Topic of the month...Paraneoplastic syndromes

INDEX  INTRODUCTION INTRODUCTION Although the discovery of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurological disorders (PNDs), the recognition and treatment of these disorders remain a challenge. Some antineuronal antibodies have a more syndrome-specific association than others, and some syndromes evoke a paraneoplastic etiology more frequently than others. Because antineuronal antibodies may occur in cancer patients without PND, their detection does not necessarily imply that a neurological disorder is paraneoplastic. This review analyzes these issues and suggests a diagnostic strategy based on criteria derived from clinical and immunological findings and the presence or absence of cancer. We provide an update on the clinical features and treatment of classic PND of the central nervous system, with the proposal of a general treatment strategy. In addition, we analyze the evidence of a hypothetically effective antitumor immunity in patients with PND, which if confirmed would have implications for treatment of the cancer and PND.

The term quot;paraneoplastic neurological disordersquot; (PNDs) refers to a group of syndromes mediated by immune responses triggered by tumors that express nervous system proteins.[1] As a result of these immune responses, discrete or multifocal areas of the nervous system degenerate, causing diverse symptoms and deficits. These immune responses are often associated with specific antineuronal antibodies that can be used as diagnostic markers of the PND and underlying cancer. Not all paraneoplastic antibodies have the same clinical significance. Some antibodies may associate with one or a limited number of neurological syndromes or histological types of cancer, while others are less specific or may occur without neurological symptoms. There are PNDs with cerebrospinal fluid (CSF) and pathological evidence of being associated with inflammatory, likely immune-mediated mechanisms but no specific antibodies or target antigens have been identified. Beside these disparities, most paraneoplastic immune responses have in common the property of being triggered at early stages of cancer, when the tumor or metastases are limited or undetectable by conventional diagnostic techniques. This, along with the detection of cytotoxic T-cell responses to onconeuronal antigens, has suggested that the small tumor burden in PND patients is largely due to an effective anticancer immunity. If correct, the use of immunosuppressants would favor tumor growth, which is not supported by clinical data. These findings and dilemmas are assessed in this review. Because the main advance in the management of PND has resulted from refined clinical and immunological diagnostic criteria and improved diagnostic tests, a major focus of this review is an update of these criteria, with the proposal of a treatment strategy.  General Diagnostic Approach  Recognizing Paraneoplastic Neurological Syndromes PNDs may affect any part of the central or peripheral nervous system, including the retina and muscle. Some PNDs are more characteristic than others and can be considered quot;classicquot; syndromes, because they usually associate with cancer or the clinical features readily evoke a paraneoplastic origin ( Table 1 ).[2] Other disorders (quot;nonclassicquot;) are less characteristic and occur more frequently without cancer association, requiring a more extensive differential diagnosis than the classic syndromes.[3] Table 1. Paraneoplastic Syndromes of the Nervous System Because PNDs are uncommon conditions, significant diagnostic delays are frequent even for the classic syndromes. In a series of 50 patients with Lambert-Eaton myasthenic syndrome (LEMS), about half of the patients were initially misdiagnosed, usually with myasthenia gravis.[4] Another study noted an inverse correlation between the severity of the neurological symptoms and the diagnosis of the PND.[5]

