Version November 2024
INTRODUCTION — Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders associated with systemic cancer and 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, damaging either one area or multiple areas. They can occur with or without detectable autoantibodies in serum and cerebrospinal fluid (CSF).
Paraneoplastic syndromes affecting the spinal cord, dorsal root ganglia, peripheral nerve, neuromuscular junction, and muscle will be reviewed here. An overview of the diagnosis of neurologic paraneoplastic syndromes and the clinical features and treatment of paraneoplastic disorders affecting other parts of the central nervous system (CNS) are reviewed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis" and "Paraneoplastic cerebellar degeneration" and "Paraneoplastic visual syndromes".)
SPINAL CORD SYNDROMES
Myelopathy — Paraneoplastic myelopathy, resulting in rapidly progressive spastic paresis with or without bowel and bladder dysfunction, usually occurs in association with involvement of other areas of the nervous system; examples include encephalitis, sensory neuronopathy, chorea, and optic neuropathy [1-3]. The most commonly associated antibodies are anti-Hu, anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, antiamphiphysin antibodies (table 1). The usual culprit is small cell lung cancer (SCLC).
Paraneoplastic myelopathy can also occur as an isolated syndrome. In such cases, the differential diagnosis is broad and includes a variety of other causes of spinal cord dysfunction and signal abnormality on spine magnetic resonance imaging (MRI). (See "Disorders affecting the spinal cord".)
In a case series of 31 patients with an isolated progressive paraneoplastic myelopathy, the most common coexisting cancers were lung and breast; kidney cancer, thyroid cancer, gynecologic cancers, and melanomas were also present in a few patients [4]. Antibodies to amphiphysin and CRMP5 were the most commonly identified paraneoplastic biomarkers, observed in eight and nine patients, respectively. Patients presented with subacute or insidiously progressive myelopathy symptoms, usually symmetric, leading to wheelchair dependence in half of patients. Spine MRI abnormalities, identified in 20 patients, included longitudinally extensive T2-hyperintense signal abnormality (extending over more than three vertebral segments), often associated with contrast enhancement. Cerebrospinal fluid (CSF) analysis often showed elevated protein levels and/or pleocytosis. Most patients did not improve, even after oncologic and/or immunosuppressive therapy. The study suggests that in patients with new-onset progressive myelopathy of unknown cause, the presence of symmetric, longitudinally extensive tract or gray matter-specific changes on spinal MRI should raise suspicion for a paraneoplastic etiology.
There are reports of patients with neuromyelitis optica spectrum disorder (NMOSD) and aquaporin-4 (AQP4) antibodies who have or later develop cancer [5,6]. The most common cancer associations are lung and breast carcinomas, but other solid tumors and lymphoma have also been reported. The frequency of paraneoplastic NMOSD is rare, and routine screening of NMOSD patients for cancer is not indicated. Based on one study, however, the presence of brainstem involvement with severe nausea and vomiting, particularly in older males (>45 years of age), may warrant cancer screening due to higher risk of a cancer association [6]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)
There are rare reports of a paraneoplastic necrotizing myelopathy. In one report of a patient with paraneoplastic necrotizing myelopathy who responded to treatment with corticosteroids but eventually died of complications of metastatic esophageal cancer, the autopsy confirmed the presence of necrosis of the spinal cord and mild inflammatory infiltrates [7].
The differential diagnosis of necrotizing myelopathy includes leptomeningeal, epidural, and intramedullary metastasis. In addition, necrotizing myelopathy can also result from viral infections (particularly of the herpes group), septic infarcts, and toxic effects of intrathecal chemotherapy and radiation therapy [8,9]. It has also been suggested that some cases of necrotizing myelopathy are secondary to NMOSD. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Disorders affecting the spinal cord" and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)
Subacute motor neuronopathy — Paraneoplastic degeneration of the anterior horn cells, referred to as subacute motor neuronopathy, was initially reported in patients with Hodgkin and non-Hodgkin lymphoma [10-13]. The disorder is characterized by subacute, progressive, painless, and often asymmetric lower motor neuron weakness. Although some patients have sensory symptoms, the neurologic examination reveals few or no objective sensory deficits.
