoantibody suggests, but does not prove, that the disorder has an autoimmune mechanism for its pathogenesis.

Abstract Enhancement has been occasionally reported in patients with paraneoplastic cerebellar degeneration but metastases can also occur in these patients and standard imaging and cerebrospinal cytology lack sensitivity and specificity. Among a retrospective case series of 31 patients with paraneoplastic cerebellar degeneration, 4 patients had enhancement at some point of their MRI. We report a series of four patients with paraneoplastic cerebellar degeneration with enhancement and possible concurrent or subsequent leptomeningeal metastases and review the literature. Patient 1 was a 66 year old man with merkel cell carcinoma who had subacute onset of ataxia with nausea. Initial MRI showed non enhancement cerebellar FLAIR changes. Paraneoplastic panel was negative in blood and CSF and seronegative PCD was diagnosed without response to immunosuppression. Eight months later he developed progressive cerebellar symptoms and diffuse leptomeningeal enhancement was found in the cerebellum and spine consistent with leptomeningeal metastates. Patient 2 is a 50 year old woman with HER2+ breast cancer who developed acute cerebellar symptoms with focal cerebellar enhancement and PCA1 antibody was present. Her symptoms stabilized with immune suppression and enhancement resolved, but CSF showed atypical cells suggestive of concurrent leptomeningeal metastases. Patients 3 and 4 both had serous ovarian carcinoma and subacute onset of cerebellar symptoms with cerebellar enhancement and PCA1 antibody with negative CSF cytology. Both stabilized with immune suppression but within months developed more diffuse widespread CNS nodular enhancement considered to be leptomeningeal enhancement. Enhancement is uncommon but not rare in paraneoplastic cerebellar degeneration, occurring in more than 10% of patients in this retrospective series. Others have reported enhancement in paraneoplastic cerebellar degeneration related to autoimmune process alone, but metastases can also occur and may be difficult to distinguish, creating a diagnostic and therapeutic dilemma.

Paraneoplastic cerebellar degeneration is a rare neurological manifestation of nonmetastatic malignancy. Its usual manifestation is subacute to chronic dizziness, gait ataxia, and dysarthria. There have been only a few cases of paraneoplastic cerebellar degeneration with acute presentation. This study describes a patient with paraneoplastic cerebellar degeneration, who presented acute vestibular syndrome and then episodically developed horizontal gaze-evoked nystagmus and gait ataxia.

Subacute cerebellar syndromes have a broad differential diagnosis, which includes paraneoplasia. Paraneoplastic cerebellar degeneration needs to be considered in this clinical situation even if initial brain imaging is normal, and the neurological prognosis is guarded even if the underlying tumour can be successfully treated.

