The term “paraneoplastic syndromes” refers to symptoms resulting from damage to organs or tissues that are remote from the site of a malignant neoplasm or its metastases.1 Paraneoplastic neurological syndromes (PNS) are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumor itself.2
An immunologic response is directed against shared antigens that are ectopically expressed by the tumor, but otherwise exclusively expressed by the nervous system. For unknown reasons, the immune system identifies these antigens as foreign and mounts an immune attack against them.3
Epidemiology including risk factors and primary prevention
PNS are rare diseases occurring in less than about 0.01% of patients with cancer.4 However, the incidence of paraneoplastic disorders varies with the neurologic syndrome and type of tumor. The more common syndromes are Lambert-Eaton myasthenic syndrome (LEMS), which affects approximately 3% of patients with small-cell lung cancer (SCLC), and myasthenia gravis (MG), which affects 15% of all patients with thymoma. However, it should be noted that not all cases of MG are considered to be paraneoplastic. One or more paraneoplastic neurologic disorder is present in up to 9% of patients with SCLC.3
Currently, it is thought that most or all paraneoplastic neurologic disorders are immune-mediated.1 The mechanism entails ectopic expression by a tumor of an antigen that normally is expressed exclusively in the nervous system. The same antigen may be processed by the immune system differently, depending on whether it is expressed in a cancer cell versus a normal cell. This suggests that additional factors may be involved in the immune response to the antigen.3,4 Numerous antibodies have been identified in association with specific PNS and are associated with intracellular antigens (Classic PNS) or cell surfaces and synaptic proteins (Encephalitis types).5
Disease progression including natural history, disease phases or stages, disease trajectory
Syndromes defined as ‘classical’ PNS include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, sensory neuronopathy, opsoclonus-myoclonus, chronic gastrointestinal pseudo-obstruction, LEMS and dermatomyositis. Each syndrome has a unique clinical presentation that often precedes a diagnosis of cancer. They may be rapidly progressive, in many cases leaving the patients severely debilitated within weeks to months.4 Most PNS associated with onconeural antibodies usually have a subacute, aggressive clinical course and then stabilize.6
Specific secondary or associated conditions and complications
MG is associated with thymoma. LEMS and paraneoplastic limbic encephalitis are associated with SCLC. Encephalitis resulting from antibodies against N-methyl-D-aspartate receptors occur in ovarian teratoma.7 Dermatomyositis has been reported in cases of breast cancer.8 Paraneoplastic cerebellar degeneration is associated with Hodgkin lymphoma, breast cancer, SCLC, ovarian cancer, and prostate carcinoma.7
Essentials of Assessment
PNS presentation often precedes cancer diagnosis. MG presents as asthenia, particularly extraocular muscle and ptosis. LEMS manifests as asthenia of the scapular and pelvic girdles, xerostomia, and sexual impotence. Paraneoplastic limbic encephalitis is characterized by depression, seizures, and memory loss. Paraneoplastic cerebellar degeneration causes diplopia, ataxia, and dysphagia.7,9
A thorough physical examination should include reflexes, muscle strength, muscle tone, sense of touch, vision and hearing, coordination, balance, mental status, mood, palpation for pathological lymph nodes, rectal and pelvic examination, and palpation of breasts and testis.9,10
Clinical functional assessment: mobility, self-care cognition/behavior/affective state
Locations for functional assessment of muscle weakness include facial (‘horizontal smile’, inability to whistle), ocular (double vision, ptosis, disconjugate eye movements), bulbar (weak cry, dysphagia, cough during meals), neck (poor head control), trunk (difficulty sitting up), respiratory (use of accessory muscles), shoulder girdle, forearm/hand, pelvic girdle, and leg/foot.11
Antibodies can be detected in the serum or CSF. Testing of serum alone may suffice for “classical” paraneoplastic antibodies but is not sufficient for some autoimmune encephalitis associated with antibodies against cell surface or synaptic proteins. Low levels of paraneoplastic antibodies may be seen in patients without PNS.3, 20
MRI can assist in the diagnosis of limbic encephalitis because the medial temporal lobes, the site of major pathology, and often show increased signal on fluid-attenuated inversion recovery (FLAIR) images and occasionally areas of contrast enhancement. Patients with paraneoplastic cerebellar degeneration may develop signs of atrophy detectable by MRI several months after the onset of symptoms. PET scan of the brain using fluorodeoxyglucose (FDG-PET) will occasionally identify hypermetabolism of the medial temporal lobes in patients with limbic encephalopathy, or of the cerebellum in patients with paraneoplastic cerebellar degeneration. 3
