Author(s): Sara Flores, MD, Catherine Cho, DO, Jennifer Tram, MD
Originally published: September 19, 2016 Last updated: January 3, 2024
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Disease/Disorder

Definition

Paraneoplastic syndromes are disorders with complex 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 a group of neurological disorders resulting from an immune response triggered by an underlying tumor that affects the central and/or peripheral nervous systems, directed originally against the tumor itself.2

Etiology

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

Population-based epidemiology studies have indicated that autoimmune disorders affecting the nervous system are not as rare as previously considered. Incidence rates are increasing over time, likely due to increased awareness and improved detection techniques.21,22The 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 disorders are present in up to 9% of patients with SCLC.3

Patho-anatomy/physiology

Although the pathogenesis of paraneoplastic neurologic syndromes is not fully understood, many of the syndromes are thought to be 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 or 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.  Antibodies targeting intracellular neuronal antigens (released after tumor-cell death) as in Classic PNS have been shown to display a cytotoxic T-lymphocyte-mediated pathogenesis. Conversely, antibodies associated with cell surfaces and synaptic proteins (Encephalitis types) display an antibody-mediated pathogenesis.3,5 PNS can affect any of the central or peripheral nervous system, from the cerebral cortex to the neuromuscular junction and muscle.21

Disease progression including natural history, disease phases or stages, disease trajectory

Syndromes defined as “classical’’ PNS include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, subacute sensory neuronopathy, opsoclonus-myoclonus syndrome, chronic gastrointestinal pseudo-obstruction (enteric neuropathy), LEMS and dermatomyositis.3,21 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

History

PNS presentation often precedes cancer diagnosis, with the large majority of tumors being diagnosed within two years of onset of the neurologic disorder.3 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 acute or subacute mood and behavioral changes, short-term memory problems, focal seizures with impaired awareness, cognitive dysfunction, and possible hypothalamic dysfunction.3 Paraneoplastic cerebellar degeneration causes diplopia, ataxia, and dysphagia.7,9  

Physical examination

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

Muscle weakness and its impact on function can be assessed by location: facial weakness (‘horizontal smile’, inability to whistle), ocular weakness (double vision, ptosis, disconjugate eye movements), bulbar (weak cry, dysphagia, cough during meals), neck (poor head control), trunk instability/weakness (difficulty sitting up), respiratory weakness (use of accessory muscles), shoulder girdle, forearm/hand, pelvic girdle, and leg/foot.11

Laboratory studies

Patients with suspected PNS should obtain both serum and CSF antibody screening. Antibodies against intracellular antigens are almost always detectable in serum. Antibodies against cell-surface or synaptic proteins may be absent in serum testing and are typically found in higher titers in CSF than serum.3 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

Imaging

Brain 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

After a paraneoplastic neurological syndrome has been diagnosed, computed tomography (CT) of the chest, abdomen, and pelvis with contrast should be performed as initial screening for associated malignances. Additional imaging studies such as mammogram or pelvic/scrotal US may be ordered as suggested by the clinical syndrome, identification of certain paraneoplastic antibodies, or other risk factors. If initial radiological assessment does not detect any malignancy, fluorodeoxyglucose positron emission tomography (FDG-PET) should be obtained, as it has been shown to have a higher sensitivity for occult malignancy compared with CT. If no tumor is detected at the time of PNS diagnosis, cancer surveillance is advised 3-6 months after initial negative screening, then every 6 months for 4 years in PNS with onconeural antibodies, with the exception of LEMS in which 2 years is sufficient.3,21

Supplemental assessment tools

Lumbar puncture can be used to confirm the presence of paraneoplastic antibodies in CSF, especially those targeted against cell-surface or synaptic proteins.3 It can also 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 stimuli.13

Early prediction of outcomes

Early diagnosis is critical as delays in care can lead to permanent neurological deficits, although literature evaluating early prognostic factors is limited.23 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 Another cohort study demonstrated that positive prognostic factors in patients with anti-NMDA receptor encephalitis included early initiation of treatment and hospitalization without ICU admission.24

Environmental

There is a paucity of evidence in the literature exploring environmental effects on the development and/or the progression of paraneoplastic syndromes. Those who are diagnosed with LEMS and are later found to have cancer will likely have a history of long-term smoking.14 For myasthenia gravis, medications including aminoglycosides, macrolides, beta-blockers, ACE inhibitors, quinidine, lidocaine, procainamide, phenytoin, prednisone, interferon, and D-penicillamine can cause exacerbation of symptoms.15 Alentorn and colleagues demonstrated a positive association between warm climate and incidence of anti-NMDA receptor encephalitis.25

Social role and social support system

Patients who have cancer may find the physical, emotional, and social effects of the disease to be distressing and diminished to quality of life. 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 An interdisciplinary team approach involving medical professionals, therapists, nursing, psychology and social work may be helpful to providing longitudinal support for patients.

Professional issues

As PNS are rare, diagnosis can be difficult, resulting in misdiagnosis or delayed treatment. 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

General approaches to treatment include removal of the antigen source by treatment of the underlying tumors immunosuppression and supportive therapy. Treatment of the underlying malignancy can involve surgical resection, chemotherapy or radiotherapy. Immunosuppression is beneficial for some conditions with antibodies against cell surface antigens such as seen in LEMS, MG, and encephalitis. Plasma exchange, IVIG, and high dose methylprednisolone are effective immunosuppressants and improve neurologic status. A good response to these initial immunosuppressants may indicate favorable long-term immunosuppression with agents like mycophenolate or azathioprine.23 Second line therapies include rituximab and cyclophosphamide. Syndromes that usually do not respond to treatment include 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 Supportive treatment includes medications for analgesia or mood as well as therapies such as physical therapy, occupational therapy, recreational therapy and speech and swallow therapy.