There are several clinical features common to most PND that suggest a paraneoplastic origin. Symptoms usually develop rapidly in days or a few weeks and then stabilize, leaving the patient severely disabled. Exceptions do occur, and some patients develop insidious forms of PND that can be misdiagnosed as chronic degenerative disorders.[6] Spontaneous neurological improvement, although reported in some syndromes, [7,8] is rare and should lead to the consideration of a nonparaneoplastic etiology. CSF studies are important to rule out disorders that may mimic PND, mainly infectious or neoplastic meningitis. Findings consistent with PND include mild pleocytosis, elevated proteins, intrathecal synthesis of immunoglobulins, sometimes with oligoclonal bands. However, similar CSF abnormalities can be encountered in any inflammatory or immune-mediated disorders of the CNS, and some patients with PND may have normal CSF studies. Although it has been suggested that brain magnetic resonance imaging (MRI) has limited diagnostic utility in the early stages of PND, recent reports indicate otherwise and support the importance of new MRI technology in the diagnosis of these disorders.[9,10] One study reported brain T2-weighted abnormalities in 71% of the patients with paraneoplastic limbic encephalitis and small-cell lung cancer (SCLC).[11] Another series of 24 patients with paraneoplastic limbic encephalitis demonstrated that all patients had fluid- attenuated inversion recovery (FLAIR) MRI abnormalities involving one or both temporal lobes.[12] In a series of 29 patients with anti-Ma2-associated encephalitis, brain MRI abnormalities were present in 71%; some of these patients had abnormalities that appeared as nodular enhancing lesions, suggesting tumor metastasis.[13] All patients who underwent repeated brain MRI had new abnormalities in subsequent studies, including patients whose initial MRI was normal (Dalmau et al, unpublished). There is also increasing evidence that brain [F18] fluorodeoxyglucose-positron emission tomography (FDG-PET) has diagnostic utility in PND.[14] In the early stages of PND, FDG-PET may show hypermetabolism in the abnormal brain regions identified by MRI, but in some patients the MRI is normal.[9] Brain biopsy is rarely required for the diagnosis of PND. Biopsy of an abnormal area identified by MRI or FDG-PET may be considered if a neoplastic process is suspected or if the clinical, CSF, and MRI findings are unusual. Abnormalities supporting but not specificof PND include infiltrates of mononuclear cells, neuronophagic nodules, neuronal degeneration, microglial proliferation, and gliosis.[15]  Searching for Antineuronal Antibodies Patients suspected to have a PND should be examined for antineuronal antibodies in their serum and CSF. These antibodies preferentially associate with restricted histological types of tumors ( Table 2 ). Therefore, in addition to supporting the diagnosis of PND, the presence of antineuronal antibodies focuses the search of the cancer to specific organs. Well-characterized antineuronal antibodies are those directed against antigens whose molecular identity is known or have been identified by several investigators. Partially characterized antibodies are those whose target antigens are unknown or require further analysis in groups of individuals serving as controls.[16-20] Table 2. Antibodies, Paraneoplastic Syndromes, and Associated Cancers

There are antibodies that associate with specific disorders but do not differentiate between paraneoplastic and nonparaneoplastic cases.[21-23] Although some of these disorders (i.e., LEMS, myasthenia gravis) can be diagnosed on clinical and electrophysiological grounds, analysis for specific antibodies is useful in several settings. For example, the recognition of overlapping syndromes, such as LEMS and paraneoplastic cerebellar degeneration (PCD), is improved by antibody analysis.[24] For other syndromes such as dysautonomia, the detection of antibodies to the neuronal acetylcholine receptor identifies a subset of patients that benefit from immunosuppression.[23] In generalized myasthenia gravis, antibodies to the acetylcholine receptor at the neuromuscular junction are detected in 80 to 90% of the patients with or without thymoma.[25] A subset of patients without these antibodies harbor antibodies to muscle specific kinase (MuSK).[26] These patients do not have thymoma and preferentially develop cranial and bulbar weakness with a higher frequency of respiratory crisis. Detection of MuSK antibodies associates with poor response to anticholinesterase treatments but good response to plasma exchange and cyclosporine.[27] Different immune responses may associate with a similar neurological disorder suggesting clinical- immunological heterogeneity ( Table 2 ). For example, antibodies to glutamic acid decarboxylase (GAD), amphiphysin, or gephyrin have all been reported in association with the stiff-man syndrome, but the majority of patients with antibodies to GAD do not have cancer.[28-30] Furthermore, several antineuronal antibodies may co-occur in the same patient, particularly if the underlying tumor is SCLC. A recent study identified concurrent Hu, CRMP5, and Zic4 antibodies in the serum or CSF of 27% of the patients with SCLC and paraneoplastic encephalomyelitis (PEM).[31] The serum of cancer patients without PND may contain antineuronal antibodies.[32] Usually the antibody titers are lower than those in patients with PND, but they can overlap. In a recent report, antibodies to Hu, CRMP5, and Zic4 were encountered in 19, 9, and 16% of SCLC patients without PND, respectively.[31] A practical implication is that the detection of any of these antibodies in a patient with neurological symptoms

