3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate Official reprint from UpToDate® www.uptodate.com ©2017 UpToDate® Overview of paraneoplastic syndromes of the nervous system Authors: Josep Dalmau, MD, PhD, Myrna R Rosenfeld, MD, PhD Section Editor: Lisa M DeAngelis, MD, FAAN, FANA Deputy Editor: April F Eichler, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: Jan 2017. | This topic last updated: Dec 06, 2016 INTRODUCTION — Paraneoplastic neurologic syndromes are a heterogeneous group of disorders caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment. These syndromes may affect any part of the nervous system, from cerebral cortex to neuromuscular junction and muscle (table 1), either damaging one area (eg, Purkinje cell, presynaptic cholinergic synapses) or multiple areas (eg, encephalomyelitis) This topic provides an overview of the pathogenesis, diagnosis, and treatment of paraneoplastic disorders Individual syndromes are discussed separately. (See "Paraneoplastic syndromes affecting peripheral nerve and muscle" and "Paraneoplastic syndromes affecting the spinal cord and dorsal root ganglia" and "Paraneoplastic and autoimmune encephalitis" and "Paraneoplastic cerebellar degeneration" and "Opsoclonus myoclonus syndrome" and "Paraneoplastic visual syndromes".) PATHOGENESIS — Although the pathogenesis of paraneoplastic neurologic syndromes is incompletely understood, immunologic factors are believed to be important because antibody and Tcell responses against nervous system antigens have been described for many of these disorders. The immunologic response is directed against shared antigens that are ectopically expressed by the tumor, but otherwise exclusively expressed by the nervous system (picture 1) [1,2], or rarely by the nervous system and testes [3]. For unknown reasons, the immune system identifies these antigens as foreign and mounts an immune attack against them. One report suggests that the immune system can mount a Tcell response to a normal protein when it is expressed in a cancer cell, suggesting that normal selfantigens may be processed differently in cancer cells than in the normal cells [4] Antibodies that occur in paraneoplastic disorders have been divided in two categories depending on the location of the antigen ● Antibodies directed against intracellular neuronal proteins (called classical paraneoplastic or onconeuronal antibodies) – These antibodies belong to the category of "wellcharacterized" paraneoplastic antibodies (table 2 and table 3), and their detection almost always indicates the presence of an underlying tumor Examples include Hu (also known as type 1 antineuronal nuclear antibody [ANNA1]), Ri (also known as type 2 antineuronal nuclear antibody [ANNA2]), Yo (also known as Purkinje cell cytoplasmic antibody type 1 [PCA1]), amphiphysin, Ma2, Tr (also known as delta/notchlike epidermal growth factorrelated receptor [DNER]), collapsin responsemediator protein5 (CRMP5), and recoverin. These antibodies are surrogate markers of the paraneoplastic disorder, but in most of these disorders, the pathogenic mechanism is believed to be mediated by cytotoxic Tcells ● Antibodies directed against neuronal cell surface or synaptic proteins – Examples include antibodies against the antiNmethylDaspartate (NMDA) receptor and the alphaamino3hydroxy5methyl4 isoxazolepropionic acid (AMPA) receptor (table 2 and table 3). These antibodies may occur with or without a https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 1/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate cancer or tumor association [5]. The frequency of a tumor association varies according to the antibody These antibodies appear to have direct pathogenic effects on the target antigens [6] To date, antibodies with a direct pathogenic effect on the target neuromuscular or neuronal antigens have only been found in a few disorders of the peripheral nerve or neuromuscular junction and in a substantial number of autoimmune encephalitides with antibodies against cell surface or synaptic proteins. Detection of these antibodies does not necessarily imply the presence of an underlying tumor, given that they can also occur in the nonparaneoplastic setting [5]. These include: ● P/Q type voltagegated calcium channel antibodies in the LambertEaton myasthenic syndrome (LEMS) [7] ● Acetylcholine receptor antibodies in myasthenia gravis (MG) [8] ● NMDA receptor antibodies in antiNMDA receptor encephalitis [911] ● AMPA receptor antibodies in a subgroup of limbic encephalitis [12,13] ● Ganglionic acetylcholine receptor antibodies in autonomic neuropathy [14] ● Recoverin antibodies in carcinoma associated retinopathy [15] ● Gammaaminobutyric acid A (GABAA) receptor antibodies in encephalopathy with refractory seizures [16] ● Leucine rich glioma inactivated 1 (LGI1) antibodies in a subgroup of limbic encephalitis [17] ● Dipeptidylpeptidase–like protein6 (DPPX) antibodies in a syndrome of central nervous system hyperexcitability, often associated with hyperekplexia [1821] Autoantibodies may also play an important role in other syndromes such as the paraneoplastic form of stiff person syndrome (often associated with amphiphysin antibodies) [22] and paraneoplastic dermatomyositis. The role of autoantibodies in the pathogenesis of these disorders is the rationale for the use of rituximab [23] Although a pathogenic role of most classical paraneoplastic antibodies has not been proven, their presence indicates the paraneoplastic nature of a neurologic disorder, and in many cases, can narrow the search for an occult tumor to a few organs (table 2 and table 3) There is evidence that some paraneoplastic neurologic syndromes without an identifiable tumor may result from immunemediated eradication of tumor cells [24]. In keeping with this hypothesis, some reports