Pathologic findings include severe neuronal degeneration of the anterior horn cells with variable inflammatory infiltrates, and demyelination with mild axonal loss of the posterior columns of the spinal cord [10,11].
The decreasing frequency of this syndrome over time suggests that the etiology could be a viral infection that was missed in the original descriptions. Alternatively, the disorder could be due to other causes that are currently prevented with the management of patients with lymphoma.
The course of the neurologic disorder is usually independent of the course of the lymphoma, although spontaneous neurologic improvement has been reported as well as improvement or stabilization in association with lymphoma treatment [10,12,14].
Stiff-person syndrome — Stiff-person syndrome is an uncommon disorder characterized by progressive muscle stiffness, rigidity, and spasms predominantly involving the axial muscles of the trunk and proximal muscles of the limbs [15,16]. Muscle spasms are usually heightened by touch, noise, or emotional distress. In some patients, pruritus is the initial symptom of paraneoplastic stiff-person syndrome [17]. Related disorders include progressive encephalomyelitis with rigidity and myoclonus (PERM), in which patients develop symptoms similar to stiff-person syndrome along with brainstem dysfunction, seizures, or encephalopathy, and stiff-limb syndrome, in which one or more limbs are affected with distal rigidity.
Paraneoplastic stiff-person syndrome usually occurs in patients with breast cancer or SCLC [15,16,18-20]. The serum of these patients often contains antibodies against amphiphysin [18,20,21]. By contrast, patients with stiff-person syndrome who do not have cancer (but who usually develop diabetes and other symptoms of endocrinopathy) have antibodies against glutamic acid decarboxylase (GAD) [22]. Both GAD65 and amphiphysin are cytoplasmic proteins that are not exposed on the cell surface; it has been suggested that amphiphysin may be transiently exposed during the process of synaptic vesicle uptake and thereby accessed by circulating antibodies. (See "Stiff-person syndrome", section on 'Pathogenesis'.)
Antibodies to the alpha-1 subunit of the glycine receptor (GlyR) (table 1) with or without concurrent GAD autoimmunity have been reported in some patients with stiff-person syndrome [23] but are more characteristic of PERM. Most patients with GlyR antibodies do not have cancer; however, in a study of 52 patients with PERM and GlyR antibodies, five patients had a previous history of neoplasms and four had tumors identified during the study of PERM (most common were breast cancer, thymoma, and lymphoma) [24]. A higher index of suspicion for cancer should be present in older adults and those who develop additional signs or symptoms such as limbic encephalitis, encephalomyelitis, or opsoclonus-myoclonus.
Treatment of paraneoplastic stiff-person syndrome consists of control of the tumor and the administration of symptomatic treatment of spasms and rigidity (eg, benzodiazepines, baclofen, tizanidine). In those who do not respond, glucocorticoids, intravenous immune globulin (IVIG), or other immunosuppressive agents can be tried. Patients with GlyR antibodies appear to be more responsive than those without antibodies or with antibodies to GAD or amphiphysin [25].
The clinical features, diagnosis, and treatment of stiff-person syndrome are reviewed in more detail elsewhere. (See "Stiff-person syndrome".)
DORSAL ROOT GANGLIA
Subacute sensory neuronopathy — Selective involvement of the dorsal root ganglia, referred to as sensory neuronopathy, results in a particularly disabling form of sensory loss with prominent sensory ataxia.
The sensory deficits of paraneoplastic subacute sensory neuronopathy typically begin with loss of vibratory sensation and joint position sense, followed by impairment in pain and temperature sensation [26]. Patients initially complain of pain or the sensation of "pins and needles" or "electric shocks." The symptoms may initially affect one extremity, but in a few weeks or months, they usually progress to involve other extremities, the face, the abdomen, or the trunk [26,27]. In a subset of patients, hyperalgesia and spontaneous pain remain the prominent symptoms, and sensory ataxia is mild or even absent [28].
