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Paraneoplastic disorders of the nervous system are important to the practicing oncologist, because these syndromes, although uncommon, produce significant neurologic dysfunction and disability. The neurologic disorder may be the first manifestation of an unrecognized systemic malignancy, and appropriate diagnosis of the paraneoplastic disorder can lead to a focused search for an underlying cancer. Paraneoplastic disorders may involve any component of the central or peripheral nervous system, and diagnosis requires careful neurologic assessment. The diagnosis is made by recognition of clinical neurologic syndromes and the use of selected laboratory studies as indicated by the clinicalpicture. Over the past 10 years, the application of molecular biologic techniques to the study ofthese disorders has elucidated much about the mechanisms that cause neurologic injury. In most cases, disordered humoral and cellular immunity has been demonstrated, and the role of novel targets for autoimmune attack is being clarified. For some paraneoplastic disorders, treatment of the underlying tumor may lead to improvement of the neurologic disorder. For others, various forms of immunosuppressive therapy may be indicated. Unfortunately, for several of the more common paraneoplastic syndromes such as paraneoplastic cerebellar degeneration or limbic encephalitis, treatment is still unsatisfactory, and further research into the exact pathophysiology is clearly needed.

Since the discovery of the first clinically relevant anti neuronal antibody specific for a paraneoplastic aetiology in 1985, the number of such reactivities has grown at a rate of about one per year. Clinicians can now diagnose a paraneoplastic syndrome much more easily. This ability is especially important because, typically, the neurological symptoms occur before the cancer is diagnosed. Early tumour diagnosis is essential, because effective treatment of the cancer still seems to be the most efficient treatment option for the neurological symptoms. Immuno modulatory therapy should, nevertheless, be initiated as early as possible and seems especially helpful for peripheral syndromes and limbic encephalitis. The recent fundamental advances in understanding of the autoimmune pathology of these disorders, especially the role of cytotoxic T cells, should eventually lead to more effective treatment options.

In a retrospective study, we determined clinical and serological findings, associated tumours, outcome and prognostic factors in 73 Hu-Ab positive patients detected in a Dutch reference laboratory. The most frequent signs and symptoms at presentation were sensory neuropathy (55 %), cerebellar degeneration (22 %), limbic encephalitis (15 %) and brainstem encephalitis (16 %). 23 % developed autonomic dysfunction including gastro-intestinal motility disorders in 14 %. In 85 % a tumour was detected, which was a lung tumour in 77 %. Signs, symptoms and associated tumours did not differ in six patients with additional neuronal antibodies (anti-amphiphysine, anti-CV2, anti-Ri). The overall 3 months, one-year and three-year survival rates from the time of diagnosis were 64 %, 40 % and 22 %. Rankin Scale Score (RS) at diagnosis and presence of tumour at the time of diagnosis predicted mortality with hazard ratios (95 % CI) of 2.6 (1.5-4.6) and 1.5 (1.1-2). The median delay between onset of symptoms and Hu-Ab diagnosis was 4 months. There was a negative association between delay RS at diagnosis (P=0.03). In a logistic regression analysis, only older age (OR=0.15; 0.02-0.63) and a higher RS at diagnosis (OR=0.29; 0.11-0.73) were associated with a lower probability of successful functional outcome. Adjusted for these factors, antitumour therapy showed a higher but statistically not significant probability of successful outcome (OR=3.5; 0.87-14.3). Our study underlines the importance of early diagnosis and start of antitumour treatment when the patient is still in a better functional state. The delay between onset of symptoms and diagnosis of PEM/SN suggests a window for improving outcome in these patients.

The precise immune mechanisms of neuronal death in anti-Hu-associated paraneoplastic encephalomyelitis (PEM) are unclear. We performed an immunohistochemical study on postmortem brain tissue from 11 patients with anti-Hu-associated PEM to further characterize the immune reaction and to ascertain possible mechanisms of neuronal death. To analyze inflammatory infiltrates, antibodies against lymphocyte subpopulations (CD3, CD20, CD4, CD8), macrophage and activated microglia (CD68), major histocompatibility complex (MHC) classes I and II (HLA-ABC and HLA-DR), and the intercellular adhesion molecules (ICAM) -1 and -3 were used. Cell death mechanisms were defined using antibodies against the cytotoxic protein TIA-1, the C9neo component of complement, the Fas receptor (CD95) and its ligand, the apoptosis effector activated caspase-3, and the apoptosis inhibitor Bcl-2. A great number of T cells expressing the cytotoxic protein TIA-1 was observed, mainly in clusters around neurons. ICAM-1 immunoreactivity was increased in the neuropil and reactive astrocytes in areas of inflammation within the central nervous system and in satellite cells of pathological dorsal root ganglia surrounding apparently normal sensory neurons. By contrast, Fas, FasL, C9neo, and activated caspase-3 immunoreactivities were negative in pathological areas. Bcl-2 immunoreactivity was found in satellite cells, but not in sensory neurons of normal and pathological dorsal root ganglia. Our data point out to an induction of a cytotoxic, non-apoptotic, neuronal death in anti-Hu-associated PEM. The increased ICAM-1 immunoreactivity may favor the infiltration of lymphocytes in the pathological areas.

