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 spinal cord, peripheral nerve, and muscle" 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 T cell 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 T cell response to a normal protein when it is expressed in a cancer cell, suggesting that normal self-antigens 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 "well-characterized" paraneoplastic antibodies (table 2), and their detection almost always indicates the presence of an underlying tumor. Examples include Hu (also known as type 1 antineuronal nuclear antibody [ANNA-1]), Ri (also known as type 2 antineuronal nuclear antibody [ANNA-2]), Yo (also known as Purkinje cell cytoplasmic antibody type 1 [PCA-1]), amphiphysin, Ma2, Tr (also known as delta/notch-like epidermal growth factor-related receptor [DNER]), collapsin response-mediator protein-5 (CRMP-5), 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 T cells.

●Antibodies directed against neuronal cell surface or synaptic proteins – Examples include antibodies against the anti-N-methyl-D-aspartate (NMDA) receptor, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the gamma-aminobutyric acid type A (GABA-A) and type B (GABA-B) receptors, and contactin-associated protein-like 2 (Caspr2), among others (table 3). These antibodies may occur with or without a 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 [5]. An underlying genetic predisposition may also play a role for some of these disorders [6].

Pathogenic effects have been demonstrated for the following antibodies:

●P/Q type voltage-gated calcium channel antibodies in the Lambert-Eaton myasthenic syndrome (LEMS) [7]

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

●NMDA receptor antibodies in anti-NMDA receptor encephalitis [9-11]

●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]

●GABA-A receptor antibodies in encephalopathy with refractory seizures [16]

●Leucine-rich glioma inactivated 1 (LGI1) antibodies in a subgroup of limbic encephalitis [17,18]

●Caspr2 antibodies in patients with encephalitis and Morvan syndrome [19]

●Dipeptidyl-peptidase-like protein-6 (DPPX) antibodies in a syndrome of central nervous system hyperexcitability, often associated with hyperekplexia [20-23]

●Metabotropic glutamate receptor 5 (mGluR5) antibodies in encephalitis not restricted to limbic encephalitis [24]

Autoantibodies may also play an important role in other syndromes such as the paraneoplastic form of stiff-person syndrome (often associated with amphiphysin antibodies) [25] and paraneoplastic dermatomyositis. The role of autoantibodies in the pathogenesis of these disorders is the rationale for the use of rituximab [26].

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).

It had been suggested that some paraneoplastic neurologic syndromes without an identifiable tumor were a result of immune-mediated eradication of tumor cells [27]. In addition, some reports suggested a more limited disease distribution and better outcome among patients with small cell lung cancer (SCLC) who developed immunity to paraneoplastic antigens [28-30]. However, review of large series of patients demonstrates that the oncologic outcome of patients with antibody-associated paraneoplastic syndromes does not significantly differ from that of patients who do not have the antibodies or a paraneoplastic syndrome [31-36].

This topic review will focus on those neurologic syndromes that are associated with either classic paraneoplastic antibodies or antibodies to the neuronal cell surface or synaptic proteins. 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 hormone-related protein, or hypoglycemia due to insulin-like growth factor 2). (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 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 Waldenström macroglobulinemia) and antibodies against myelin-associated glycoprotein (MAG). (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

INCIDENCE — Paraneoplastic disorders are more frequent than previously considered, with an incidence that varies with the neurologic syndrome and type of tumor. The more common syndromes are Lambert-Eaton myasthenic syndrome (LEMS), which affects approximately 3 percent of patients with small cell lung cancer (SCLC), and myasthenia gravis (MG), which affects 15 percent of all patients with thymoma. One or more paraneoplastic neurologic disorders are 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 a paraproteinemia-related disease including multiple myeloma, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinemia, and skin changes) syndrome, multicentric Castleman disease, or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Each of these paraproteinemias is associated with different neuropathic syndromes. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Peripheral nerve' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Neurologic disease' and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "POEMS syndrome" and "HHV-8-associated multicentric Castleman disease".)

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 pseudo-obstruction, Lambert-Eaton 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 classic paraneoplastic antibodies and cancer that develops within five years of the diagnosis of the neurologic disorder.

●A neurologic syndrome (classical or not) with "well-characterized" paraneoplastic antibodies and no cancer. Well-characterized paraneoplastic antibodies are those directed against antigens whose molecular identity is known or that have been identified by several investigators, while partially characterized antibodies are those whose target antigens are unknown or require further analysis (table 2) [40]. These well-characterized antibodies include anti-Hu, CV2/CRMP-5, 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 partially characterized paraneoplastic antibodies (eg, not the well-characterized antibodies described above) and no cancer.

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

Antibody screening — Well-characterized 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 [41-43].

By 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 approximately 15 percent of patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, the antibodies are detectable in CSF but not in serum. In patients suspected to have these disorders (eg, anti-NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and gamma-aminobutyric acid type A [GABA-A] or type B [GABA-B] receptors, among others) (table 3), CSF should be included in the analysis.

Important tenets of antibody screening include:

●While antibodies such as P/Q type voltage-gated 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 stiff-person syndrome, patients with GAD antibodies rarely have cancer, while patients with amphiphysin usually have an underlying tumor [46,47]. (See "Stiff-person syndrome".)

●The serum of cancer patients without paraneoplastic neurologic syndromes may contain paraneoplastic antibodies, although the titers are usually lower [28,48,49].