On neurologic examination, there is usually moderate to severe involvement of all sensory modalities. These sensory deficits frequently lead to prominent ataxia, which is exacerbated by eye closure and associated with pseudoathetoid movements of the fingers and extremities. Other neurologic findings may include sensorineural hearing loss, diminished taste sensation, and symmetric or asymmetric reduction or loss of deep tendon reflexes.
As in other paraneoplastic disorders, symptoms typically predate the discovery of a tumor. The association with pain may erroneously lead to the diagnosis of radiculopathy or polyneuropathy. In one case control study, clinical features that distinguished this syndrome from a sensory neuropathy included limb ataxia, asymmetric distribution, and sensory loss other than in the legs [29].
Neurophysiologic studies usually show reduced or absent sensory potentials with normal or borderline motor nerve conduction velocities. Abnormal motor conduction velocity with axonal and demyelinating features may occur, complicating the differential diagnosis between peripheral nerve and dorsal root ganglia involvement. Neurophysiologic features that can help distinguish sensory neuronopathy from peripheral nerve disorder include at least one absent or three low (<30 percent of normal) sensory action potentials in the arms with fewer than two abnormal motor nerve conduction studies (NCS) in the legs [29].
The cerebrospinal fluid (CSF) may be normal but often shows moderate pleocytosis, increased protein, intrathecal synthesis of immunoglobulin G (IgG), and oligoclonal bands.
Histologic examination reveals a mononuclear cell infiltrate in the dorsal root ganglia that is probably immune mediated, neuronal degeneration, and proliferation of the satellite cells (Nageotte nodules) (picture 1). There is also a variable involvement of the dorsal and ventral nerve roots, and secondary demyelination of the spinal cord dorsal columns [27]. Sural nerve biopsy shows a reduction in myelinated fiber density with depletion of large fibers most prominent in those with more severe sensory ataxia [28].
Approximately 80 percent of patients with paraneoplastic subacute sensory neuronopathy have small cell lung cancer (SCLC), usually in association with anti-Hu antibodies (table 1). Many of these patients progress to paraneoplastic encephalomyelitis [1]. Some patients have anti-collapsin-responsive mediator protein 5 (CRMP5) antibodies, directed against antigens present on peripheral nerves, often in conjunction with anti-Hu antibodies [30]. If both antibodies are present, a mixed axonal and demyelinating sensory motor neuropathy may be superimposed on subacute sensory neuronopathy. Well-characterized paraneoplastic antibodies such as anti-Hu and anti-CRMP5 are almost always detectable in serum; only in rare instances will the CSF reveal antibodies undetected in serum. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Diagnostic evaluation'.)
Aside from SCLC, other tumors associated with subacute sensory neuronopathy include breast, prostate, or colon cancers; lymphoma; or uterine sarcoma. Thus, tumor screening with computed tomography (CT) and/or 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) should be performed in patients with suspected paraneoplastic sensory neuronopathy [31].
The differential diagnosis also includes toxic side effects of chemotherapeutic drugs (such as cisplatin, paclitaxel, docetaxel, and vinca alkaloids) and immune checkpoint inhibitors. Cisplatin neuropathy and paraneoplastic sensory neuronopathy can usually be distinguished by the fact that cisplatin produces a large fiber neuropathy affecting position and vibration sense almost exclusively and sparing pain and temperature sense, whereas the paraneoplastic disorder affects all sensory modalities. Sensory neuronopathy can also be seen in association with autoimmune disorders (eg, Sjögren's disease, celiac disease, autoimmune hepatitis) and infections (eg, Epstein-Barr virus, human immunodeficiency virus, varicella-zoster) [32,33]. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy" and "Approach to the patient with sensory loss", section on 'Sensory neuronopathies'.)