suggest a more limited disease distribution and better outcome among patients with smallcell lung cancer (SCLC) who develop immunity to paraneoplastic antigens [2527]. However, review of most large series of patients demonstrates that the oncologic outcome of patients with antibodyassociated paraneoplastic syndromes does not significantly differ from that of patients who do not have the antibodies or a paraneoplastic syndrome [2833] Cellmediated immunity also appears to play an important role in paraneoplastic neurologic disorders. Tcell responses directed against the same tumor antigens can be demonstrated in some patients, although the relative contribution of cellular and humoral immunity to the clinical and pathologic manifestations is an unresolved issue [3436] This topic review will focus on those neurologic syndromes that are associated with paraneoplastic antibodies There are also nonimmunologic mechanisms that can be involved in paraneoplastic neurologic syndromes and are discussed elsewhere. These include [37]: ● Metabolic abnormalities due to tumoral secretion of hormones or cytokines (eg, hyponatremia due to antidiuretic hormone, hypercalcemia due to parathyroid hormonerelated protein, or hypoglycemia due to https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 2/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate insulinlike growth factorII). (See "Hypercalcemia of malignancy: Mechanisms" and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".) ● Competition between the tumor and the nervous system for a substrate (eg, carcinoid tumors and tryptophan). (See "Clinical features of the carcinoid syndrome".) ● The synthesis by the tumor of immunoglobulins that react with the peripheral nervous system (eg, a distal, symmetric, and slowly progressive sensorimotor peripheral neuropathy in Waldenstrom's macroglobulinemia) and antibodies against myelinassociated glycoprotein (MAG). (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of Waldenström macroglobulinemia".) INCIDENCE — Paraneoplastic disorders (PND) are more frequent than previously considered, with an incidence that varies with the neurologic syndrome and type of tumor. The more common syndromes are LambertEaton myasthenic syndrome (LEMS), which affects approximately 3 percent of patients with smallcell lung cancer (SCLC), and myasthenia gravis (MG), which affects 15 percent of all patients with thymoma. One or more paraneoplastic neurologic disorder is present in up to 9 percent of patients with SCLC (mostly LEMS, sensory neuronopathy, and limbic encephalitis) [38]; for most other solid tumors, the incidence is far less than 1 percent [39] Paraneoplastic peripheral neuropathies affect 5 to 15 percent of patients with plasma cell dyscrasias associated with malignant monoclonal gammopathies. More than 50 percent of patients with the rare osteosclerotic form of myeloma develop a predominantly motor paraneoplastic peripheral neuropathy. Patients with all forms of myeloma, but usually the osteosclerotic type, can develop a severe, symmetric, sensorimotor neuropathy with muscle atrophy in association with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin). (See "Clinical presentation and management of thymoma and thymic carcinoma" and "POEMS syndrome".) GENERAL DIAGNOSTIC CONSIDERATIONS — Many paraneoplastic syndromes develop in the early stages of cancer, and the presence of a tumor or tumor recurrence can be difficult to demonstrate Diagnostic criteria — Given the challenges that can arise in diagnosing paraneoplastic syndromes of the nervous system, an international panel of neurologists has worked to establish more rigorous diagnostic criteria [40]. These criteria divide patients with suspected paraneoplastic syndromes into "definite" and "possible" categories as follows Definite syndromes include [40]: ● A "classical" syndrome and cancer that develops within five years of diagnosis of the neurologic disorder. A classical syndrome is defined as a neurologic syndrome that is frequently associated with cancer. Classical syndromes include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus myoclonus, subacute sensory neuronopathy, chronic gastrointestinal pseudoobstruction, LambertEaton myasthenic syndrome (LEMS), and dermatomyositis ● A nonclassical syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission ● A nonclassical syndrome with paraneoplastic antibodies and cancer that develops within five years of the diagnosis of the neurologic disorder ● A neurologic syndrome (classical or not) with "wellcharacterized" paraneoplastic antibodies and no cancer Wellcharacterized paraneoplastic antibodies are those directed against antigens whose molecular identity is known or that have been identified by several investigators, while partiallycharacterized antibodies are those https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 3/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate whose target antigens are unknown or require further analysis (table 2 and table 3) [40]. These well characterized antibodies include antiHu, CV2/CRMP5, Ri, Yo, Tr, Ma2, and amphiphysin. Possible syndromes include [40]: ● A classical syndrome as defined above, no paraneoplastic antibodies, no cancer, but at high risk to have an underlying tumor ● A neurologic syndrome (classical or not) with partiallycharacterized paraneoplastic antibodies (eg, not the wellcharacterized antibodies described above) and no cancer ● A nonclassical syndrome, no paraneoplastic antibodies, and cancer present within two years of diagnosis Antibody screening — Wellcharacterized paraneoplastic antibodies against intracellular antigens (classical paraneoplastic or onconeuronal antibodies) are almost always detectable in serum; only in rare instances will the cerebrospinal fluid (CSF) reveal