Supplemental assessment tools
Lumbar puncture can be used to confirm serum antibodies and identify new antibodies seen in certain PNS encephalitis. Electrophysiologic findings include LEMS, MG, and dermatomyositis.3 For LEMS a compound muscle action potential (CMAP) is often less than 10% of normal, however at frequencies from 22 to 50 Hz, the CMAP increases. An increase of 100% is typical of LEMS.12 For MG repetitive nerve stimulation (RNS) studies and single-fiber electromyography (SFEMG) are used. In RNS, the nerve is electrically stimulated at 2 to 3 Hz and shows a decremental response in the CMAP amplitude with the few stimuli.13
Early prediction of outcomes
Some reports suggest a more limited disease distribution and better outcome among patients with SCLC who develop immunity to paraneoplastic antigens. However, 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 PNS.3
Among those who are diagnosed with LEMS who are later found to have cancer will likely have a history of long-term smoking.14 For MG, medications including aminoglycosides, macrolides, betablockers, ACE inhibitors, quinidine, lidocaine, procainamide, phenytoin, prednisone, interferon, and D-penicillamine, can cause exacerbation of symptoms.15
Social role and social support system
Patients who have cancer may find the physical, emotional, and social effects of the disease to be stressful. Effective coping strategies to deal with stress, such as relaxation and stress management techniques, have been shown to have lower levels of depression, and anxiety.16
As PNS are rare, the diagnosis is difficult and frequently the patient is misdiagnosed. Neurological symptoms usually develop before the diagnosis of the tumor.4 Prompt oncologic treatment is beneficial. The failure of the neurologic syndrome to respond to treatment may be due to irreversible neuronal damage that occurred before treatment.3
Rehabilitation Management and Treatments
Available or current treatment guidelines
Two general approaches to treatment include: removal of the antigen source by treatment of the underlying tumors, and Immunosuppression. Immunosuppression is beneficial for some conditions, with antibodies against cell surface antigens seen in LEMS, MG, and encephalitis. Plasma exchange, IVIG, and methylprednisolone are effective immunosuppressants and improve neurologic status. Second line therapies include rituximab and cyclophosphamide. Syndromes that usually do not respond to treatment includes most of the classical paraneoplastic syndromes associated with antibodies against intracellular antigens.3 Some examples include limbic encephalitis, opsoclonus-myoclonus syndrome, and Lambert Eaton myasthenic syndrome.17
At different disease stages
Rapid detection and immediate treatment of the underlying tumor appears to offer the best chance of stabilizing the patient and preventing further neurological deterioration.10 The different subtypes of PNS are defined by the presence or the absence of paraneoplastic antibodies and the type of antibodies. Management and treatment should be tailored to each subtype.4 There are no established protocols for the treatment of most paraneoplastic syndromes, but if the patient’s condition is deteriorating, the physician usually uses a combination of either plasma exchange or intravenous immune globulin and immunosuppressive agents such as corticosteroids, cyclophosphamide, or tacrolimus. A few isolated case reports describe responses to various immunotherapeutic interventions encourage physicians to combine immunotherapy with treatment of the cancer in a desperate situation. Since the pathologic features of paraneoplastic neurologic disorders suggest that a destructive immune response is typically present, treatment with immunosuppression should begin as expeditiously as possible. Some disorders, such as the Lambert–Eaton myasthenic syndrome and myasthenia gravis, respond well to immunosuppression and subsequently to treatment of the underlying tumor.1
Coordination of care
Coordination between the physiatrist, therapist, oncologist, and neurologist are necessary. Particular attention should be made when coordinating physical therapy and any concurrent cancer treatment to ensure there are no scheduling conflicts and to ensure that the patient can actively participate in therapy. In severely debilitated patients, for example, the elderly and bedridden, immunotherapy treatment is often withheld because of the very small chance of clinically relevant neurological improvement.10
Patient & family education
The patient should be aware of the cancer prognosis and what symptoms reflect worsening prognosis of the cancer and what symptoms are purely associated with nerve damage that resulted from the PNS. Furthermore, the patient and family should be aware of which subsets of PNS can be treated with immunotherapy.
