Overview of paraneoplastic syndromes of the nervous system uptodate

® ® Antibodies directed against intracellular neuronal proteins called classical paraneoplastic or onconeuronal antibodies – These antibodies belong to the category of "wellcharacterize

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3/1/2017 Overview of paraneoplastic syndromes of the nervous system UpToDate

Official reprint from 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

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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

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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

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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:

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]:

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

P/Q type voltagegated calcium channel antibodies in the LambertEaton myasthenic syndrome (LEMS) [7]

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Acetylcholine receptor antibodies in myasthenia gravis (MG) [8]

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NMDA receptor antibodies in antiNMDA receptor encephalitis [911]

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AMPA receptor antibodies in a subgroup of limbic encephalitis [12,13]

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Ganglionic acetylcholine receptor antibodies in autonomic neuropathy [14]

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Recoverin antibodies in carcinoma associated retinopathy [15]

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Gammaaminobutyric acid A (GABAA) receptor antibodies in encephalopathy with refractory seizures [16]

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Leucine rich glioma inactivated 1 (LGI1) antibodies in a subgroup of limbic encephalitis [17]

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Dipeptidylpeptidase–like protein6 (DPPX) antibodies in a syndrome of central nervous system

hyperexcitability, often associated with hyperekplexia [1821]

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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

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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]:

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".)

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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".)

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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

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A nonclassical syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission

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A nonclassical syndrome with paraneoplastic antibodies and cancer that develops within five years of the diagnosis of the neurologic disorder

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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

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Possible syndromes include [40]:

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:

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

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.

A classical syndrome as defined above, no paraneoplastic antibodies, no cancer, but at high risk to have an underlying tumor

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A neurologic syndrome (classical or not) with partiallycharacterized paraneoplastic antibodies (eg, not the wellcharacterized antibodies described above) and no cancer

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A nonclassical syndrome, no paraneoplastic antibodies, and cancer present within two years of diagnosis

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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".)

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The serum of cancer patients without paraneoplastic neurologic syndromes may contain paraneoplastic

antibodies, although the titers are usually lower [25,48,49]

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Different antibodies can be associated with the same paraneoplastic neurologic syndrome and conversely, the same antibody may be associated with different syndromes [5052]

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Several paraneoplastic antibodies may cooccur in the same patient, particularly if the underlying tumor is smallcell lung cancer (SCLC) [50,51]

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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:

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

The combination of negative cytology for malignant cells and the absence of meningeal enhancement on MRI can reasonably exclude leptomeningeal metastases

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Inflammatory changes (eg, pleocytosis, intrathecal synthesis of immunoglobulin G [IgG], oligoclonal bands) can support the presence of an inflammatory or immunemediated neurologic disorder [62]

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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'.)

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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

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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

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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)

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

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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.)

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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:

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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.)

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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

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