antibodies undetected in serum [4143] In contrast, antibodies to cell surface or synaptic proteins (those that associate with encephalitis with or without a cancer association) frequently occur only in CSF, or the serum may give misleading results. The frequency of these problems depends on the antigen. For example, in about 15 percent of patients with antiNmethylD aspartate (NMDA) receptor encephalitis, the antibodies are detectable in CSF but not in serum. In patients suspected to have these disorders (eg, antiNMDA, alphaamino3hydroxy5methyl4isoxazolepropionic acid [AMPA], and gammaaminobutyric acid [GABA] A or B receptors, among others (table 2 and table 3)), CSF should be included in the analysis. Important tenets of antibody screening include: ● While antibodies such as P/Q type voltagegated calcium channel antibodies in patients with LEMS, acetylcholine receptor antibodies in myasthenia gravis (MG), and most encephalitis syndromes related to neuronal cell surface and synaptic antibodies associate with specific syndromes, they do not differentiate between paraneoplastic and nonparaneoplastic cases [14,44,45]. This is in contrast with other antibodies, such as glutamic acid decarboxylase (GAD) or amphiphysin. In the context of stiffperson syndrome, patients with GAD antibodies rarely have cancer, while patients with amphiphysin usually have an underlying tumor [46,47]. (See "Stiffperson syndrome".) ● The serum of cancer patients without paraneoplastic neurologic syndromes may contain paraneoplastic antibodies, although the titers are usually lower [25,48,49] ● Different antibodies can be associated with the same paraneoplastic neurologic syndrome and conversely, the same antibody may be associated with different syndromes [5052] ● Several paraneoplastic antibodies may cooccur in the same patient, particularly if the underlying tumor is smallcell lung cancer (SCLC) [50,51] As noted above, wellcharacterized paraneoplastic antibodies are sometimes found in patients with cancer but without neurologic symptoms and patients with neurologic disorders without an identifiable cancer [5]. However, wellcharacterized paraneoplastic antibodies (table 2 and table 3) rarely, if ever, occur in normal individuals [53 55]. The presence of such antibodies should demand a careful search for an underlying neoplasm. The specificity and clinical significance of antibodies against neuronal cell surface or synaptic proteins is discussed in more detail separately Testing for paraneoplastic antibodies can facilitate the recognition of the simultaneous occurrence of two or sometimes three paraneoplastic neurologic syndromes in one patient. As an example, patients with SCLC and https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 4/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate paraneoplastic cerebellar degeneration develop LEMS more frequently than expected [56]. Since the development of both disorders is highly disabling, and LEMS usually responds to treatment, all patients with SCLC who develop paraneoplastic cerebellar symptoms should be examined for LEMS. In almost all patients with LEMS, lower extremity reflexes are absent; sometimes they reappear after exercise. Another association is the development of LEMS in about 6 percent of patients with antiHu associated paraneoplastic encephalomyelitis [57]. (See "Clinical features and diagnosis of LambertEaton myasthenic syndrome".) Other diagnostic tests — The diagnosis may be particularly difficult in patients with known cancer and neurologic symptoms in whom paraneoplastic antibodies cannot be detected. Absence of these antibodies does not exclude a paraneoplastic syndrome; however, the presumptive diagnosis requires the absence of the metastatic and nonmetastatic complications such as brain or leptomeningeal metastases and toxic effects of prior therapies In the absence of characteristic antibodies in the serum, specific diagnostic tests may be helpful for some paraneoplastic syndromes: MRI — Neuroimaging can assist in the diagnosis of limbic encephalitis because the medial temporal lobes, the site of major pathology, often show increased signal on fluidattenuated inversion recovery (FLAIR) images and occasionally areas of contrast enhancement. Patients with paraneoplastic cerebellar degeneration may develop signs of atrophy detectable by magnetic resonance imaging (MRI) several months after the onset of symptoms [56,58]; however, for most paraneoplastic syndromes, neuroimaging studies are normal or nonspecific PET — Positron emission tomography of the brain using fluorodeoxyglucose (FDGPET) will occasionally identify hypermetabolism of the medial temporal lobe(s) in patients with limbic encephalopathy [59], or of the cerebellum in patients with paraneoplastic cerebellar degeneration [60] Lumbar puncture — Although detection of paraneoplastic antibodies in CSF confirms that the disorder is paraneoplastic, in our experience these antibodies are usually present in the serum as well [43]. Exceptions include some patients with antiTr antibodies and patients with antibodies to antigens expressed in the cell membrane of hippocampal neurons [41,42]. For the latter disorders (eg, antiNMDA receptor encephalitis), CSF examination is critical because serum testing may be negative and antibody titers are higher in CSF than in serum [61]. CSF examination can assist in making the diagnosis of paraneoplastic syndromes in two other ways: ● The combination of negative cytology for malignant cells and the absence of meningeal enhancement on MRI can reasonably exclude leptomeningeal metastases ● Inflammatory changes (eg, pleocytosis, intrathecal synthesis of immunoglobulin G [IgG], oligoclonal bands) can support the presence of an inflammatory or immunemediated neurologic disorder [62] Electrophysiology — Some