of unknown cause suggests a PND and predicts an underlying cancer, usually SCLC. However, detection of these antibodies does not preclude ruling out other complications of cancer, particularly if the syndrome is not a classic PND.  Searching for an Occult Cancer The discovery of an occult neoplasm in association with a particular neurological syndrome remains the gold standard of diagnosing PND. In addition to the clinical history, evaluation of risk factors for cancer, and serological cancer markers, most patients will need chest and abdomen computed tomography (CT) as part of the initial evaluation or restaging of cancer. The need for other tests will vary with the patient's gender and type of syndrome or antineuronal antibody; these may include pelvic or vaginal ultrasound, mammograms, or testicular ultrasound. Recent studies have demonstrated that total-body FDG-PET is useful in identifying tumors not visible with other studies.[14,33] Despite the sensitivity of FDG-PET scan, there are instances where antineuronal antibodies can lead to the discovery of neoplasms that escape PET detection.[34] The presence of a second cancer should be suspected if the tumor identified is different from the cancer that usually associates with a specific syndrome or antineuronal antibody or does not express the neuronal antigen.[5] Patients with classic PND or with nonclassic PND but positive antineuronal antibodies, whose tumor is not found, need close cancer surveillance. A common practice is to repeat evaluations every 6 months (i.e., body CT or FDG-PET). The cancer usually manifests within the first 4 years of the PND, but there are rare instances where the expected type of tumor was demonstrated 10 years later.[35]  Patients With Cancer who Develop Neurological Symptoms In patients with cancer the suspicion of a PND is usually based on the type of neurological syndrome (i.e., classic PND) and absence of other etiologies including metastasis to the nervous system, vascular and infectious disorders, metabolic abnormalities, malnutrition, and side effects of cancer treatment.[3] Patients in cancer remission who develop a PND should be examined for tumor recurrence. If a specific antineuronal antibody is identified, the clinical significance varies according to the type of antibody and neurological disorder (see diagnostic criteria, below).  Diagnostic Criteria of PND Because antineuronal antibodies are not always present in patients with PND and the presence of these antibodies can occur in cancer patients without PND, a set of criteria was recently proposed by a group of investigators.[36] These criteria take into account: (1) the type of neurological syndrome ( Table 1 ); (2) the type of anti-neuronal antibody ( Table 2 ); and the presence or absence of cancer. Based on this information two levels of evidence have been proposed: definite PND or possible PND ( Table 3 ). Table 3. Diagnostic Criteria of PND of the CNS

 Classic Paraneoplastic Neurological Disorders of the Central Nervous System  Paraneoplastic Cerebellar Degeneration PCD manifests as a pancerebellar, usually symmetrical syndrome that evolves rapidly in several days or weeks. At the early stages of PCD, the brain MRI is normal, or may rarely show cerebellar cortical enhancement with gadolinium; as the disease progresses, cerebellar atrophy develops.[3] PCD may occur in isolation or in association with symptoms of more widespread involvement of the CNS (encephalomyelitis). The association of a subacute cerebellar ataxia with LEMS is highly suggestive of a paraneoplastic origin of both disorders. Paraneoplastic cerebellar degeneration usually precedes the diagnosis of the tumor. In these patients the differential diagnosis should include any of the disorders shown in Table 4 . In patients with known cancer, the differential diagnosis includes all the previously indicated neurological complications of cancer, specifically including the cerebellar toxicity of 5-fluoruracil and cytosine arabinoside.[37,38] Thiamine deficiency resulting in Wernicke's encephalopathy and ataxia has been reported in patients with leukemia or lymphoma.[39] Table 4. Differential Diagnosis of Some Classic PND Almost all well-characterized antineuronal antibodies have been reported in association with paraneoplastic ataxia ( Table 2 ). Serological markers that identify patients with quot;purequot; PCD include Yo,[40] Tr,[41] voltage-gated calcium channel (VGCC), and Zic antibodies.[31,42] Patients with VGCC antibodies should be examined for LEMS. However, despite the detection of these antibodies some patients do not develop LEMS.[24] Between 30 and 40% of patients with PCD do not harbor antineuronal antibodies, and the diagnosis relies on the exclusion of other etiologies and demonstration of the cancer.  Paraneoplastic Limbic Encephalitis Patients with paraneoplastic limbic encephalitis may present with anxiety, depression, confusion, delirium,