Measurement of Treatment Outcomes
Improvement from immunotherapy treatment can be measured by any increase in Rankin score or a 10-point increase in Barthel functional index.18 Functional Independence Measure (FIM) is a useful measurement in the setting of acute inpatient rehabilitation.19
Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Symptoms of PNS may include ataxia, dizziness, nystagmus, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, vision problems, and sensory loss in the limbs. PNS may precede the diagnosis of underlying malignancy. The discovery and detection of antibodies continues to expand and can help expedite direct care. Antibodies to neuronal surface antigens, synaptic receptors, intracellular antigens, neuromuscular junction antigens, voltage gated potassium channels, glutamate receptors, GABA and glycine receptors have been found3, 5 Some of these antibodies are excellent predictors of a better response to immunotherapy. Less frequently, patients may develop another PNS clinically different from the first.6
Cutting Edge/ Emerging and Unique Concepts and Practice
Novel associations between clinical encephalitic syndromes, and serologic presence of neuronal surface antibodies with or without underlying cancer have been developed in recent years. The classic paraneoplastic encephalitis syndromes (e.g., limbic encephalitis with SCLC) occur more frequently in older adults, are more likely to herald an underlying neoplasm, are clinically typically uniphasic with variable stabilization, and are limited in their response to therapy. As opposed to the classic PND, these recently characterized autoimmune encephalitis syndromes are generally more common, occur in younger age groups, respond more frequently to therapy, and may show relapses.20
Gaps in the Evidence-Based Knowledge
No studies have conclusively proved that paraneoplastic antibodies are pathogenic; nevertheless, the paraneoplastic antibodies are useful diagnostic markers that can be used also to classify the different subtypes of PNS. The hypothesis that PNS are immune-mediated remains to be proved.4 Also, studies in animals have failed to reproduce PNS.1
- Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 2003; 349:1543–1554.
- Leypoldt F, Wandinger K-P. Paraneoplastic neurological syndromes. Clin. Exp. Immunol. 2014; 175:336–348.
- Joseph Dalmau MRR. Overview of paraneoplastic syndromes of the nervous system. In: Patrick Y Wen AFE, ed. UpToDate.
- Honnorat J, Antoine J-C. Paraneoplastic neurological syndromes. Orphanet J. Rare Dis. 2007; 2:22.
- Iorio R, Spagni G, Masi G. Paraneoplastic neurological syndromes. Seminars in diagnostic pathology. 2019;36(4):279-292. doi:10.1053/j.semdp.2019.06.005
- Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr. Opin. Neurol. 2012; 25:795–801.
- Santacroce L. Paraneoplastic Syndromes Clinical Presentation: History, Physical Examination. Available at: http://emedicine.medscape.com/article/280744-clinical. Accessed April 21, 2016.
- Sandhu NP, Zakaria S, Degnim AC, Boughey JC. Dermatomyositis presenting as a paraneoplastic syndrome due to underlying breast cancer. BMJ Case Rep. 2011; 2011. Available at: http://dx.doi.org/10.1136/bcr.10.2010.3416.
- Anon. Paraneoplastic syndromes of the nervous system Tests and diagnosis – Mayo Clinic. Available at: http://www.mayoclinic.org/diseases-conditions/paraneoplasticsyndromes/basics/tests-diagnosis/con-20028459. Accessed April 21, 2016.
- de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist 2006; 11:292–305.
- Jackson CE. A clinical approach to muscle diseases. Semin. Neurol. 2008; 28:228–240.
- Darnell RB, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin. Oncol. 2006; 33:270–298.
- Bird SJ. Diagnosis of myasthenia gravis. In: Jeremy M Shefner, Ira N Targoff, John F Dashe, ed. UpToDate. Waltham, MA: UpToDate; 2015.
- Gilhus NE. Lambert-eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy. Autoimmune Dis. 2011; 2011:973808.
- Bird SJ. Treatment of myasthenia gravis. In: Jeremy M Shefner, Ira N Targoff, John F Dashe, ed. UpToDate. Waltham, MA: UpToDate; 2015.
- Anon. Psychological Stress and Cancer. National Cancer Institute. Available at: http://www.cancer.gov/about-cancer/coping/feelings/stress-fact-sheet. Accessed April 21, 2016.
- Gozzard P, Maddison P. Which antibody and which cancer in which paraneoplastic syndromes? – PubMed – NCBI. Available at: http://eresources.library.mssm.edu:2132/pubmed/20858627.
- Vernino S, O’Neill BP, Marks RS, O’Fallon JR, Kimmel DW. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro. Oncol. 2004; 6:55–62.
- Fu JB, Raj VS, Asher A, et al. Inpatient rehabilitation performance of patients with paraneoplastic cerebellar degeneration. Arch. Phys. Med. Rehabil. 2014; 95:2496–2499.
- Gultekin SH. Recent developments in paraneoplastic disorders of the nervous system. Surg. Pathol. Clin. 2015; 8:89–99.
Original Version of the Topic
Subhadra Nori, MD, Andrew Kamal Abdou, DO. Neuromuscular Manifestations of Neoplasms and Paraneoplastic Syndromes. 9/19/2016
Subhadra Nori, MD
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