Introduction : Les syndromes neurologiques paranéoplasiques (SNP) sont des maladies auto-immunes rares affectant le système nerveux central, associées à la présence d'un cancer et satellites de la réponse immune anti-tumorale. Ces pathologies sont associées à la présence d’auto-anticorps, dont la détection dans le sang ou le LCR des patients permet de poser le diagnostic. Ces auto-anticorps sont dirigés contre une protéine du soi, exprimée à la fois dans la tumeur et dans le SNC, appelée l'antigène onconeuronal. Les facteurs amenant à la rupture de tolérance immune dans les SNP restent inconnus à ce jour. Des travaux récents dans les cancers de l'ovaire et du sein associés au syndrome Yo ont permis de montrer que les antigènes onconeuronaux Yo sont surexprimés dans la tumeur. De plus, il existe fréquemment des mutations et des gains de nombre de copie des gènes codant pour les antigènes Yo. Ces altérations des antigènes onconeuronaux ne sont pas retrouvées dans les autres SNP (cancers du poumon associé aux anticorps anti-Hu par exemple) et les facteurs déclenchants de la rupture de tolérance immune dans ces cancers sont encore plus mystérieux. Les objectifs de ce travail de thèse sont d'approfondir l'analyse du lien entre la tumeur et l'auto-immunité paranéoplasique. Le premier axe d'étude était la comparaison de deux couples de syndromes associés au même type de cancer (syndrome Ri et Yo associés à des cancers du sein, syndrome RGS8 et DNER associés à des lymphomes de Hodgkin). Le deuxième axe portait sur l'analyse des potentielles altérations des antigènes onconeuronaux dans le syndrome Ri.Méthodes : La première étude de ce travail de thèse portait sur une cohorte de cancers du sein associés au syndrome de Ri, utilisant des données clinico-pathologiques, génomiques et transcriptomiques. La seconde étude portait sur patients atteints du syndrome RGS8 et utilisait des données clinico-pathologiques et le séquençage par immunoprécipitation de Phage (PhIP-seq).Résultats : Les cancers du sein Ri sont d’un sous-type particulier (Luminal B) différent de celui observé dans les cancers Yo (HER2-driven) et présentent des particularités génétiques qui les différencient des tumeurs Luminal B contrôles. Aucune altération des antigènes onconeuronaux n'a été retrouvée dans les tumeurs Ri. En revanche, la réaction immune anti-tumorale, composée majoritairement d’un infiltrat lymphocytaire B intra-tumoral, est comparable à celle observée dans les cancers du sein Ri et Yo.Concernant le syndrome RGS8, deux patients présentent un lymphome de Hodgkin d'un sous-type spécifique rare nodulaire à prédominance lymphocytaire, différents des formes nodulaires-sclérosantes classiques associées au syndrome DNER. Les auto-anticorps détectés chez tous les patients enrichissaient le même épitope sur la protéine RGS8, une protéine intracellulaire physiologiquement exprimée dans les cellules de Purkinje mais dont on retrouve également une expression ectopique dans les cellules de lymphome des patients atteints du syndrome RGS8.Conclusion : chaque syndrome paranéoplasique est associé à un sous-type spécifique de cancer présentant des particularités génétiques. Les altérations de l'antigène (surexpression, variation du nombre de copies et mutation) peuvent déclencher la rupture de la tolérance immune mais ne sont pas présentes dans tous les syndromes paranéoplasiques. L'immunité antitumorale associée aux PNS est atypique du fait de l’importance de l’infiltrat lymphocytaire B. Ces résultats constituent un pas en avant dans notre compréhension de l'immunité paranéoplasique et fournissent des indices sur les marqueurs prédictifs potentiels qui pourraient être utiles pour personnaliser la prise de décision médicale en immunothérapie anti-cancéreuse
Background: Paraneoplastic cerebellar degeneration (PCD) are rare autoimmune disorders affecting an otherwise immune-privileged site: the central nervous system. This autoimmunity is associated with the presence of a cancer and is satellite of the anti-tumor immune response, the B-cell response originating a secretion of autoantibodies that are diagnostic hallmarks of these disorders. These autoantibodies are directed against a protein expressed both in the tumor and in the CNS, the so-called onconeural antigen. The triggers of the immune tolerance breakdown and the exact relationship between the tumor, the immune system and the neurological symptoms are still not totally understood. Recent studies have allowed to show that in some tumors associated with paraneoplastic syndromes (namely ovarian and breast cancers associated with Yo syndrome), the onconeural antigen is overexpressed due to the presence of a gain or amplification in the gene locus and may present mutations while in others, none of these alterations of the onconeural antigen are present (e.g. lung cancers in Hu syndrome). The objectives of this thesis work are to further analyze the link between the tumor and the paraneoplastic autoimmunity by comparing two syndromes associated with the same type of cancer (Ri and Yo syndrome associated with breast cancers, RGS8 and DNER syndrome associated with Hodgkin’s lymphoma) and to search for antigen alterations in another syndrome (Ri syndrome).Methods: we conducted two studies within the frame of this thesis work. A first study on a clinical and pathological cohort of breast cancers associated with Ri-syndrome using clinicopathological data, DNA-sequencing, and whole-transcriptome analysis. A second analysis on three patients with RGS8-syndrome using clinicopathological data and Phage Immunoprecipitation sequencing (PhIP-seq).Results: Ri breast cancers were a subtype different than one observed in Yo with uncommon genetic features that singularize them among their subtype. Neither overexpression nor genetic alteration of the Ri onconeural antigens were found in Ri breast cancers. Conversely, the anti-tumor immune reaction in Ri breast cancers was similar to the one found in Yo: an atypical intratumoral B-cell infiltration.Concerning RGS8 paraneoplastic cerebellar degeneration, two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, whereas DNER is associated with the classical nodular-sclerosing form. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-syndrome.Conclusion: each paraneoplastic syndrome is associated with a specific histomolecular subtype of cancer with uncommon genetic features, which provides the first evidence of a tight link between oncogenesis and paraneoplastic immunity. Alterations of the antigen (overexpression, copy number variation and mutation) may be the mechanism of immune tolerance breakdown in several different syndromes but are not ubiquitous. The antitumor immunity seems to be an atypical B-cell response in several subtypes irrespective of the tumor type and antigen alterations. These results are a step forward in our understanding of paraneoplastic immunity and provide clues on potential predictive markers of paraneoplastic immunity that may be of use in personalizing medical decision of immunotherapy in the field of oncology

The priority in the investigation of sporadic adult-onset ataxia is to identify potentially treatable causes, to improve gait or to reduce risk of recurrence. Disorders such as multiple sclerosis, alcohol-related cerebellar degeneration, and vitamin B12 deficiency are far more common than rarer causes such as paraneoplastic syndromes or recessive genetic disorders. Routine biochemistry, magnetic resonance imaging, and cerebrospinal fluid studies are typically performed as part of the workup to guide any further intervention and investigations. Advances in genetic testing using next-generation sequencing are revealing that many patients with presumed nongenetic sporadic ataxias have a genetic cause for their symptoms. Expert opinion to guide genetic testing in cases in which no alternative cause of ataxia is found is advisable.