hallucinations, seizures, short-term memory loss, and dementia. MRI usually shows abnormalities in the medial temporal lobes in T2 or FLAIR sequences. Some of these abnormalities may be hypermetabolic in FDG-PET studies.[10] The electroencephalogram (EEG) often demonstrates uni- or bilateral temporal lobe epileptic discharges or slow background activity.[8] The combination of clinical, MRI, EEG, and CSF findings along with antineuronal antibody testing identifies most cases of paraneoplastic limbic encephalitis. The antibodies more frequently associated with this disorder include anti-Hu,[11] anti-Ma2,[43] anti- CRMP5,[44] and rarely anti-voltage-gated potassium channel antibodies.[22] The latter occur more frequently in patients without cancer;[22] this disorder responds better to immunotherapy than other types of limbic encephalitis.[22] About 40% of patients with paraneoplastic limbic encephalitis are seronegative or have uncharacterized antibodies.[8,20] Viral encephalitis should particularly be considered in the differential diagnosis of paraneoplastic limbic encephalitis ( Table 4 ). Herpes simplex encephalitis usually results in hemorrhagic necrosis of the medial aspect of the temporal and orbital frontal lobes. Human herpesvirus 6 encephalitis typically affects bone marrow transplant recipients; the clinical and MRI features of this disorder can mimic to perfection paraneoplastic limbic encephalitis.[45] Polymerase chain reaction analysis of the CSF usually establishes the diagnosis of these viral disorders.  Paraneoplastic Encephalomyelitis Patients with paraneoplastic encephalomyelitis (PEM) disorder develop symptoms of multifocal involvement of the CNS, including limbic system, cerebellum, brain stem, and spinal cord. Frequent accompanying sensory and autonomic deficits result from involvement of the dorsal root ganglia and sympathetic or parasympathetic peripheral nerves and ganglia. Symptoms resulting from limbic or cerebellar encephalitis are similar to those described for the isolated forms of these disorders. Paraneoplastic brain stem encephalitis rarely occurs in isolation.[46] The pathological findings predominate in the lower brain stem, usually medulla and inferior olivary nuclei.[47] In the spinal cord the inflammatory process can result in lower motor neuron dysfunction or a mixed syndrome in which the corticospinal tracts are also involved. Because most patients have additional neurological symptoms (i.e., sensory deficits, ataxia), the differential diagnosis with motor neuron disease is rarely an issue.[47] Autonomic dysfunction includes gastrointestinal paresis and pseudo-obstruction, orthostatic hypotension, cardiac arrhythmias, erectile dysfunction, hyperhidrosis, urinary retention, and abnormal pupillary reflexes. Paraneoplastic dysautonomia rarely occurs in isolation; it usually accompanies PEM or LEMS.[47] Antibodies to the ganglionic acetylcholine receptors have been reported in some patients with cancer as well as in idiopathic pandysautonomia.[23] The antineuronal antibodies more frequently encountered in PEM are anti-Hu, anti-CRMP5, anti-Zic, and less frequently anti-amphiphysin.[31,48,49] All of these antibodies associate with SCLC and may co-occur in the same patient. Anti-Ma2 encephalitis predominantly affects the limbic system, hypothalamus, and upper brain stem; the tumors more frequently involved are testicular germ-cell neoplasms and non-SCLC.[50]  Paraneoplastic Sensory Neuronopathy Patients with paraneoplastic sensory neuronopathy develop pain, numbness, and sensory deficits that can affect limbs, trunk, and cranial nerves, including hearing loss. The diagnosis of radiculopathy or multineuropathy is often first considered because the sensory deficits can be asymmetric and non-length- dependent.[51] In addition to the sensory loss, the resulting syndrome includes sensory ataxia and decreased or absent reflexes. Nerve conduction studies show decreased or absent sensory nerve action potentials with normal or near-normal motor conduction velocities.[52] Paraneoplastic sensory neuronopathy may occur in