Paraneoplastic syndromes associated with lung cancer are diverse in their presentation, pathophysiology, and implications. They can be seen as a diagnostic and therapeutic challenge or as an opportunity to detect an otherwise asymptomatic malignancy. Unraveling the mechanisms that produce these syndromes will lead to insight into tumor biology that will be translated into novel approaches for early detection and therapy.

Paraneoplastic neurologic disorders (PND) refer to neurologic disorders of unknown cause that occur at higher frequency in patients with cancer than in the general population. There is increasing evidence that many of these disorders are immune mediated and associated with cytotoxic antitumor immunity. The identification of the immune responses in these patients facilitates the diagnosis of the PND and has led to the cloning and characterization of the target antigens in the nervous system and tumor.

Human homologue of polypyrimidine tract binding protein (PTB), a possible autoantigen for cancer-associated retinopathy (CAR), was isolated from a human retinal cDNA library. This homologue, named PTB-like protein (PTBLP), encodes a 532 amino acid residue and has a 75% homology to the human PTB. The human PTBLP had four RNA recognition motifs (RRMs) and had a RNA binding ability. There are four splicing variants in PTBLP. The CAR serum recognized the full length form of PTBLP and the antigenic determinant was localized within 12 amino acids of the C-terminal region. The sequence was included in the fourth RRM sequence.

We reviewed 200 patients with paraneoplastic encephalomyelitis (PEM) and anti-Hu antibodies to show possible clinical differences with respect to previous series, and to identify patient, tumour and treatment-related characteristics associated with neurological disability and survival. The median age of the 200 patients was 63 years (range 28-82 years) and 75% were men. The predominant neurological syndromes were sensory neuropathy (54%), cerebellar ataxia (10%), limbic encephalitis (9%) and multifocal involvement (11%). Sensorimotor neuropathies with predominant motor involvement were observed in only 4% of the patients. Pathological or X-ray evidence of a tumour was obtained in 167 patients (83%) and was a small-cell lung cancer (SCLC) in 74% of those with histological diagnosis. Coexistence of extrathoracic tumours with SCLC was rare (0.5%). Positive Hu immunoreactivity was observed in the extrathoracic tumours of six out of seven patients in whom autopsy or long-term follow-up ruled out a coexisting SCLC. PEM preceded the diagnosis of the tumour in 71% of patients (mean delay +/- SD 6.5 +/- 7.0 months; range 0.1-47 months). In the 24 patients in whom the tumour diagnosis was the initial event, PEM predicted the progression or relapse of the tumour in 87% of them. No tumour was found in 33 patients, including four who had a post-mortem study and four with >5 years of follow-up. In a logistic regression analysis, treatment of the tumour, associated or not with immunotherapy, was an independent predictor of improvement/stabilization of PEM [odds ratio 4.56; 95% confidence interval (CI) 1.62-12.86]. Cox multivariate analysis indicated that the variables independently associated with mortality were: age >60 years [relative risk (RR) 1.49; 95% CI 1.05-2.12], Rankin score at diagnosis >3 (RR 1.60; 95% CI 1.12-2.28), more than one area of the nervous system affected (RR 1.61; 95% CI 1.08-2.40), and absence of treatment (RR 2.56; 95% CI 1.76-3.71). We conclude that, unlike previous series, the majority of our patients were male, and there was a low occurrence of predominantly motor neuropathies and extrathoracic tumours coexisting with SCLC. When the diagnosed extrathoracic tumour expresses Hu antigens, further tests to rule out a coexisting SCLC are probably unnecessary. Finally, the predictors of mortality and PEM evolution found in the study may be important in the design of future therapeutic protocols, and emphasize the importance of early diagnosis and treatment of the underlying tumour.