paraneoplastic syndromes of the peripheral nervous system are associated with characteristic electrophysiologic findings. These include LEMS, MG, neuromyotonia, and dermatomyositis However, these findings are also present when the same neurologic syndrome is not associated with a tumor Nevertheless, electrophysiologic findings that confirm the underlying syndrome may still be helpful by directing the search for the neoplasm to specific organs (eg, lung with LEMS, and thymus with MG) Occult malignancy — While paraneoplastic syndromes are most often diagnosed in the setting of a known malignancy, it is common for a paraneoplastic disorder to develop before a cancer is identified The clinical syndrome and identification of certain paraneoplastic antibodies may suggest a specific underlying tumor and direct investigations (table 2 and table 3). In most other instances, the tumor is revealed by computed tomography (CT) of the chest, abdomen, and pelvis. Additional tests, such as mammogram, breast MRI, or https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 5/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate ultrasound of the pelvis or testes, are ordered when suggested by the clinical syndrome and identification of certain paraneoplastic antibodies or the presence of other risk factors Whole body FDGPET combined with CT is useful in demonstrating occult neoplasms or small metastatic lesions and is a reasonable alternative to sequential testing starting with CT and mammography [6365]. In one case series of 104 patients, sensitivity and specificity of FDGPET were 80 and 67 percent, compared with 30 and 71 percent for CT [66]. Results from another small study found that FDGPET combined with CT scanning increased sensitivity and accuracy of tumor diagnosis in patients with paraneoplastic syndromes [67] A negative PET/CT scan does not rule out underlying cancer; use of other imaging modalities (eg, magnetic resonance imaging, ultrasound) or repeating PET/CT scan after a severalmonth interval can be fruitful. A 2010 taskforce recommended repeat cancer screening in three to six months after an initial negative evaluation, followed by screening every six months up until four years, if testing remains unrevealing [68]. In LEMS, screening for two years is sufficient. Also, if an identified cancer is not consistent with the paraneoplastic syndrome or the identified antibody, continued search for another neoplasm should be considered [69] TREATMENT AND PROGNOSIS OVERVIEW — Because the majority of neurologic paraneoplastic syndromes are immunemediated, two general approaches to therapy have been tried: removal of the antigen source by treatment of the underlying tumors, and suppression of the immune response. The likelihood of response varies by syndrome; additional predictors of response are not well understood In general, in the paraneoplastic disorders with antibodies against intracellular antigens (classical paraneoplastic or onconeuronal antibodies), in which the underlying pathogenic mechanism is thought to be cytotoxic Tcell mediated, the response to treatment (antitumor plus immunotherapy) is less satisfactory than in those disorders associated with antibodies against cell surface or synaptic proteins, in which the pathogenic mechanism is antibodymediated ● Syndromes likely to respond to treatment – Immunosuppression is beneficial for some conditions, such as the LambertEaton myasthenic syndrome (LEMS) and myasthenia gravis (MG). In these conditions, plasma exchange or intravenous immune globulin (IVIG) (eg, 0.4 g/kg daily for five days) is usually effective in suppressing the immune response and improving neurologic status, at least in the short term. (See "Paraneoplastic syndromes affecting peripheral nerve and muscle", section on 'LambertEaton myasthenic syndrome'.) Encephalitides associated with antibodies against cell surface antigens such as antiNmethylDaspartate (NMDA) receptor, alphaamino3hydroxy5methyl4isoxazolepropionic acid (AMPA) receptor, gamma aminobutyric acid B (GABAB) receptor, and leucine rich glioma inactivated 1 (LGI1), among others, are also fairly responsive to immunosuppressive therapies. These disorders are usually treated with first line immunotherapeutics (steroids, IVIG or plasma exchange), and if these fail, second line therapies such as rituximab or cyclophosphamide are often effective. (See "Paraneoplastic and autoimmune encephalitis".) ● Syndromes that may respond to treatment – Although most patients with paraneoplastic peripheral neuropathies do not have paraneoplastic antibodies, there is often evidence of inflammatory mechanisms likely related to an immunemediated etiology, such as cerebrospinal fluid (CSF) pleocytosis, increased CSF proteins, or the presence of inflammatory infiltrates on nerve biopsy. For peripheral neuropathies, and particularly those with predominant demyelinating features, plasmapheresis, IVIG, and rituximab can be effective In cancerassociated disorders that are probably antibodymediated, such as opsoclonus myoclonus [70], stiffperson syndrome [71], and dermatomyositis [72], the approach to treatment is usually similar to that https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 6/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate used for syndromes associated with antibodies against cell surface antigens. (See "Opsoclonus myoclonus syndrome" and "Stiffperson syndrome" and "Initial treatment of dermatomyositis and polymyositis in adults".) ● Syndromes that usually do not respond to treatment – This includes most of the classical paraneoplastic syndromes associated with antibodies against intracellular antigens, such as paraneoplastic cerebellar degeneration, encephalomyelitis, the subgroup of limbic encephalitis with antibodies to intracellular antigens, myelitis, and