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 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. 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, physicians may consider plasma exchange or intravenous immune globulin and immunosuppressive agents such as corticosteroids, cyclophosphamide, or tacrolimus. A favorable response to initial immunosuppression would warrant consideration of long term immunosuppression for at least one year.23  

Coordination of care

Coordination between the physiatrist, therapist, oncologist, and neurologist are paramount. Particular attention should be made when coordinating therapies and any concurrent cancer treatment to ensure there are no scheduling conflicts and to ensure that the patient can actively participate in therapy. Patients with fatigue or appetite loss from concurrent cancer treatment may benefit from the addition of appetite stimulants or an appropriate sleep hygiene regimen. Additionally, in severely debilitated patients, the elderly and bedridden, immunotherapy treatment may be deferred because of the very small likelihood of clinically relevant neurological improvement.10

Patient & family education

Frequent education of the patient and family helps patients make informed decisions regarding their disease course. The patient should be aware of the cancer prognosis and what symptoms reflect worsening course of the cancer versus what symptoms are associated entirely with nerve damage caused by the PNS. Furthermore, the patient and family should be counseled regarding appropriate treatment options for the underlying malignancy including surgery, chemotherapy and radiotherapy, when appropriate.

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

PNS is difficult to diagnose but early diagnosis and initiation of treatment is critical to prevent permanent neurological deficits. Symptoms of PNS may include ataxia, encephalitis, peripheral neuropathy, memory problems, seizures, sensory motor neuropathies, anorexia, rapid weight loss and fatigue.23 PNS may precede the diagnosis of the 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 found, and some of these antibodies are excellent predictors of favorable response to immunotherapy,3,5 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 such as limbic encephalitis with SCLC occur more frequently in older adults, are more strongly associated with underlying malignancy, 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 Further research also aims to further characterize diagnostic criteria for PNS using factors like antibody type, presence of malignancy and clinical presentation.26

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 proven.4 Development of specific criteria to facilitate early diagnosis of PNS is also ongoing.

References

  1. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 2003; 349:1543–1554.
  2. Leypoldt F, Wandinger K-P. Paraneoplastic neurological syndromes. Clin. Exp. Immunol. 2014; 175:336–348.
  3. Joseph Dalmau MRR. Overview of paraneoplastic syndromes of the nervous system. In: Patrick Y Wen AFE, ed. UpToDate.
  4. Honnorat J, Antoine J-C. Paraneoplastic neurological syndromes. Orphanet J. Rare Dis. 2007; 2:22.
  5. 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
  6. Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr. Opin. Neurol. 2012; 25:795–801.
  7. Santacroce L. Paraneoplastic Syndromes Clinical Presentation: History, Physical Examination. Available at: http://emedicine.medscape.com/article/280744-clinical. Accessed April 21, 2016.
  8. 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.
  9. 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.
  10. de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist 2006; 11:292–305.
  11. Jackson CE. A clinical approach to muscle diseases. Semin. Neurol. 2008; 28:228–240.
  12. Darnell RB, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin. Oncol. 2006; 33:270–298.
  13. Bird SJ. Diagnosis of myasthenia gravis. In: Jeremy M Shefner, Ira N Targoff, John F Dashe, ed. UpToDate. Waltham, MA: UpToDate; 2015.
  14. Gilhus NE. Lambert-eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy. Autoimmune Dis. 2011; 2011:973808.
  15. Bird SJ. Treatment of myasthenia gravis. In: Jeremy M Shefner, Ira N Targoff, John F Dashe, ed. UpToDate. Waltham, MA: UpToDate; 2015.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. Gultekin SH. Recent developments in paraneoplastic disorders of the nervous system. Surg. Pathol. Clin. 2015; 8:89–99.
  21. Devine MF, Kothapalli N, Elkhooly M, et al. Paraneoplastic neurological syndromes: clinical presentations and management.
  22. Vogrig A, Gigli GL, Segatti S, et al. Epidemiology of paraneoplastic neurological syndromes: a population-based study. J Neurol. 2020;267(1):26-35.
  23. Kannoth S. Paraneoplastic neurologic syndrome: A practical approach. Ann Indian Acad Neurol. 2012;15(1): 6-12.
  24. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis: a cohort study. Lancet Neurol. 2013; 12(2): 157-165.
  25. Alentorn A, Berzero G, Alexopoulos H, et al. Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis – A Systematic Review. Biomedicines. 2023; 11(6): 1525.
  26. Graus F, Vogrig A, Muniz-Castrillo S, et al. Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes. Neurol Neuroimmunol Neuroinflamm. 2021; 8(4): e1014.

Original Version of the Topic

Subhadra Nori, MD, Andrew Kamal Abdou, DO. Neuromuscular Manifestations of Neoplasms and Paraneoplastic Syndromes. 9/19/2016

Previous Revision(s) of the Topic

Subhadra Nori, MD. Neuromuscular Manifestations of Neoplasms and Paraneoplastic Syndromes. 12/28/2020

Author Disclosure

Sara Flores, MD
Nothing to Disclose

Catherine Cho, DO
Nothing to Disclose

Jennifer Tram, MD
Nothing to Disclose