LE is characterized by the subacute onset of confusion with marked reduction of the short-term memory. Seizures are not uncommon and may antedate by months the onset of cognitive deficit 10. Other patients have a more insidious onset with depression or hallucinations that can lead to confusion the diagnosis with that of a psychiatric illness. Among LE patients, 50% have small-cell lung cancer (SCLC), 20% have a testicular tumor and 8% have breast cancer 11. Hu-Ab are present in up to 50% of patients with LE and lung cancer 1011. A minority of patients with LE and lung cancer may harbour CV2-Ab or amphiphysin-Ab 1213. Ma2-Ab are present in the great majority of patients with LE and testicular cancer. Unlike patients with lung cancer, these patients usually present with diencephalic and upper brainstem symptoms that identify a characteristic syndrome in addition to limbic encephalitis 14. Recently, VGKC-Ab have been found in some LE cases without associated cancer 15.

Paraneoplastic cerebellar ataxia (PCA) is characterized by the rapid development of severe pancerebellar dysfunction due to an extensive loss of Purkinje neurons with relative preservation of other cerebellar neurons. Computed tomography (CT) and magnetic resonance imaging (MRI) studies are initially normal but demonstrate cerebellar atrophy in the later stages of the disease.

Different autoantibodies have been reported in PCA (Table 1). Yo-Ab are present in patients with PCA and ovary, breast, or other gynecological malignancies 1617. Tr-Ab are markers of patients with PCA and Hodgkin's disease 1819. Unlike Yo-Ab, Tr-Ab usually disappear after treatment of the tumor or, in a few patients, are only found in the CSF 18. Hu-Ab are reported in 23% of patients with PCA and lung cancer 20. PCA and SCLC is also characteristic for patients with CV2-Ab 1221. Zic4-Ab, Ma2-Ab and VGCC-Ab are present in nearly 40% of patients with PCA and lung cancer (usually SCLC) 222324. About half of these patients present a coincident Lambert-Eaton myasthenic syndrome 20.

Opsoclonus is defined by the presence of spontaneous, arrhythmic and large amplitude conjugate saccades occurring in all directions of gaze, without saccadic interval. Opsoclonus is usually associated with myoclonus of the limbs and trunk, and sometimes, with encephalopathy. Paraneoplastic OM is observed in three clinical settings: 1) pediatric patients with neuroblastoma 2526; 2) adult female patients with Ri-Ab, whose underlying tumor is usually breast cancer 2728, and 3) adult patients without paraneoplastic antibodies whose tumor is almost always SCLC 2930. There are individual case reports associated with other tumors including carcinoma of the uterus, Fallopian tube, breast, bladder, thyroid, thymus, chondrosarcoma, and Hodgkin's disease. A few patients with OM and SCLC or neuroblastoma may harbour Hu-Ab 31.

The paraneoplastic retinopathies include three well-characterized syndromes 32. Cancer-associated retinopathy (CAR) is almost always associated with SCLC. Symptoms usually present bilaterally and reflect the simultaneous dysfunction of both cones and rods. Patients present with photosensitivity, reduced visual acuity, decreased color perception, ring scotomas, nyctalopia, and prolonged dark adaptation 33. Ophthalmoscopic examination typically shows attenuated arterioles, and electroretinogram discloses flat or severely attenuated photic and scotopic responses. Most of the patients with CAR have recoverin-Ab, but other rare antibodies have also been described 3435.

Melanoma-associated retinopathy (MAR) usually occurs after the diagnosis of malignant melanoma, often at the stage of metastases. Patients with MAR usually have nearly normal visual acuity and color vision but develop sudden shimmering, flickering photopsias, night blindness, and mild peripheral visual field loss 33. Symptoms are explained by dysfunction of rods, whereas cones are not affected 36. Typical findings in electroretinogram include a markedly reduced or absent dark-adapted b-wave, along with a slightly attenuated a-wave to scotopic stimulus. Patients with MAR usually harbor rod-bipolar-cell-Ab 37.

Uveitis, optic neuropathy or retinopathy are also observed in some patients with CV2-Ab 123839.

Patients with CGP present with weight loss, persistent constipation and abdominal distension due to damage of the neurons of the enteric plexuses 40. Some patients may present with dysphagia, nausea and vomiting due to esophageal dysmotility or gastroparesis, or more frequently, with severe constipation. Radiologic studies show small bowel, colonic or gastric dilatation. Esophageal manometry may reveal spasms or achalasia. The most commonly associated tumor and antibodies are SCLC and Hu-Ab or CV2-Ab, respectively. Some patients with subacute parasympathetic and sympathetic autonomic failure and prominent gastrointestinal dysfunction may also have antibodies directed against the neuronal autonomic ganglion-type of acetylcholine receptors (nAchR antibodies) 41. In these cases, the main associated tumors are thymoma and SCLC.

SSN is characterized by primary damage of the sensory nerve cell body of the dorsal root ganglia. A paraneoplastic origin is only one of the causes of SSN 42. The most common low associated tumor is SCLC 43. The main clinical complains at onset are pain and paresthesias with asymmetric distribution that involves the arms rather than the legs. Later, pain is replaced by numbness, limb ataxia, and pseudoathetotic movements of the hands. The neurologic examination shows abolition of the deep tendon reflexes and involvement of all modalities of sensation with clear predominance of the joint position. Electrophysiologic studies show marked, but not restricted, involvement of the sensory fibres 44. Most of the patients with SSN have Hu-Ab, CV2-Ab or amphiphysin-Ab 12133142.