Treatment with glucocorticoids, plasma exchange, and intravenous immune globulin (IVIG) is usually ineffective [1,34,35], although there are a few reported exceptions to this general rule [36,37]. In one report, the combination of IVIG plus cyclophosphamide and methylprednisolone resulted in disease stabilization in 2 of 10 patients with anti-Hu antibody-associated paraneoplastic sensory neuronopathy [36]. Early diagnosis and treatment of the tumor is likely the best approach to stabilize (or improve) the neurologic symptoms.
PERIPHERAL NERVE
Acute sensorimotor radiculoneuropathy — A disorder clinically identical to Guillain-Barré syndrome (GBS), acute sensorimotor radiculoneuropathy occurs at higher-than-expected frequency in patients with cancer, mostly Hodgkin and non-Hodgkin lymphomas and, less commonly, solid tumors [38]. Patients develop acute-onset rapidly progressive sensorimotor or pure motor neuropathy and the cerebrospinal fluid (CSF) shows elevated protein and normal or only slightly elevated cell counts. The neuropathy may develop at any stage of the cancer and can herald cancer recurrence. Treatment is the same as for GBS, with some studies suggesting that patients with cancer have worse neurologic outcomes [38]. (See "Guillain-Barré syndrome in adults: Treatment and prognosis".)
Chronic sensorimotor neuropathy — A chronic sensorimotor neuropathy not due to an identifiable cause (eg, metabolic or nutritional deficits, chemotherapy toxicity, among others) may occur in cancer patients, mostly in patients with lung cancer and lymphoma. Symptoms typically develop in patients with advanced disease, well after the diagnosis of malignancy has been made.
Patients are usually not very debilitated by their neurologic symptoms, which typically consist of mild to moderate distal symmetric sensorimotor deficits. This type of neuropathy rarely associates with paraneoplastic antibodies and is slowly progressive, with weakness a late occurrence.
By contrast, patients with paraneoplastic antibodies (eg, collapsin-responsive mediator protein 5 [CRMP5]) develop a more rapidly progressive sensorimotor neuropathy; these antibodies usually associate with small cell lung cancer (SCLC) or thymoma. Electrophysiologic studies show a mix of axonal and demyelinating features [30]. These neuropathies are very disabling and respond poorly to immunotherapy or treatment of the tumor.
Neuropathies associated with lymphoproliferative disorders — Peripheral neuropathy can be a manifestation of several lymphoproliferative disorders associated with elevated paraprotein, including multiple myeloma, POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin changes) syndrome, and Waldenström macroglobulinemia. These peripheral nerve syndromes are reviewed separately:
●Multiple myeloma – Peripheral neuropathy is uncommon in multiple myeloma at the time of initial diagnosis and, when present, is usually due to associated immunoglobulin light chain (AL) amyloidosis or POEMS. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Neurologic disease' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Systemic presentations'.)
●POEMS syndrome – POEMS is a monoclonal plasma cell disorder in which neuropathy is a defining feature. In most cases, the neuropathy of POEMS is a symmetric, ascending sensorimotor polyneuropathy. Electrophysiologic and pathologic studies show both demyelination and axonal degeneration. The neuropathy is often the presenting feature of POEMS and may initially be confused with chronic inflammatory demyelinating polyneuropathy (CIDP). (See "POEMS syndrome", section on 'Peripheral neuropathy'.)
●Multicentric Castleman disease – Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder that may occur with or without POEMS syndrome. Neuropathy in patients with iMCD is variable and can range from a mild sensory neuropathy to the severe sensorimotor neuropathy of POEMS. (See "HHV-8-negative/idiopathic multicentric Castleman disease".)
●Waldenström macroglobulinemia – Neuropathy is present in approximately 20 percent of patients with Waldenström macroglobulinemia at the time of diagnosis. The neuropathy is usually a distal, symmetric, and slowly progressive sensorimotor neuropathy. Neuropathies may occur with or without antibodies against myelin-associated glycoprotein (MAG), GM1 ganglioside, or asialo-GM1 ganglioside. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)
Autonomic neuropathy — Paraneoplastic autonomic dysfunction frequently accompanies other paraneoplastic symptoms, including encephalomyelitis and sensory neuronopathy, but it can be the only manifestation of an underlying malignancy [39].