Cancer-associated retinopathy (CAR) is a blinding disease, which can be mediated by autoimmune reactions with a specific calcium-binding retinal protein, recoverin. A number of recent studies demonstrate that agents that mobilize intracellular calcium can protect neurons from apoptotic death induced by a variety of insults. In this study, we investigated the effect of one such agent, potassium, on the survival of mammalian rod photoreceptors exposed to antirecoverin IgG. Primary cell cultures of rat retinal neurons were grown in a chemically defined medium, and cells were exposed to antirecoverin IgG for 72 hr in various concentrations of potassium and the surviving cells counted. Rod photoreceptors were quantitated using antirhodopsin immunofluorescence microscopy, and total cell numbers were determined by 4',6-diamidino-2-phenylindole (DAPI) staining of nuclei. Apoptosis was evaluated by TdT-mediated biotin-dUTP nick-end labeling (TUNEL), cell death-detection ELISA, and DNA laddering. The present study shows that elevated extracellular K+ ([K+](o)) protects retinal neurons from antirecoverin antibody-mediated cell death. The protective effects of ([K+](o)) were shown to be time- and dose-dependent. The inhibition of antirecoverin IgG-mediated death of photoreceptors by elevated ([K+](o)) suggests that the mobilization of internal calcium stores rescues the cells by interfering with apoptotic signal transduction pathways. These data also suggest that the death of photoreceptor cells occurring in CAR possibly can be prevented by reagents and/or environmental changes that mobilize intracellular calcium., (Copyright 2001 Wiley-Liss, Inc.)

Shifts of the point of fixation between two targets aligned on one eye that are located near and far (Müller paradigm) stimulates a combined saccadic-vergence movement. In normal subjects, this test paradigm often induces saccadic oscillations of about 0.3 degrees at 20 to 30 Hz. We measured eye movements using the magnetic search coil technique in 2 patients recovering from viral opsoclonus-myoclonus syndrome, comparing saccadic-vergence responses to the Müller paradigm with conjugate saccades between distant targets. Both patients exhibited intermittent conjugate ocular oscillations of about 4 to 5 degrees amplitude at about 10 Hz. Combined saccadic-vergence movements induced these oscillations twice as often as did conjugate saccades. One patient also exhibited disjunctive ocular oscillations at 10 Hz while sustaining fixation on the near target. The Müller paradigm provides a useful clinical and experimental technique for inducing saccadic oscillations. The probable mechanism is that pontine omnipause neurons, which normally gate saccades, are inhibited during the sustained vergence movement that follows the saccadic component of the response to the Müller paradigm.

Cancer can affect the peripheral nervous system by non-metastatic, sometimes immune-mediated mechanisms. Recognition of these paraneoplastic syndromes is important because it can lead to the detection of the tumor, and also helps to avoid unnecessary studies to determine the cause of the neurologic symptoms in patients with cancer. Many paraneoplastic syndromes of the peripheral nervous system are not associated with serum antibodies that serve as markers of paraneoplasia. For this group of disorders the diagnosis depends on the clinician's index of suspicion and conventional electrophysiologic and laboratory tests. Treatment of the tumor, immunotherapy, or both may improve some of these syndromes. This review focuses on paraneoplastic syndromes of the spinal cord, peripheral nerve, and muscle., (Copyright 2000 John Wiley & Sons, Inc.)

Despite a broad clinical spectrum, paraneoplastic enecephalomyelitis/sensory neuronopathy (PEM/SSN) is characterized by the presence of a common autoantibody, referred to as anti-Hu or type I anti-neuronal nuclear antibody (ANNA-1). The target of these antibodies is a family of four Hu antigens: three (Hel-N1, HuC, HuD) are neural-specific, while the fourth (HuR) is ubiquitous. Here, we have analysed by enzyme-linked immunosorbent assay (ELISA) the immunoreactivity of all four Hu antigens in serum from 75 patients with ANNA-1 autoantibodies and looked for clinical correlations. IgG in all the patients' sera bound to each of the four antigens, and the titers correlated with those of the ANNA-I immunofluorescence assay. Median titers for the neural-specific antigens (range: 56, 892-90,051) were significantly higher than for HuR (36,799). Patients with gastrointestinal dysmotility or subacute sensory neuronopathy had the highest median titers to all four antigens, while patients with sensorineural deafness had the lowest titers. The results indicate a heterogeneous immune response to individual Hu antigens in patients with PEM/SSN, and that the titers to these antigens as a group, rather than individually, correlate with clinical profile. Furthermore, these results suggest that ELISA analysis of a single neural-specific Hu antigen is sufficient for serological screening in PEM/SSN., (Copyright 1999 Academic Press.)