cancerassociated retinopathy. In these patients, the treatment approach of removing the antibodies from serum (eg, plasma exchange, IVIG) usually fails; immunotherapies addressing Tcell mechanisms should be considered early (eg, cyclophosphamide or rituximab, which decreases Bcell antigen presentation to Tcells) [73]. Prompt control of the tumor and immunotherapy may stabilize or result in partial improvement [74], but rarely to the degree of recovery that frequently occurs with disorders associated with antibodies against cell surface or synaptic proteins Across the spectrum of paraneoplastic syndromes, there is some evidence that prompt oncologic treatment and immunotherapy (immunomodulation, immunosuppression) can be beneficial, especially if instituted during the time of symptom progression rather than after deficits have been fully established [73,75,76]. The failure of the neurologic syndrome to respond to treatment may be due to irreversible neuronal damage that occurred before the diagnosis was made and treatment begun. Rare patients may develop a second paraneoplastic syndrome, after recovering or stabilizing from the first. In one case series of eight such patients, the second paraneoplastic syndrome revealed cancer relapse in five and a second cancer in one patient [77] SUMMARY — Paraneoplastic neurologic syndromes are a heterogeneous group of disorders caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment. These syndromes may affect any part of the nervous system from cerebral cortex to neuromuscular junction and muscle (table 1) ● Paraneoplastic neurologic syndromes are believed to result when an immunologic response is directed against shared antigens that are ectopically expressed by the tumor, but otherwise predominantly expressed by the nervous system. Antibodies can be detected in the serum or cerebrospinal fluid (CSF) of many, but not all, patients with paraneoplastic syndromes. (See 'Pathogenesis' above.) ● Patients suspected of having a paraneoplastic neurologic syndrome should be examined for paraneoplastic antibodies. Testing of serum alone may suffice for "wellcharacterized" or "classical" paraneoplastic antibodies, but is not sufficient for some autoimmune encephalitides associated with antibodies against cell surface or synaptic proteins. When these disorders are suspected, CSF should be examined (table 2 and table 3). Important caveats include the following: • Low levels of some paraneoplastic antibodies may be seen in the serum of cancer patients without paraneoplastic syndromes • Wellcharacterized paraneoplastic antibodies rarely, if ever, occur in normal individuals. The presence of such antibodies should demand a careful search for an underlying neoplasm • Some, but not all, paraneoplastic antibodies may be associated with different neurologic syndromes and the same neurologic syndrome may be associated with different paraneoplastic antibodies. (See 'Antibody screening' above.) ● Neuroimaging studies, lumbar puncture, and electrophysiology tests can be helpful in characterizing the neurologic syndrome. (See 'Other diagnostic tests' above.) ● The paraneoplastic syndrome may precede the diagnosis of underlying malignancy. In such cases, the clinical syndrome and identification of certain paraneoplastic antibodies may suggest a specific underlying https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 7/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate tumor and direct investigations (table 2 and table 3). (See 'Occult malignancy' above.) ● Two general approaches to treatment include: removal of the antigen source by treatment of the underlying tumors, and suppression of the immune response. (See 'Treatment and prognosis overview' above.) Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Dalmau J, Gultekin HS, Posner JB. Paraneoplastic neurologic syndromes: pathogenesis and physiopathology. Brain Pathol 1999; 9:275 2. Dalmau J, Furneaux HM, CordonCardo C, Posner JB. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol 1992; 141:881 3. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50:339 4. Savage PA, Vosseller K, Kang C, et al. Recognition of a ubiquitous self antigen by prostate cancer infiltrating CD8+ T lymphocytes. Science 2008; 319:215 5. Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 2010; 257:509 6. Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci 2015; 1338:94 7. Lang B, NewsomDavis J, Wray D, et al. Autoimmune aetiology for myasthenic (EatonLambert) syndrome Lancet 1981; 2:224 8. Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330:1797 9. Dalmau J, Gleichman AJ, Hughes EG, et al. AntiNMDAreceptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7:1091 10. Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of antiNMDA receptor encephalitis. J Neurosci 2010; 30:5866 11. Planagumà J, Leypoldt F, Mannara F, et al. Human Nmethyl Daspartate receptor antibodies alter memory and behaviour in mice. Brain 2015; 138:94 12. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65:424 13. Peng X, Hughes EG, Moscato EH, et al. Cellular plasticity induced by antiαamino3hydroxy5methyl4 isoxazolepropionic acid (AMPA) receptor encephalitis antibodies. Ann Neurol 2015; 77:381 14. Vernino S, Low PA, Fealey RD, et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343:847 15. Ohguro H, Nakazawa M. Pathological roles of recoverin in cancerassociated retinopathy. Adv Exp Med Biol 2002; 514:109 16. PetitPedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014; 13:276 17. Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsyrelated LGI1 in limbic encephalitis neutralize LGI1ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013; 33:18161 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 8/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate 18. Boronat A, Gelfand JM, GresaArribas N, et al. Encephalitis and antibodies to dipeptidylpeptidaselike protein6, a subunit of Kv4.2 potassium channels. Ann Neurol 2013; 73:120 19. Balint B, Jarius S, Nagel S, et al. Progressive encephalomyelitis with rigidity and myoclonus: a new variant with DPPX antibodies. Neurology 2014; 82:1521 20. Tobin WO, Lennon VA, Komorowski L, et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 2014; 83:1797 21. Piepgras J, Höltje M, Michel K, et al. AntiDPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons. Neurology 2015; 85:890 22. Geis C, Weishaupt A, Hallermann S, et al. Stiff person syndromeassociated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010; 133:3166 23. Dalakas MC. Invited article: inhibition of B cell functions: implications for neurology. Neurology 2008; 70:2252 24. Darnell RB, DeAngelis LM. Regression of smallcell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 1993; 341:21 25. Graus F, Dalmou J, Reñé R, et al. AntiHu antibodies in patients with smallcell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997; 15:2866 26. Maddison P, NewsomDavis J, Mills KR, Souhami RL. Favourable prognosis in LambertEaton myasthenic syndrome and smallcell lung carcinoma. Lancet 1999; 353:117 27. Wirtz PW, Lang B, Graus F, et al. P/Qtype calcium channel antibodies, LambertEaton myasthenic syndrome and survival in small cell lung cancer. J Neuroimmunol 2005; 164:161 28. Graus F, KeimeGuibert F, Reñe R, et al. AntiHuassociated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138 29. Dalmau J, Graus F, Rosenblum MK, Posner JB. AntiHuassociated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992; 71:59 30. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998; 50:652 31. Sillevis Smitt P, Grefkens J, de Leeuw B, et al. Survival and outcome in 73 antiHu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002; 249:745 32. Rojas I, Graus F, KeimeGuibert F, et al. Longterm clinical outcome of paraneoplastic cerebellar degeneration and antiYo antibodies. Neurology 2000; 55:713 33. Monstad SE, Drivsholm L, Storstein A, et al. Hu and voltagegated calcium channel (VGCC) antibodies related to the prognosis of smallcell lung cancer. J Clin Oncol 2004; 22:795 34. Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 2000; 47:9 35. Benyahia B, Liblau R, MerleBéral H, et al. Cellmediated autoimmunity in paraneoplastic neurological syndromes with antiHu antibodies. Ann Neurol 1999; 45:162 36. Tanaka M, Tanaka K, Shinozawa K, et al. Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and antiYo antibody. J Neurol Sci 1998; 161:88 37. Posner JB. Neurologic Complications of Cancer, FA Davis, Philadelphia 1995 38. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology 2015; 85:235 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 9/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate 39. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 2000; 23:1800 40. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135 41. Bernal F, Shams'ili S, Rojas I, et al. AntiTr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology 2003; 60:230 42. Vitaliani R, Mason W, Ances B, et al. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005; 58:594 43. McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMOIgG. Neurology 2011; 76:1108 44. Motomura M, Johnston I, Lang B, et al. An improved diagnostic assay for LambertEaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995; 58:85 45. PozoRosich P, Clover L, Saiz A, et al. Voltagegated potassium channel antibodies in limbic encephalitis Ann Neurol 2003; 54:530 46. Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABAergic neurons and pancreatic beta cells in stiffman syndrome. N Engl J Med 1990; 322:1555 47. Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128kd synaptic protein in three women with the stiffman syndrome and breast cancer. N Engl J Med 1993; 328:546 48. Drlicek M, Bianchi G, Bogliun G, et al. Antibodies of the antiYo and antiRi type in the absence of paraneoplastic neurological syndromes: a longterm survey of ovarian cancer patients. J Neurol 1997; 244:85 49. Dalmau J, Furneaux HM, Gralla RJ, et al. Detection of the antiHu antibody in the serum of patients with small cell lung cancera quantitative western blot analysis. Ann Neurol 1990; 27:544 50. Bataller L, Wade DF, Graus F, et al. Antibodies to Zic4 in paraneoplastic neurologic disorders and smallcell lung cancer. Neurology 2004; 62:778 51. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004; 56:715 52. McKeon A, Tracy JA, Pittock SJ, et al. Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond. Arch Neurol 2011; 68:1282 53. Knudsen A, Monstad SE, Dørum A, et al. Ri antibodies in patients with breast, ovarian or small cell lung cancer determined by a sensitive immunoprecipitation technique. Cancer Immunol Immunother 2006; 55:1280 54. Monstad SE, Storstein A, Dørum A, et al. Yo antibodies in ovarian and breast cancer patients detected by a sensitive immunoprecipitation technique. Clin Exp Immunol 2006; 144:53 55. McKeon A, Lennon VA, Lachance DH, et al. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol 2009; 66:735 56. Mason WP, Graus F, Lang B, et al. Smallcell lung cancer, paraneoplastic cerebellar degeneration and the LambertEaton myasthenic syndrome. Brain 1997; 120 ( Pt 8):1279 57. Voltz R, Carpentier AF, Rosenfeld MR, et al. P/Qtype voltagegated calcium channel antibodies in paraneoplastic disorders of the central nervous system. Muscle Nerve 1999; 22:119 58. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of antiMa2associated encephalitis. Brain 2004; 127:1831 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 10/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate 59. Basu S, Alavi A. Role of FDGPET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PETMRI correlates. Mol Imaging Biol 2008; 10:131 60. Choi KD, Kim JS, Park SH, et al. Cerebellar hypermetabolism in paraneoplastic cerebellar degeneration. J Neurol Neurosurg Psychiatry 2006; 77:525 61. GresaArribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during followup of anti NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13:167 62. Psimaras D, Carpentier AF, Rossi C, PNS Euronetwork. Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 2010; 81:42 63. Rees JH, Hain SF, Johnson MR, et al. The role of [18F]fluoro2deoxyglucosePET scanning in the diagnosis of paraneoplastic neurological disorders. Brain 2001; 124:2223 64. YounesMhenni S, Janier MF, Cinotti L, et al. FDGPET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127:2331 65. McKeon A, Apiwattanakul M, Lachance DH, et al. Positron emission tomographycomputed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol 2010; 67:322 66. Patel RR, Subramaniam RM, Mandrekar JN, et al. Occult malignancy in patients with suspected paraneoplastic neurologic syndromes: value of positron emission tomography in diagnosis. Mayo Clin Proc 2008; 83:917 67. Linke R, Schroeder M, Helmberger T, Voltz R. Antibodypositive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology 2004; 63:282 68. Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011; 18:19 69. Leyhe T, Schüle R, Schwärzler F, et al. Second primary tumor in antiMa1/2positive paraneoplastic limbic encephalitis. J Neurooncol 2006; 78:49 70. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (antiCD20) adjunctive therapy for opsoclonus myoclonus syndrome. J Pediatr Hematol Oncol 2006; 28:585 71. Buckley C, Vincent A. Autoimmune channelopathies. Nat Clin Pract Neurol 2005; 1:22 72. Levine TD. Rituximab in the treatment of dermatomyositis: an openlabel pilot study. Arthritis Rheum 2005; 52:601 73. Vernino S, O'Neill BP, Marks RS, et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol 2004; 6:55 74. Shams'ili S, de Beukelaar J, Gratama JW, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006; 253:16 75. KeimeGuibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (AntiHu, antiYo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000; 68:479 76. Rosenfeld MR, Dalmau J. Current Therapies for Paraneoplastic Neurologic Syndromes. Curr Treat Options Neurol 2003; 5:69 77. Ducray F, Graus F, Vigliani MC, et al. Delayed onset of a second paraneoplastic neurological syndrome in eight patients. J Neurol Neurosurg Psychiatry 2010; 81:937 Topic 5188 Version 22.0 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 11/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate GRAPHICS Paraneoplastic syndromes of the nervous system Paraneoplastic syndromes of the central nervous system Encephalomyelitis* Myelitis* Limbic encephalitis* Brainstem encephalitis* Cerebellar degeneration* Opsoclonus myoclonus ataxia* Visual syndromes Cancer associated retinopathy* Melanoma associated retinopathy* Optic neuritis Necrotizing myelopathy Motor neuron syndrome Subacute motor neuronopathy Other syndromes Stiffperson syndrome* Subacute sensory neuronopathy* Paraneoplastic syndromes of the peripheral nervous system Chronic sensorimotor neuropathy Association with plasma cell dyscrasias Acute sensorimotor neuropathy GuillainBarré syndrome Plexitis (eg, brachial neuritis) Autonomic neuropathy* Vasculitis of nerve and muscle Paraneoplastic syndromes of the neuromuscular junction and muscle Myasthenia gravis* LambertEaton myasthenic syndrome* Dermatomyositis/polymyositis Neuromyotonia* Acute necrotizing myopathy Cachectic myopathy * Syndromes in which specific paraneoplastic markers have been identified in more than three patients. However, the absence of antibodies does not exclude a paraneoplastic etiology Graphic 50304 Version 3.0 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 12/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate Reactivity of paraneoplastic antineuronal antibodies Reactivity of different paraneoplastic antibodies with the nervous system. Panel A: Reactivity of antiHu antibodies with human cerebral cortex. There is predominant staining of the nuclei of the neurons (with sparing of the nucleoli), and milder staining of the cytoplasm. Glial cells are not immunoreactive. Panel B: Reactivity of antiYo antibodies with rat cerebellum. There is intense immunolabeling of the cytoplasm of the Purkinje cells and of neurons of the molecular layer. Panel C: Reactivity of antiTr antibodies with rat cerebellum There is a characteristic dotlike immunolabeling of the cytoplasm of Purkinje cells and the neuropil of the molecular layer of cerebellum. Panel D: Reactivity of antiMa2 (Ta) antibodies with human cerebral cortex. This antibody reacts with the nucleoli of the neurons, and shows mild immunolabeling of the cytoplasm; glial cells are not immunoreactive Courtesy of Josep Dalmau, MD, PhD Graphic 56327 Version 2.0 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 13/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate Antibodies, paraneoplastic syndromes, and associated cancers Antibody Syndrome Associated cancers Wellcharacterized paraneoplastic antibodies* AntiHu (ANNA1) Encephalomyelitis including cortical, limbic, brainstem encephalitis, cerebellar degeneration, myelitis, sensory neuronopathy, and/or autonomic dysfunction SCLC, other AntiYo (PCA1) Cerebellar degeneration Gynecological, breast AntiRi (ANNA2) Cerebellar degeneration, brainstem encephalitis, opsoclonus myoclonus Breast, gynecological, SCLC AntiTr (DNER) Cerebellar degeneration Hodgkin lymphoma AntiCV2/CRMP5 Encephalomyelitis, cerebellar degeneration, chorea, peripheral neuropathy SCLC, thymoma, other AntiMa proteins ¶ (Ma1, Ma2) Limbic, hypothalamic, brainstem encephalomyelitis (infrequently cerebellar degeneration) Testicular germ cell tumors, lung cancer, other solid tumors