Autonomic dysfunction is associated with a variety of symptoms including, among others, orthostatic hypotension, dry mouth, erectile dysfunction, sphincter incontinence, gastroparesis, intestinal pseudo-obstruction, and cardiac arrhythmias that can lead to sudden death [40]. Paraneoplastic enteric neuropathy is a limited form in which patients have isolated gastrointestinal dysmotility (gastroparesis). Signs of sympathetic hyperactivity, such as excessive spontaneous sweating, may occur as a true paraneoplastic phenomenon or from local infiltration of sympathetic nerves by the tumor. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)
The tumor most frequently involved is SCLC; these patients usually have anti-Hu antibodies and, less frequently, anti-CRMP5 antibodies. Other tumors include carcinoma of the pancreas, thyroid, and rectum; Hodgkin lymphoma; and carcinoid tumors of the lung [39,41]. Some of these patients have antibodies against ganglionic acetylcholine receptors (AChR), which can also occur in patients without cancer [42,43].
The treatment should focus on antitumor treatment; immune therapy is more effective in patients with ganglionic AChR antibodies [44] than in patients with classic paraneoplastic antibodies (anti-Hu) or no antibodies.
Vasculitic neuropathy — A paraneoplastic peripheral nerve vasculitis typically presents with painful, symmetric or asymmetric sensorimotor deficits resembling a multifocal mononeuropathy and, in some patients, proximal motor weakness [45,46]. The diagnosis is confirmed by biopsy, which shows a predominantly cytotoxic (CD8+) T cell infiltrate in small-sized vessels in the absence of necrosis and malignant cells [47,48]. (See "Clinical manifestations and diagnosis of vasculitic neuropathies", section on 'Clinical Features'.)
Diagnosis of the vasculitis usually precedes the discovery of a cancer. The tumors most frequently involved are cancer of the lung (usually SCLC), prostate, and endometrium, and both Hodgkin and non-Hodgkin lymphomas [46].
As with vasculitic neuropathies that are not associated with cancer, immunosuppressive therapy (eg, glucocorticoids, cyclophosphamide, rituximab) is indicated and may lead to improvement in symptoms. Treatment of the tumor may also improve the neurologic disorder. (See "Treatment and prognosis of nonsystemic vasculitic neuropathy".)
Checkpoint inhibitor-associated neuropathies — Immune checkpoint inhibitors used for cancer therapy have been associated with a variety of neurologic immune-related adverse events, including a wide range of neuropathy phenotypes [49]. Syndromes can occur in the presence or absence of autoantibodies to intracellular (onconeuronal) antigens [50]. Immune-related neuropathies are important to recognize and distinguish from other causes of neuropathy, as treatment may require withdrawal of the offending agent and glucocorticoids (table 2). (See "Toxicities associated with immune checkpoint inhibitors", section on 'General principles'.)
Accumulating reports describe a wide range of cranial and peripheral neuropathies associated with checkpoint inhibitor therapy [49,51-55]. The overall incidence has been estimated between 1 percent with single-agent therapy and up to 3 percent with combination therapy [56]. Common phenotypes include GBS-like syndrome, other polyneuropathies, and cranial neuropathy [49]. Cases of small fiber/autonomic neuropathy, antineutrophil cytoplasmic antibody (ANCA)-associated mononeuritis multiplex, acute length-dependent sensorimotor axonal polyneuropathy, sensory neuronopathy, and neuralgic amyotrophy have also been described. Compared with cytotoxic chemotherapy-induced neuropathy, presentations are more likely to be acute/subacute and involve additional organ systems [49]. Neuropathy onset occurred after a median of three cycles of immunotherapy with a wide range [57].
Electrodiagnostic studies and CSF testing should be performed in most patients to characterize the neuropathy; detect coexisting meningitis, inflammatory myopathy, or neuromuscular junction disease; and rule out infectious and direct neoplastic involvement (eg, leptomeningeal metastases). Approximately half of patients have a mild to moderate pleocytosis and/or elevated protein in CSF [49]. Brain and spine MRI with and without contrast may show gadolinium enhancement of cranial nerves or spinal nerve roots. Such findings are nonspecific but may lend further support to an inflammatory etiology in the context of other test results.