isolation, but often precedes or coincides with the development of PEM, suggesting a common pathogenic mechanism. In both instances, detection of anti-Hu antibodies is frequent.[53] Sensorimotor neuropathies associated with anti-Hu antibodies often result from mixed involvement of dorsal root ganglia and peripheral nerves. In the latter, serum anti-CRMP5 antibodies can also be present.[48,49] Up to 18% of patients with paraneoplastic sensory neuronopathy do not have serum antineuronal antibodies.[53] The differential diagnosis is shown in Table 4 ; in cancer patients it includes chemotherapy- induced neuropathy (cisplatin, paclitaxel, docetaxel, vincristine). In patients without cancer, Sjögren's syndrome should be considered; some patients with this syndrome can develop dorsal root ganglia dysfunction along with myelopathy and encephalopathy, mimicking PEM.[54]  Paraneoplastic Opsoclonus-Myoclonus Opsoclonus is an eye movement disorder characterized by chaotic, conjugate, arrhythmic, and multidirectional saccades. These symptoms often associate with myoclonus and truncal ataxia. The tumors more frequently involved are SCLC, breast and gynecological cancers in adults, and neuroblastoma in children. The majority of patients do not harbor antineuronal antibodies. Detection of anti-Ri antibodies usually indicate the presence of breast or gynecological cancers, or less frequently SCLC.[55] Other antineuronal antibodies that may occur in a minority of patients include Hu,[56] CRMP5/CV2,[48] Zic2,[57] amphiphysin,[49] Yo,[40] and Ma2 antibodies.[13] Paraneoplastic opsoclonus may respond to treatment, but improvement depends on tumor control.[7] There is an idiopathic form of opsoclonus-myoclonus for which there are no serological markers. Two patients with this disorder had antibodies to the adenomatous polyposis coli protein (APC).[57] Compared with paraneoplastic opsoclonus, patients with idiopathic opsoclonus are younger and the disorder responds better to immunotherapy.[7] The differential diagnosis of opsoclonus is extensive, particularly if a paraneoplastic origin is suspected but the presence of a tumor is not known ( Table 4 ).  Treatment and Outcome of Paraneoplastic Neurological Disorders Studies have emphasized the importance of early cancer treatment to achieve the stabilization or improvement of the PND.[58] Chalk and colleagues demonstrated improvement of the neuromuscular transmission in 10 of 11 patients with LEMS after treating the tumor.[59] In a study of paraneoplastic opsoclonus, all patients who received oncological treatment showed complete or partial neurological improvement, while those whose cancer was not treated showed neurological deterioration, regardless of immunotherapy.[7] For other PND of the CNS, the neurological response to oncological treatment is less satisfactory. Improvement or stabilization of anti-Hu-associated PEM was observed in 37% of patients who received antineoplastic therapy.[5] Patients with pure sensory neuronopathy were more likely to improve than those with PEM. The neurological response to oncological treatment was worse in a series of patients with anti- Yo-associated PCD in which none of 25 patients with this disorder improved after cancer therapy. Furthermore, 37% of these patients developed PCD while undergoing cancer therapy or during tumor remission.[60] In contrast, patients with anti-Ma2 encephalitis may show dramatic improvement of neurological symptoms after cancer treatment or immunotherapy. In a series of 18 patients with anti-Ma2 encephalitis, seven patients had complete or partial remission of neurological symptoms, usually in association with complete tumor response to therapy.[13] A more recent series of 38 patients with anti-Ma2 encephalitis showed that 33% had neurological improvement, three with complete recovery; 21% had long-term stabilization (median follow-up 3½; years); and 46% deteriorated. Features associated with improvement or stabilization included male gender, underlying testicular germ-cell tumors with complete response to treatment, and

