Antineural antibodies and paraneoplastic neurologic syndromes

The discovery that many paraneoplastic syndromes of the nervous system associate with the presence of specific antineuronal antibodies in the serum and cerebrospinal fluid of patients has facilitated the recognition of these disorders and attracted the interest of clinical and laboratory investigators. In this review, the authors discuss the most common immunological findings associated with paraneoplastic syndromes of the nervous system, and provide a practical clinical review of those associated with antineuronal antibodies.     

Value of Hu antibody determinations in the follow-up of paraneoplastic neurologic syndromes

The long-term evolution of Hu antibody (Hu-Ab) titers in patients with paraneoplastic neurologic syndromes (PNSs) is not known. Described is the evolution of Hu-Ab titers in 35 patients with PNS with a median follow-up of 32 months (range 6 to 108 months). No correlation was observed between Hu-Ab titers and neurologic outcome, tumor evolution, or type of treatment. Serial Hu-Ab determinations are not useful for monitoring the clinical outcome of patients with PNS.     

Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens

BACKGROUND Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited. OBJECTIVE To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted. DESIGN Retrospective single-center case series of patients with PND treated with tacrolimus. SETTING The Rockefeller University Hospital, a research hospital in New York, New York. PATIENTS Twenty-six patients with PND with high titer (≥1:1000) anti-HuD, anti-Yo, or anti-CRMP5 autoantibodies were enrolled. Patients were referred from Memorial Sloan Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events. INTERVENTIONS Patients were treated with tacrolimus, 0.15-0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone, tapered off during 1 to 4 weeks. MAIN OUTCOME MEASURES The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described. RESULTS Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus. CONCLUSIONS A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00378326.     

Neuro-ophthalmology and paraneoplastic syndromes

PURPOSE OF REVIEW: To describe the neuro-ophthalmological manifestations of paraneoplastic syndromes and their immunological associations. RECENT FINDINGS: Neuro-ophthalmological signs and symptoms are usually present in paraneoplastic syndromes of the central nervous system. Unlike opsoclonus, less characteristic eye movement abnormalities are difficult to recognize as presenting symptoms of paraneoplastic syndromes. In this setting, the detection of several antibodies, including anti-Hu, Yo, Ma2, Ri, Tr, CV2/CRMP5 or voltage-gated calcium channel antibodies may help to establish that the neuro-ophthalmological disorder is paraneoplastic. Among the recently characterized antibodies, those against the Ma proteins often associate with brainstem encephalitis and vertical gaze paralysis. A small subset of patients with opsoclonus and ataxia harbor anti-Ri antibodies. In other patients, there is preliminary evidence that the autoantigens of opsoclonus reside in the postsynaptic density, but no dominant antibody marker has been identified. Uveitis and optic neuritis are rare accompaniments of paraneoplastic encephalomyelitis; some of these patients harbor anti-CV2/CRMP5 in association with other antibodies. Studies on paraneoplastic retinopathy indicate that immunity to retinal proteins other than recoverin can result in a similar syndrome to that associated with recoverin antibodies, and that melanoma-associated retinopathy may associate with several retinal antibodies. SUMMARY: There is increasing recognition of an extensive variety of neuro-ophthalmological abnormalities as manifestations of paraneoplastic syndromes and of several antineuronal antibodies as clinical markers of these disorders. Basic immunological studies support the pathogenic role of some of these antibodies, and are elucidating the pathogenic mechanisms that underlie these and other antibody-associated paraneoplastic syndromes.     

Paraneoplastic neurologic syndromes: approaches to diagnosis and treatment

There is increasing evidence that many paraneoplastic neurologic syndromes are immune-mediated. Because symptoms usually have an acute onset and precede the tumor diagnosis, the recognition of a neurologic disorder as a paraneoplastic syndrome is challenging. The poor response to treatment of many paraneoplastic neurologic syndromes has been attributed to the early, irreversible pathological changes involving the nervous system. This may account for the more frequent responses to therapy of some paraneoplastic neurologic syndromes affecting the peripheral nerves and neuromuscular junction compared with those that produce neuronal degeneration. This review focuses on the current therapeutic approaches to immune-mediated paraneoplastic neurologic syndromes, including prompt recognition of the disorder, detection and treatment of the associated tumor, and, in some disorders, immunosuppressive therapy.     