●Different antibodies can be associated with the same paraneoplastic neurologic syndrome and, conversely, the same antibody may be associated with different syndromes [50-52].

●Several paraneoplastic antibodies (well and/or partially characterized) may co-occur in the same patient, particularly if the underlying tumor is small cell lung cancer (SCLC) [50,51].

As noted above, well-characterized classic paraneoplastic antibodies are sometimes found in patients with cancer but without neurologic symptoms and in patients with neurologic disorders without an identifiable cancer [53]. However, these antibodies (table 2) rarely, if ever, occur in normal individuals [54-56]. The presence of these antibodies should demand a careful search for an underlying neoplasm. The specificity and clinical significance of antibodies against neuronal cell surface or synaptic proteins are discussed in more detail separately. (See "Paraneoplastic and autoimmune encephalitis".)

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 paraneoplastic cerebellar degeneration develop LEMS more frequently than expected [57]. 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 approximately 6 percent of patients with anti-Hu-associated paraneoplastic encephalomyelitis [58]. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

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.

Diagnostic tests that may be helpful for some paraneoplastic syndromes include:

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 fluid-attenuated inversion recovery (FLAIR) images (image 1) 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 [57,59]; however, for most paraneoplastic syndromes, neuroimaging studies are normal or nonspecific.

PET — Positron emission tomography (PET) of the brain using fluorodeoxyglucose (FDG-PET) will occasionally identify hypermetabolism of the medial temporal lobe(s) in patients with limbic encephalopathy [60], or of the cerebellum in patients with paraneoplastic cerebellar degeneration [61].

Lumbar puncture — Although detection of classic paraneoplastic antibodies in CSF confirms that the disorder is paraneoplastic, in our experience these antibodies are usually present in the serum as well, except in some patients with anti-Tr antibodies [41,43]. By contrast, CSF examination is critical in patients suspected of having antigens to neuronal cell surface or synaptic proteins (eg, anti-NMDA receptor encephalitis) because serum testing may be negative, and antibody titers are higher in CSF than in serum [62]. (See 'Antibody screening' above.)

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 immune-mediated neurologic disorder [63].

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 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 FDG-PET 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 [64-66]. In one case series of 104 patients, sensitivity and specificity of FDG-PET were 80 and 67 percent, respectively, compared with 30 and 71 percent for CT [67]. Results from another small study found that FDG-PET combined with CT scanning increased sensitivity and accuracy of tumor diagnosis in patients with paraneoplastic syndromes [68].

A negative PET/CT scan does not rule out underlying cancer; use of other imaging modalities (eg, MRI, ultrasound) or repeating PET/CT scan after a several-month 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 [69]. 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 [70].

TREATMENT AND PROGNOSIS OVERVIEW — Because the majority of neurologic paraneoplastic syndromes are immune mediated, 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 T cell mediated, the response to treatment (antitumor plus immunotherapy) is less satisfactory than in those disorders associated with antibodies against neuronal cell surface or synaptic proteins, in which the pathogenic mechanism is antibody mediated.

●Syndromes likely to respond to treatment – Immunosuppression is beneficial for some conditions, such as the Lambert-Eaton 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 "Lambert-Eaton myasthenic syndrome: Treatment and prognosis".)

Encephalitides associated with antibodies against neuronal cell surface antigens or synaptic proteins such as anti-N-methyl-D-aspartate (NMDA) receptor, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, gamma-aminobutyric acid B (GABA-B) receptor, and leucine-rich glioma inactivated 1 (LGI1), among others, are also fairly responsive to immunosuppressive therapies. These disorders are usually treated with intravenous methylprednisolone, IVIG, or plasma exchange. If these fail, rituximab and/or cyclophosphamide are often effective. For patients that are severely affected, consideration can be given to starting rituximab as part of the initial therapeutic regimen. (See "Paraneoplastic and autoimmune encephalitis", section on 'Treatment and prognosis'.)

●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 immune-mediated 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 cancer-associated disorders that are probably antibody mediated, such as opsoclonus myoclonus [71], stiff-person syndrome [72], and dermatomyositis [73], the approach to treatment is usually similar to that used for syndromes associated with antibodies against cell surface antigens. (See "Opsoclonus-myoclonus syndrome" and "Stiff-person syndrome" and "Initial treatment of dermatomyositis and polymyositis in adults".)

●Syndromes that usually do not respond to treatment – This includes most of the paraneoplastic syndromes associated with classic paraneoplastic antibodies that target intracellular antigens, such as paraneoplastic cerebellar degeneration, encephalomyelitis, the subgroup of limbic encephalitis with classic paraneoplastic antibodies to intracellular antigens, myelitis, and cancer-associated retinopathy. In these patients, the treatment approach of removing the antibodies from serum (eg, plasma exchange, IVIG) usually fails; immunotherapies addressing T cell mechanisms should be considered early (eg, cyclophosphamide or rituximab, which decreases B cell antigen presentation to T cells) [74]. Prompt control of the tumor and immunotherapy may stabilize or result in partial improvement [75], 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 [74,76,77]. 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 [78].

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 "well-characterized" or "classical" paraneoplastic antibodies, but is not sufficient for some autoimmune encephalitides associated with antibodies against neuronal 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.

•Well-characterized 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 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.)