LEMS is an autoimmune disorder of the neuromuscular junction characterized by muscle weakness and autonomic dysfunction and, on electromyography, by low compound muscle action potential after nerve stimulation with decrement at low frequency stimulation (3 Hz) of more than 10% and increment after high frequency stimulation (more than 20 Hz or preferably maximal voluntary contraction) of more than 100% 4546.

Almost 60% of patients with LEMS are paraneoplastic and SCLC is the main associated cancer, detected mostly within two years after the diagnosis of LEMS 4546. No serological marker for the paraneoplastic etiology exists. VGCC-Ab are present in nearly all patients with LEMS, and these antibodies do not differ between the paraneoplastic and non-paraneoplastic form. In rare cases, patients with paraneoplastic LEMS develop cerebellar degeneration 47. In contrast, some patients with paraneoplastic cerebellar degeneration may have VGCC-Ab without clinical signs or symptoms of myasthenic muscle weakness 48.

SPS is a rare neurological disorder characterized by stiffness, more prominent in axial muscles, with co-contraction of agonist and antagonist muscle groups and painful spasms precipitated by sensory stimuli. Electromyography reveals the existence of continuous motor unit activity in the affected muscles at rest. Detection of GAD-Ab in almost 70% of patients suggests an autoimmune mechanism.

A paraneoplastic variant of SPS has been described in association with breast cancer in women harbouring amphiphysin-Ab 4950. In these patients, the onset of stiffness in upper limbs is suggestive of paraneoplastic etiology. SPS has also been reported in association with colon and lung cancer, Hodgkin's disease, and malignant thymoma.

Paraneoplastic EM is characterized by involvement of different areas such as hippocampus, lower brainstem, spinal cord or dorsal root ganglia in one and the same time 4. The clinical picture reflects the variable anatomic involvement and includes: LE, brainstem syndromes, autonomic dysfunction, myelitis, CGP or SSN. In 75% of patients, the underlying neoplasm is SCLC. SSN, LE and cerebellar ataxia are the most common clinical syndromes. The autonomic nervous system is affected in 30% of the patients (orthostatic hypotension, urinary retention, pupillary abnormalities 51, impotence and dry mouth). Most of the patients present Hu-Ab, CV2-Ab or amphiphysin-Ab 12213152.

Dermatomyositis is an idiopathic inflammatory myopathy with characteristic cutaneous manifestations including heliotrope rash of the periorbital skin, erythematous scaly plaques on dorsal hands with periungual telangiectasia and photosensitive poikilodermatous eruption. The myopathy is generally symmetrical and slowly progressive during a period of weeks to months affecting mainly the proximal muscles. A paraneoplastic origin is suspected in 30% of patients 5354 and the main associated cancer are ovarian, lung, pancreatic, stomach, and colorectal cancers, and non-Hodgkin lymphoma. Many autoantibodies such as nuclear antibodies or myositis-associated antibodies have been recognized in dermatomyositis, but none are linked to tumors. The treatment of paraneoplastic dermatomyositis should be directed primarily to the tumor, but immunosuppressive treatments including corticosteroids, azathioprin and immunoglobulins are also important.

For patient with a neurological disorder that is highly suspected to be paraneoplastic but for whom no cancer has yet been identified, detection of the tumor is essential but may be difficult since the tumors initially may be histologically small and localized 68. If paraneoplastic antibodies are present, they direct the tumor search to specific organs. If a SCLC is suspected, the tumor is generally detected by chest CT scan 6970. If a gynecological tumor is suspected, careful breast and pelvic examination, mammography and pelvic CT scan are recommended. If no malignancy is revealed during initial workup, surgical exploration and removal of pelvic organs may be warranted, particularly in postmenopausal women 16. The use of whole-body positron emission tomography with fluorodeoxyglucose (FDG-PET) should be reserved for patients with paraneoplastic antibodies for whom conventional imaging has failed to identify a tumor or when lesions are difficult to biopsy 6871. In patients without paraneoplastic antibodies, the sensitivity and specificity of FDG-PET are less significant 72. If a tumor which does not fit the known tumor pattern associated with PNS is identified, it should be checked for atypical expression of the relevant antigen 31 and the possibility of a second malignant disorder must be considered 73.

The different subtypes of PNS are defined by the presence or the absence of paraneoplastic antibodies and the type of antibodies. Management and treatment should be tailored to each subtype. For example, patients with SCLC and PCA have different course of the neurological disorder, response to treatment, tumor prognosis and cause of death, according to the presence or the absence of Hu-Ab 20. Patients with Ma2-Ab generally develop limbic and brainstem encephalitis with testis tumors, but patients with Ma2-Ab and additional antibodies directed against other Ma proteins develop additional cerebellar symptoms and have tumors other than testis neoplasms 23. The mean survival time for patients with SCLC and CV2-Ab is 2.5 times longer than for patients with the same cancer, similar neurological symptoms and Hu-Ab 74. All these data suggest that the type of the immunological stimulation against the tumor can determine a specific course of the neurological disorder and give information of whether the immunological response against the tumor is more or less effective.

However, PNS rarely improves with immunomodulatory treatment as in the majority of cases the neurological symptoms are due to neuronal damage. The early and non-reversible destruction of neural structures by the inflammatory process accounts for both the severity of most PNS and for the usual ineffectiveness of immunomodulatory treatments 78. The best chance of at least stabilizing the syndrome is to induce a complete response of the tumor 7. Although immunotherapy is rarely effective, the use of intravenous immunoglobulins, steroids or plasmapheresis is indicated because a few patients have been reported to improve with these treatments 7875. Patients with Tr-Ab and Ma2-Ab and testicular cancer are more likely to improve than those with other antibodies 1418.