Treatment includes glucocorticoids in most cases and temporary or permanent withdrawal of checkpoint inhibitor therapy, depending on the severity of the toxicity (table 2). Most patients improve with glucocorticoid therapy [58], although deaths have been reported in association with respiratory failure [49,52,59]. Intravenous immune globulin (IVIG) and rituximab have been used in severe or relapsing cases [49].
NEUROMUSCULAR JUNCTION
Lambert-Eaton myasthenic syndrome — The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular junction caused by antibodies directed against voltage-gated calcium channels (VGCC). Approximately 50 percent of patients with LEMS have cancer, almost always small cell lung cancer (SCLC). The presence of antibodies against SOX1 in patients with LEMS predicts the presence of an SCLC [60]. As is often seen with paraneoplastic neurologic syndromes, the neurologic symptoms usually precede the detection of the neoplasm. Some patients have combined paraneoplastic cerebellar degeneration and LEMS. (See "Paraneoplastic cerebellar degeneration".)
The clinical features, diagnosis, and treatment of LEMS are discussed in detail elsewhere. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis" and "Lambert-Eaton myasthenic syndrome: Treatment and prognosis".)
Myasthenia gravis — Myasthenia gravis is an autoimmune disorder of the neuromuscular junction caused in approximately 85 percent of patients by antibodies against the acetylcholine receptor (AChR) [61]. In approximately 10 percent of patients, myasthenia is a paraneoplastic manifestation of a thymic tumor, most commonly thymoma. Thymectomy is indicated in these patients and often results in an improvement in symptoms. Diagnosis and management of myasthenia with and without associated thymoma are reviewed separately. (See "Clinical manifestations of myasthenia gravis" and "Diagnosis of myasthenia gravis" and "Overview of the treatment of myasthenia gravis".)
Aside from thymoma, myasthenia gravis rarely occurs in patients with other cancers (SCLC, thyroid and breast cancers, and Hodgkin lymphoma). In such cases, a paraneoplastic association is less clear. An exception may be rare cases of myasthenia gravis seen in association with follicular dendritic cell sarcoma [62,63]. (See "Follicular dendritic cell sarcoma".)
New-onset myasthenia gravis or exacerbation of previously diagnosed myasthenia have been reported as an immune-related adverse event in cancer patients treated with immune checkpoint inhibitors [64]. A particularly severe immune-related adverse event of checkpoint inhibitors is the combination of myositis, myocarditis, and myasthenia gravis [65]. For all neurologic complications of immune checkpoint inhibitors, older age and paraneoplastic-like syndromes are associated with poorer outcomes [66]. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic'.)
MUSCLE FUNCTION
Dermatomyositis and polymyositis — Dermatomyositis and polymyositis are idiopathic inflammatory myopathies characterized by proximal skeletal muscle weakness and evidence of muscle inflammation. In adults, dermatomyositis often associates with malignancy. This is less clear for polymyositis, with cohort studies reporting conflicting results.
Approximately 10 to 15 percent of adults with dermatomyositis are diagnosed with a malignancy, usually within the first two to three years after diagnosis [67]. As a result of this, active tumor surveillance is recommended during this period. The risk of cancer also appears to be higher in women. Certain serum myositis antibodies appear to confer increased risk of cancer (eg, antibodies to nuclear matrix protein 2 [NXP-2] and transcription intermediary factor 1 gamma). The most common tumors are cancer of the breast, lung, ovary, and stomach, and non-Hodgkin lymphoma. (See "Malignancy in dermatomyositis and polymyositis".)
The diagnosis and treatment of dermatomyositis and polymyositis are discussed in detail elsewhere. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Initial treatment of dermatomyositis and polymyositis in adults".)