limited involvement of the nervous system (Dalmau, unpublished data). The reasons for the better outcome of patients with anti-Ma2 encephalitis are unclear. However, this disorder frequently associates with testicular germ-cell tumors, which in contrast to other cancers can be completely removed and are very responsive to oncological treatments. Although PND of the CNS usually do not respond to immunotherapy alone, there are several case reports of patients who stabilized or improved after immunosuppression or immunomodulatory treatments, such as plasma exchange or intravenous immunoglobulins (IVIg).[58,61] The main disorders that may show response to immunotherapy or corticosteroids are opsoclonus-myoclonus and limbic encephalitis.[7,22] A recent series of selected patients (Rankin disability score between 2 and 4) with diverse PND showed that in patients without a known tumor, immunotherapy (plasma exchange and oral cyclophosphamide) at the early stages of the PND may result in improvement; patients with multifocal encephalomyelitis were not included.[62] Figure 1. Recommended approach to treatment of PND of the CNS. AMay include IVIg and/or intravenous or oral steroids and/or plasma exchange. BMay include cyclophosphamide and/or rituximab, or tacrolimus. Variable efficacy (class 4 to 5 level of evidence) has been reported for IVIg, steroids, plasma exchange, or protein-A immunoglobulin G absorption, cyclophosphamide, and rituximab.[58,75-77] Tacrolimus has been suggested as treatment;[78] clinical studies are not available. *Because patients with limbic encephalitis or opsoclonus/myoclonus may show dramatic improvement to immunosuppression, patients with these two disorders and KPS < 50 may be considered for immunosuppression. KPS, Karnofsky performance status.  Assessment of the Clinical Efficacy of Antitumor Immunity It has been suggested that paraneoplastic immunity is clinically effective in controlling tumor growth, accounting for the small size and limited metastatic burden of tumors associated with PND. However, there

are only two clinical series, both in patients with SCLC, supporting this hypothesis. One study was conducted in patients without PND and showed that those with low titers of anti-Hu antibodies were more likely to have limited tumor stage and better response to chemotherapy than patients without antibodies. [63] In this study the strongest association was between the presence of anti-Hu antibodies and increased response to chemotherapy; the mechanisms underlying the chemosensitivity were not examined. The second study compared SCLC patients with and without LEMS and found that patients with LEMS had longer survival. Because 14 of the 15 LEMS patients developed the neurological disorder before the tumor diagnosis, a lead-time bias could not be ruled out. In addition to these two series, other data supporting clinically effective antitumor immunity derives from a small number of patients with spontaneous tumor regression.[64-67] However, the evidence for the tumor regression is often unclear. Some of the reported patients received oncological treatment and therefore the tumor regression was not spontaneous;[66] others lacked pathological demonstration of a tumor;[65,66] and others did not have detectable immune responses.[67] Despite experimental evidence that some patients with PCD develop cytotoxic T-cell responses against the paraneoplastic antigen (Yo or CDR2) expressed by the tumor,[68] all series of patients with anti-Yo- associated PCD raise doubt on the efficacy of the antitumor immune response.[40,60] For example, in a series of 19 patients with PCD, the neurological disorder preceded or coincided with the diagnosis of the cancer in 15 patients, and in seven the paraneoplastic antibodies led to exploratory laparotomy. Despite this, 72% of all patients had stage III ovarian cancer.[69] In another series, 34 of 55 patients with anti-Yo- associated PCD developed neurological symptoms that led to the search for cancer, usually ovarian or breast cancer.[40] Regardless of this lead-time bias, seven patients had widely metastatic cancer and 26 regional metastases, a figure closely similar to that encountered in patients without PND. In another series of 34 patients with anti-Yo-associated PCD, all 12 patients with breast cancer and 15 of 18 patients with gynecological cancers had metastatic lymph nodes at the time of tumor diagnosis.[60] The median survival was 100 months for patients with breast cancer and 22 for those with gynecological cancer. All large series of patients with PND of the CNS suggest a lead-time bias of early tumor diagnosis as a result of increased surveillance.[5,35,47,60,69-71] In each of these studies most patients developed PND before the tumor diagnosis, and none of the patients had spontaneous tumor regression. Furthermore, recent FDG- PET studies in SCLC patients without PND show that ~60% have limited disease at the time of tumor diagnosis.[72] These studies suggest that with better diagnostic techniques the tumor staging of patients without PND is becoming similar to that of patients with PND in whom the neurological disorder or detection of antibodies prompt the search for cancer. Furthermore, in two series of patients with PND the use of immunotherapy did not favor tumor growth as one would expect if the antitumor immune response was clinically effective.[62,73] Overall, rather than an effective antitumor immunity, most clinical series of PND suggest that the immune response is triggered at early stages of cancer development and that the neurological symptoms forewarn of the presence of a tumor that otherwise would have clinically manifested months or years later. For example, carcinoma in situ of the testis (also known as intratubular germ-cell tumor) takes ~5 years to become invasive, and therefore detectable.[74] We reported two patients whose PND led to the diagnosis of carcinoma in situ of the testis at the preinvasive stage.[13]  General Treatment Strategy for PND of the CNS In summary, data from the above studies suggest: (1) the diagnosis and treatment of the tumor is the main factor associated with stabilization or improvement of PND and should be the main goal in the management of these disorders; (2) there is no evidence that immunosuppression favors tumor growth in PND patients; and (3) some patients benefit from immunosuppression. In view of these conclusions, a general treatment strategy for PND of the CNS is proposed (Fig. 1).[75-78] Because the simultaneous use of chemotherapy and some immunosuppressants may result in significant