This chapter explores the historical development of understanding about the structure, function, and disorders of the cerebellum. The chosen papers represent the following development: the discovery that the cerebellum is concerned with movement control rather than movement generation; the first recognition of a distinct spinocerebellar disorder; recognition of the existence of dominantly-inherited ataxias; the delineation of the classic motor features of ataxia; the formal recognition of paraneoplastic cerebellar degenerations; the description of truncal ataxia due to anterior vermal damage in chronic alcoholics; the demonstration of long-term depression at the parallel fibre; the discovery of the first gene (ATXN 1) for a dominantly-inherited spinocerebellar ataxia; the revelation that episodic ataxia type 2 is an ion channel disorder; and the recognition of a cerebellar role in cognition and emotional regulation.

Downbeat nystagmus is a common type of central vestibular nystagmus that often produces oscillopsia or blurred vision. It is a vertical jerk-waveform nystagmus with upward slow phases and downward quick phases. In this chapter, we begin by reviewing the clinical features of downbeat nystagmus. We next list the common causes for downbeat nystagmus, which include inherited cerebellar degenerations, acquired cerebellar degenerations, congenital hindbrain anomalies, stroke, tumors, and medications. We then discuss the workup and management of paraneoplastic cerebellar degeneration, which is most commonly associated with cancers of the lung, ovary, and breast. Lastly, we review medical treatment options for downbeat nystagmus.

This chapter reviews clinical features (with illustrative video cases) and pathophysiology of medullary lesions, including Wallenberg’s syndrome and oculopalatal tremor. Manifestations and pathophysiology of three cerebellar syndromes are described (flocculus and paraflocculus, nodulus and ventral uvula, dorsal vermis and fastigial nucleus), applying these principles to interpret the effects of developmental disorders (e.g., Chiari malformation), hereditary ataxia, paraneoplastic cerebellar degeneration, cerebellar stroke, and cerebellar tumors. Characteristics of pontine lesions are discussed, including lesions of the abducens nucleus, paramedian pontine reticular formation (PPRF), internuclear ophthalmoplegia (INO), one-and-a-half syndrome, slow horizontal saccades, and saccadic oscillations. The effects of midbrain lesions are summarized, including lesions affecting the rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF), interstitial nucleus of Cajal, posterior commissure, and more diffuse processes causing slow vertical saccades or vertical gaze palsy (dorsal midbrain syndrome), including Whipple’s disease. Effects of lesions affecting the superior colliculus, thalamus, and pulvinar are also discussed.

A 60-year-old man sought care for painless, symmetric, ascending weakness and sensory loss affecting the lower, greater than upper, extremities, progressing over 3 weeks with associated orthostatism. He was diffusely areflexic and had symmetric weakness, distal greater than proximal, with normal bulbar strength. Muscle atrophy was not appreciated, and fasciculations were absent. Sensory examination revealed pan-sensory loss at the feet and hands. His gait was unsteady with prominent steppage. He was unable to climb stairs, kneel, or arise without assistance. Pertinent medical and social history included a spinal fusion at C5-T1, a 10-pack-year smoking history, and congestive heart failure, New York Heart Association class III with an intracardiac defibrillator for ventricular fibrillation, and taking carvedilol and furosemide. Needle electromyography and nerve conduction studies showed a severe axonal sensory-motor polyneuropathy with proximal involvement, suggesting polyradicular colocalization. Cerebrospinal fluid obtained during unremarkable spinal myelography, for exclusion of spinal compression, showed normal and abnormal findings: total nucleated cells, 3/µL; glucose, 87 mg/dL; and protein, 326 mg/dL. Sural nerve biopsy showed marked active axonal injury without significant inflammatory infiltrates. Expanded autoimmune neuroimmunologic testing by indirect immunofluorescence staining identified the classic pattern for antineuronal nuclear antibody type 1 –immunoglobulin G. Chest radiography and computed tomography showed a consolidation and volume loss in the left lower lobe without identifiable mass. The patient was diagnosed with paraneoplastic axonal sensory-motor polyneuropathy in the setting of antineuronal nuclear antibody type 1-immunoglobulin G positivity and likely small cell lung carcinoma. Acute motor axonal neuropathy was thought to be the diagnosis, and the patient was treated with plasma exchange. He continued to worsen and was transferred to the intensive care unit with new shortness of breath. Escalated therapy with intravenous immunoglobulin did not help. He had development of urinary retention, bulbar weakness, confusion, and flail limbs in all extremities. On identification of antineuronal nuclear antibody type 1-immunoglobulin G, he was treated with intravenous methylprednisolone, but his condition worsened. The patient and his family opted for comfort measures. His defibrillator was turned off, and he died 20 days after first coming to the hospital. At autopsy, small cell lung carcinoma of the left lung was identified without bronchial mass or metastasis. Neural tissues had diffuse microglial activation, with scattered microglial nodules and prominent perivascular chronic lymphocytic infiltrates. Antineuronal nuclear antibody type 1-immunoglobulin G autoimmunity was first reported in 1965. Patients had sensory neuropathy with nonmetastatic cancer and dorsal ganglia degeneration at autopsy. Neuropathy is the most common neurologic presentation, but the neurologic phenotypes have expanded since the original descriptions to include cerebellar, cognitive, and spinal cord involvement.