Acute necrotizing myopathy — Immune-mediated necrotizing myopathy is a rare disorder characterized by symmetric, painful, predominantly proximal weakness leading to severe disability over one to three months [68]. The serum creatine kinase concentration is markedly elevated, and muscle biopsy shows minimal inflammation, patchy necrosis, and perimysial alkaline phosphatase staining. The etiology can be drug induced (eg, statins), idiopathic, associated with a connective tissue disorder, or paraneoplastic. (See "Statin muscle-related adverse events", section on 'Neuromuscular disorders'.)
In one series of 115 patients with necrotizing myopathy, 10 percent of patients had an associated malignancy diagnosed within three years before or after the myopathy [69]. An additional 5 percent of patients had a more remote cancer diagnosis. Most cancers were adenocarcinomas (eg, breast, gastric, hepatocellular, bladder, endometrial). Patients with antibodies to 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) or without myositis-specific antibodies were more likely to have cancer than those with antibodies to signal recognition particle (SRP). Of note, HMG-CoA antibodies were seen in patients with and without prior statin exposure.
Glucocorticoids combined with other immunosuppressive therapies and tumor treatment (when appropriate) can result in neurologic improvement. Patients with cancer have worse outcomes [70,71].
Paraneoplastic neuromyotonia — Neuromyotonia, also called peripheral nerve hyperexcitability or Isaacs syndrome, is characterized by muscle cramps and stiffness associated with spontaneous and continuous muscle fiber activity of peripheral nerve origin [72]. It is often associated with a sensorimotor polyneuropathy. Thymoma, small cell lung cancer (SCLC), and Hodgkin lymphoma are the most commonly associated neoplasms [72,73].
In some cases, neuromyotonia is associated with antibodies to contactin-associated protein-like 2 (Caspr2), and approximately 20 percent of these patients have thymoma [74,75]. Rarely, patients with predominant neuromyotonia may have antibodies to leucine-rich glioma inactivated 1 (LGI1), a protein related to potassium channels [76]. Many patients with neuromyotonia are antibody negative, but this does not rule out a paraneoplastic etiology [77]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-LGI1 encephalitis'.)
Symptoms include muscle cramps, muscle twitching (myokymia, fasciculations), stiffness, pseudomyotonia (delayed relaxation), carpopedal spasms, increased sweating, and sometimes motor weakness. The involved muscles are often hypertrophic. Intestinal pseudo-obstruction occurs rarely [78]. The serum creatine kinase concentration may be elevated.
Patients with neuromyotonia may develop symptoms of central nervous system (CNS) dysfunction, including confusion, memory loss, hallucinations, seizures, insomnia, and other sleep alterations, which are collectively referred to as "agrypnia excitata." The association of neuromyotonia and CNS symptoms is called Morvan syndrome and is usually accompanied by prominent autonomic dysfunction; it often occurs with antibodies against Caspr2, and 40 percent of these patients have an underlying thymoma [79-81].
The electromyogram (EMG) shows fibrillations, fasciculations, and spontaneous firing of single motor units as doublet, triplet, or multiplet discharges that have a high intraburst frequency and occur at irregular intervals [82]. These motor discharges persist during sleep, general anesthesia, and proximal nerve block, and they may disappear by blocking the neuromuscular junction.
The autoimmune basis of this disorder, whether paraneoplastic or otherwise acquired, is suggested by the response to immunotherapy and demonstration of antibodies in some patients (table 1). The absence of antibodies does not rule out a paraneoplastic etiology, however, and patients with neuromyotonia should be screened for thymoma and other tumors [72,83,84].
Treatment with plasma exchange or intravenous immune globulin (IVIG) is usually of benefit; other potentially effective treatments include phenytoin, carbamazepine, and diazepam [72,85].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paraneoplastic neurologic disorders".)
SUMMARY AND RECOMMENDATIONS
●Spinal cord syndromes
•Myelopathy – Rapidly progressive myelopathy (spastic paresis, sensory loss, with or without bowel and bladder dysfunction) can occur as an isolated paraneoplastic syndrome or, more commonly, in association with involvement of other areas of the nervous system. Antibodies that may be detected include anti-Hu, anti-collapsin-responsive mediator protein 5 (CRMP5), and, less frequently, antiamphiphysin (table 1). (See 'Myelopathy' above.)