Antiamphiphysin Stiffperson syndrome, encephalomyelitis Breast, lung cancer Antirecoverin Δ Cancerassociated retinopathy SCLC Antibipolar cells of the retina ◊ Melanomaassociated retinopathy Melanoma Partiallycharacterized paraneoplastic antibodies* AntiZic 4 Cerebellar degeneration SCLC AntiANNA3 Sensory neuronopathy, encephalomyelitis No tumor or Hodgkin lymphoma AntiPCA2 Encephalomyelitis, cerebellar degeneration SCLC ANNA: antinuclearnuclear antibody; DNER: Delta/Notchlike epidermal growth factorrelated receptor; PCA: Purkinje cell antibody; SCLC: small cell lung cancer. * Wellcharacterized antibodies are those directed against antigens whose molecular identity is known, or that have been identified by several investigators. (Graus F, et al. J Neurol Neurosurg Psychiatry 2004; 75:1135.) ¶ Antibodies to Ma2: younger than 45 years, usually men with testicular germ cell tumors; older than 45, men or women with lung cancer and less frequently other tumors. Ma1 antibodies often associated with tumors other than germ cell neoplasms and confers a worse prognosis, with more prominent brainstem and cerebellar dysfunction. Δ Other antibodies reported in a few or isolated cases include antibodies to tubbylike protein and the photoreceptorspecific nuclear receptor. ◊ Target antigens include transducinb, rhodopsin, and arrestin, among others Graphic 77919 Version 15.0 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 14/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate Autoimmune encephalitis syndromes with antibodies against neuronal cell surface/synaptic proteins Antigen target Clinical syndrome Tumor or other associations NMDAR Multistage syndrome with memory and behavioral disturbances, psychosis, seizures, dyskinesias, and autonomic dysfunction Agedependent presence of ovarian teratoma, rarely other tumors in older patients or males; often has virallike prodrome LGI1 Limbic encephalitis, seizures 50% with hyponatremia AMPAR Limbic encephalitis, psychiatric disturbances 70% (variable solid tumors); relapses are common GABAA receptor Rapidly progressive encephalopathy, refractory seizures, status epilepticus, epilepsia partial continua 40% (thymoma); MRI with multifocal cortical subcortical FLAIR and T2 abnormalities without contrast enhancement GABAB receptor Seizures, limbic encephalitis 50% with cancer (mostly SCLC) CASPR2 Morvan's syndrome, encephalitis with core symptoms, rarely, isolated neuromyotonia Thymoma and variable solid tumors IgLON Abnormal sleep behavior, REM and nonREM parasomnias, brainstem dysfunction No cancer association, often chronic and slowly progressive DPPX Encephalopathy with CNS hyperexcitabilty, myoclonus, tremor, often preceded by weight loss, diarrhea or gastrointestinal symptoms Two patients reported with Bcell neoplasms GlyR Encephalomyelitis with muscle spasms, rigidity, myoclonus, hyperekplexia A past history of cancer and a concurrent cancer diagnosis have been reported mGluR5 Limbic encephalitis, prosopagnosia, involuntary movements Hodgkin lymphoma* or no tumor mGluR1 Cerebellar degeneration Hodgkin lymphoma or no tumor NMDAR: NmethylDaspartate receptor; LGI1: leucinerich glioma inactivated protein1; AMPAR: alphaamino3hydroxy5 methyl4isoxazolepropionic acid receptor; GABA: gammaaminobutyric acid; CASPR: contactinassociated proteinlike 2; GlyR: glycine receptor; mGluR: metabotropic glutamate receptor; FLAIR: fluid attenuated inversion recovery; SCLC: small cell lung cancer. * The cooccurrence of limbic encephalitis and Hodgkin lymphoma is known as Ophelia syndrome Graphic 111054 Version 1.0 https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 15/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate Contributor Disclosures Josep Dalmau, MD, PhD Grant/Research/Clinical Trial Support (with spouse): Euroimmun Inc, [Identification of antibodies associated with disorders of the nervous system-paraneoplastic and nonparaneoplastic (diagnostic tests to measure these antibodies in serum and CSF)] Patent Holder (with spouse): Euroimmun, Inc, (We hold a patent for the use of NMDAR as an antibody test that has been licensed to Euroimmun and for which we receive royalties); Athena Diagnostics (We hold a patent for the use of Ma2 as an antibody test that has been licensed to Athena and for which we receive royalties) Myrna R Rosenfeld, MD, PhD Patent Holder/Royalties: Euroimmun Inc [NMDAR encephalitis (antibody tests)]; Athena [Ma2 encephalitis (antibody tests)] Grant/Research/Clinical Trial Support: Euroimmun [autoimmune encephalitis (antibody testing kits)]; CELLEX Foundation (spouse) [unrestricted research grant focus on memory alteration in autoimmune encephalitis] Lisa M DeAngelis, MD, FAAN, FANA Nothing to disclose April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)] Contributor disclosures are reviewed for conflicts of interest by the editorial group When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence Conflict of interest policy https://www.uptodate.com/contents/overviewofparaneoplasticsyndromesofthenervoussystem/print 16/16 ... https://www .uptodate. com/contents /overview of paraneoplastic syndromes of the nervous system/ print 11/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate GRAPHICS Paraneoplastic syndromes of the nervous system Paraneoplastic syndromes of the central nervous system. .. https://www .uptodate. com/contents /overview of paraneoplastic syndromes of the nervous system/ print 12/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate Reactivity of paraneoplastic antineuronal antibodies... https://www .uptodate. com/contents /overview of paraneoplastic syndromes of the nervous system/ print 4/16 3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate paraneoplastic cerebellar degeneration develop LEMS more frequently than expected [56]. Since the