toxicity, two levels of immunological intervention are suggested. Patients with progressive PND who are receiving chemotherapy should be considered for immunosuppression or immunomodulation that may include oral or intravenous corticosteroids, IVIg, or plasma exchange. Patients with progressive PND who are not receiving chemotherapy should be considered for more aggressive immunosuppression that may include oral or intravenous cyclophosphamide, tacrolimus, cyclosporine, or rituximab. Although there is no compelling evidence than any of these immunosuppressants is better than others for patients with PND, the authors favor the use of corticosteroids, IVIg, and cyclophosphamide. Clinical trials with homogeneous groups of PND patients (same antibody, same syndrome) assessing the proposed treatment design and immunosuppressants should be the focus of future studies. References 1. Dalmau JO, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin Oncol 1997;24:318-328 2. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 2000;23:1800- 3. Posner JB. Neurologic Complications of Cancer. Philadelphia F.A. Davis Company; 1995 4. O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111:577-596 5. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148 6. Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Hu-associated paraneoplastic sensory neuropathy. Neurology 1994;44:2258-2261 7. Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 2001;124:437-443 8. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481-1494 9. Dadparvar S, Anderson GS, Bhargava P, et al. Paraneoplastic encephalitis associated with cystic teratoma is detected by fluorodeoxyglucose positron emission tomography with negative magnetic resonance image findings. Clin Nucl Med 2003;28:893-896 10. Fakhoury T, Abou-Khalil B, Kessler RM. Limbic encephalitis and hyperactive foci on PET scan. Seizure 1999;8:427-431 11. Alamowitch S, Graus F, Uchuya M, Rene R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain 1997;120:923-928 12. Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 2003;78:1363-1368 13. Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J. Molecular and clinical diversity in

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47. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992;71:59-72 48. Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001;49:146- 154 49. Saiz A, Dalmau J, Butler MH, et al. Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma. J Neurol Neurosurg Psychiatry 1999;66:214-217 50. Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 1999;122:27-39 51. Horwich MS, Cho L, Porro RS, Posner JB. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol 1977; 2:7-19 52. Camdessanche JP, Antoine JC, Honnorat J, et al. Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 2002;125:166- 175 53. Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol 1998;44: 976-980 54. de Seze J, Stojkovic T, Hachulla E, et al. Myelopathy-Sjogren's syndrome association: analysis of clinical and radiological findings and clinical course. Rev Neurol (Paris) 2001;157:669-678 55. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29:241-251 56. Hersh B, Dalmau J, Dangond F, Gultekin S, Geller E, Wen PY. Paraneoplastic opsoclonus-myoclonus associated with anti-Hu antibody. Neurology 1994;44:1754-1755 57. Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J. Autoantigen diversity in the opsoclonus-myoclonus syndrome. Ann Neurol 2003;53:347-353 58. Rosenfeld MR, Dalmau J. Current therapies for paraneoplastic neurologic syndromes. Curr Treat Options Neurol 2003; 5:69-77 59. Chalk CH, Murray NM, Newsom-Davis J, O'Neill JH, Spiro SG. Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology 1990;40:1552- 1556 60. Rojas I, Graus F, Keime-Guibert F, et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000;55:713-715 61. David YB, Warner E, Levitan M, Sutton DM, Malkin MG, Dalmau JO. Autoimmune paraneoplastic cerebellar degeneration in ovarian carcinoma patients treated with plasma-pheresis and immunoglobulin. A case report. Cancer 1996;78: 2153-2156 62. Vernino S, O'Neill BP, Marks RS, O'Fallon JR, Kimmel DW. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neurooncol 2004;6:55-62

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Topic of the month...Paraneoplastic syndromes

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