•Subacute motor neuronopathy – Paraneoplastic degeneration of the anterior horn cells causes subacute, progressive, painless, and often asymmetric lower motor neuron weakness. The disorder has been described primarily in association with lymphoma. (See 'Subacute motor neuronopathy' above.)
•Stiff-person syndrome – Rare cases of stiff-person syndrome have a paraneoplastic etiology, often associated with antiamphiphysin antibodies. Breast cancer and small cell lung cancer (SCLC) are the most commonly associated neoplasms. (See 'Stiff-person syndrome' above.)
●Dorsal root ganglia syndromes
•Subacute sensory neuronopathy – Sensory neuronopathy is a particularly disabling form of sensory loss presenting with loss of vibratory and joint position sense and sensory ataxia; other sensory modalities become impaired as well. Asymmetric radicular pain and dysesthesias can be the presenting symptoms. Most patients have SCLC and anti-Hu antibodies. (See 'Subacute sensory neuronopathy' above.)
●Peripheral nerve syndromes
•Acute sensorimotor radiculoneuropathy – A syndrome identical to the Guillain-Barré syndrome (GBS) may occur as a paraneoplastic syndrome, usually in association with Hodgkin lymphoma. Treatment and prognosis is similar to that for GBS that is not associated with cancer. (See 'Acute sensorimotor radiculoneuropathy' above and "Guillain-Barré syndrome in adults: Treatment and prognosis".)
•Sensorimotor neuropathy – Paraneoplastic sensorimotor neuropathies range from mild, nondisabling forms associated with advanced cancer to more severe and disabling neuropathies associated with autoantibodies (eg, anti-CRMP5/CV2, antiamphiphysin) or a variety of plasma cell dyscrasias. (See 'Chronic sensorimotor neuropathy' above and 'Neuropathies associated with lymphoproliferative disorders' above.)
•Autonomic neuropathy – Autonomic dysfunction can occur as an isolated paraneoplastic syndrome or in association with other neurologic syndromes. When seen along with paraneoplastic encephalomyelitis, it is often associated with SCLC and anti-Hu antibodies. When isolated, it may associate with ganglionic acetylcholine receptor (AChR) antibodies (autoimmune autonomic ganglionopathy), usually in the absence of an underlying cancer. (See 'Autonomic neuropathy' above.)
•Vasculitic neuropathy – Paraneoplastic peripheral nerve vasculitis typically presents with painful, asymmetric sensorimotor deficits resembling a multifocal mononeuropathy. Biopsy demonstrates the vasculitis. (See 'Vasculitic neuropathy' above.)
●Neuromuscular junction syndromes
•Lambert-Eaton myasthenic syndrome – Lambert-Eaton is an autoimmune disorder of the neuromuscular junction caused by antibodies against voltage-gated calcium channels. Approximately 50 percent of patients have cancer, almost always SCLC. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis" and "Lambert-Eaton myasthenic syndrome: Treatment and prognosis".)
●Muscle syndromes
•Dermatomyositis – Dermatomyositis is the inflammatory myopathy most commonly associated with malignancy. Acute necrotizing myopathy is a rarer and more severe muscle disorder that can occur in association with cancer. (See "Malignancy in dermatomyositis and polymyositis" and 'Acute necrotizing myopathy' above.)
•Neuromyotonia – Neuromyotonia (Isaacs syndrome) is characterized by muscle cramps and stiffness, muscle twitching (myokymias, fasciculations) during rest, delayed muscle relaxation, carpopedal spasms, increased sweating, local muscle hypertrophy, and sometimes motor weakness. Thymoma, SCLC, and Hodgkin lymphoma are the most commonly associated neoplasms. Some of these patients have antibodies against contactin-associated protein-like 2 (Caspr2). (See 'Paraneoplastic neuromyotonia' above.)
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