Update on paraneoplastic syndromes

PURPOSE OF REVIEW: This review discusses the varied clinical spectrum of neurologic paraneoplastic disorders, describes recent advances in our understanding of autoimmunity in these disorders, and outlines a practical clinical approach to patient management. RECENT FINDINGS: Paraneoplastic disorders may affect any part of the central or peripheral nervous system. Although relatively uncommon, these disorders are a significant cause of severe and permanent neurologic disability. Syndromes such as limbic encephalitis or opsoclonus-myoclonus should always raise suspicion of a paraneoplastic condition, but any paraneoplastic syndrome can also occur in patients without a neoplasm. Most neurologic paraneoplastic disorders are thought to be caused by an autoimmune reaction directed against 'onconeural' antigens expressed by neurons and tumor cells. Some syndromes such as Lambert-Eaton myasthenic syndrome and neuromyotonia are clearly mediated by autoantibodies. Much less is known about the immunopathogenesis of syndromes that affect the central nervous system, although a growing body of evidence implicates cellular immune effectors in causing neuronal injury. Many patients have circulating antineuronal antibodies, which can be useful in identifying a neurologic disorder as paraneoplastic and in finding the associated neoplasm. Early diagnosis of the neurologic disorder and prompt initiation of tumor treatment probably increase the likelihood of neurologic improvement. SUMMARY: Neurologists must be able to recognize the clinical manifestations of neurologic paraneoplastic disorders, and to distinguish them from other causes of neurologic dysfunction in cancer patients. Early diagnosis of paraneoplastic syndromes maximizes the likelihood of a favorable oncologic and neurologic outcome.     

Diagnostics of paraneoplastic neurological syndromes

This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.     

Dysexecutive syndromes in neurologic disease

Damage to the frontal structures may lead to a diverse set of changes in cognitive, behavioral, or emotional domains. While lesion studies have demonstrated distinct impairments related to pathology in different frontal regions, it is clear that the frontal lobe syndrome is not restricted to damage to frontal regions. Therefore, the broad range of impairments in executive functioning evident in neurologic disease is often referred to as the dysexecutive syndrome. This review provides an overview of how executive functioning has been traditionally defined and measured. The components of executive function such as planning, cognitive flexibility and set-shifting, initiation and self-generation, response inhibition, serial ordering and sequencing, are discussed with respect to traditional measures and neural substrates. This is followed by profiles of frontal-executive dysfunction in aging, traumatic brain injury, frontotemporal dementia, and Parkinson's disease. Since no one specific neurologic disorder has a predilection to damage isolated to the frontal lobes, profiles of the dysexecutive syndrome are related to damage to several regions in addition to the frontal lobes. Finally, there is a discussion of ecological validity and the impact of executive deficits on everyday functioning. The recent development of executive tests with greater ecological validity is reviewed and discussed, and suggestions for future directions for research are provided.     

Anticerebellar antibodies in serum and cerebrospinal fluid of a patient with oat cell carcinoma of the lung and paraneoplastic cerebellar degeneration

A 56-year-old man was seen with subacute cerebellar degeneration and was found to have oat cell carcinoma of the lung. Antibodies to cerebellar Purkinje cells and granule cells were detected in both serum and cerebrospinal fluid (CSF), and intrathecal antibody synthesis was suggested by serum CSF antibody ratios, CSF IgG index, and CSF IgG synthesis rate. The patient's condition improved slightly with plasmapheresis, corticosteroids, and therapy of his underlying tumor, but he continued to exhibit a severe cerebellar deficit until his death more than one year later. Paraneoplastic cerebellar degeneration may be accompanied by synthesis of anticerebellar antibodies, both systemically and within the central nervous system.     

Intravenous immunoglobulin therapy in paraneoplastic neurological syndromes

Journal of Neurology - Combining clinical and immunological information, a neurological syndrome can now be diagnosed as a “definite” or “possible” paraneoplastic syndrome...     

Regulatory T cells in paraneoplastic neurological syndromes

Focusing on CD4(+)CD25(+) regulatory T lymphocytes (T(reg)), we studied the gene expression of T(reg) functional molecules in peripheral blood lymphocytes of patients with paraneoplastic neurological syndrome (PNS), including Lambert-Eaton myasthenic syndrome (LEMS) with small cell lung carcinoma (SCLC) and anti-Hu- or anti-Yo-antibody-positive PNS. T(reg)-rich subsets were sorted from the patients' peripheral blood mononuclear cells, and the mRNA expression levels of their functional genes were measured. The expression levels of FOXP3, TGF-beta and CTLA4 mRNA in T(reg)-rich subsets of PNS patients were down-regulated compared with that of SCLC patients without PNS. These results suggest that T(reg) dysfunction plays a role in PNS development.