Cancer and/or its treatments can produce a wide variety of disorders of the peripheral nervous system, including affecting the motor or sensory neurons, autonomic nerves or their fibers, nerve roots, plexi, single or multiple mononeuropathies or entrapments, peripheral neuropathies, neuromuscular junction disorders or damage of the muscles themselves.1
- Direct effects of cancer on the peripheral nervous system include mechanical compression or infiltration of tissues, as well as endoneural/perineural, hematogenous, lymphatic, and leptomeningeal spread.2
- Cancer can cause an altered immune response causing distinct paraneoplastic syndromes, a constellation of systemic signs and symptoms secondary to the presence of a malignancy and by definition exclude direct sequelae of tumor expansion or metastasis.3
- Cancer treatments (chemotherapy, radiation, surgery) can cause direct and indirect damage to the peripheral nervous system (ie plexopathy, mononeuropathies, peripheral neuropathy) and muscles (ie radiation induced fibrosis).3
Epidemiology including risk factors and primary prevention
- The true prevalence of all neuromuscular disease in the cancer population is unknown due to a paucity of large scale population-based studies of the various cancer pain syndromes, nor do we have many prospective population-based studies to estimate the probability that a particular cancer, treatment, or patient will be effected by a neuromuscular disorder.4
- Prominent neuromuscular manifestations include:
- Approximately 38% of patients who have had multiple chemotherapeutic agents develop chemotherapy-induced neuropathy. This incidence varies tremendously based on the kind of chemotherapeutic agents used with higher incidences noted in platinum-based agents, taxanes, vinca alkaloids, and bortezomib.5
- 15-20% of breast cancer patients may have a brachial plexopathy.4
- 50% of patients with the rare osteosclerotic myeloma have a peripheral neuropathy as part of the POEMS syndrome.
- 15% of patients with thymoma develop myasthenia gravis (MG).
- 3% of patients with small-cell lung cancer develop Lambert-Eaton myasthenic syndrome (LEMS).6
- Patients who have undergone hematopoietic stem cell transplant with resultant graft-versus-host disease (GVHD) demonstrate a high association of autoimmune neuromuscular disorders.3
- Less frequent complications include neurologic paraneoplastic syndromes, which are estimated to occur in only 0.01% of patients with cancer. Vascular, infectious, and metabolic disorders are also rare causes of peripheral neuropathy in cancer patients.6
Radiculopathies related to cancer:
- Most commonly related to metastatic disease and can be the result of compression by tumor in the epidural space or by leptomeningeal involvement.
- Nerve root injury can occur by direct compression causing demyelination and axonal injury or by vascular compromise of radicular arteries resulting in ischemia and infarction.
- Other mechanisms include nerve root infiltration with tumors, such as neurofibroma and lymphoma.2
Plexopathies (primary neoplasm/direct invasion/metastasis):
- Neoplastic plexopathies most commonly involve the brachial plexus with benign lesions outnumbering malignant ones.
- Primary brachial plexus tumors are most frequently related to the nerve sheath with both schwannomas and neurofibromas showing a predilection for the upper plexus.
- Although lumbosacral and cervical plexopathies are less common than brachial plexopathies, they are more likely to be of neoplastic origin.
- Plexopathy can also result from direct plexus invasion from an adjacent primary lesion (ie apical lung tumors affecting the lower brachial plexus), metastatic lesions through lymphatic spread seen in breast cancer with axillary lymph node involvement, and hematogenous spread found in hematologic malignancies.
- Although rare, neoplastic processes can also affect a plexus directly through intraneural or perineural metastases, or remotely as a result of paraneoplastic phenomenon.
- Pathophysiologic findings in plexopathies are commonly related to axon disruption and conduction failure, as opposed to demyelination.7
- Benign and malignant peripheral nerve sheath tumors (MPNST) can arise throughout the body and may be related to either the nerve sheath components or adjacent cells, such as pericytes and endothelial cells.
- 50% of all malignant peripheral nerve sheath tumors are related to neurofibromatosis type-1 (NF-1), an autosomal dominant disorder from a genetic mutation to the NF-1 gene, a tumor suppressor protein. The remainder arise sporadically or following radiation therapy. The only current treatment for MPNST is surgical resection to achieve negative margins. 8;9
- Chemotherapy-induced Peripheral Neuropathy. Chemotherapies have different mechanisms of actions in order to fight tumors. The pathophysiologic mechanism by which these drugs effects the neuromuscular system is poorly understood, but is likely a result of their effects to normal cellular components as they would affect tumor cell. There appears to be two distinct anatomical targets on peripheral nerves on which these agents act; the distal axon and the dorsal root ganglia (DRG). Damage to the DRG tends to be more complete and irreversible compared to axonal injury.3
- Paraproteinemias, most commonly seen in monoclonal gammopathy of undetermined significance (MGUS), can also affect peripheral nerve function through axonal degeneration with or without amyloid deposition. They are heterogeneous and form distinct syndromes based on the associated monoclonal antibody.1;10;11The prototypical paraneoplastic peripheral neuropathy, subacute sensory neuropathy, is associated with anti-Hu antibodies and can affect the dorsal root ganglia of sensory nerves with associated inflammatory infiltrates, as well as autonomic and motor cell bodies and nerve axons.
- Cranial nerves (CNs) have a cerebral parenchymal and intracavitary course in the skull prior to having a set exit from the skull. Extracranially, CNs either travel within cavities or soft tissue of the head and neck or even further, like CNX.
- Cranial neuropathies due to neoplastic lesions intracranially can occur due to primary brain/skull tumors, leptomeningeal carcinomatosis or from local solid metastases to any site among the intracavitary course including, the cavernous sinus, the Meckel’s cave, and the orbital fissure.
- Extracranially CNs, including CNV and VII, can be the site of antero- and retro-grade spread from skin, head, and neck tumors. Nasopharyngeal tumors can affect CNIX and XII.1
Neuromuscular junction disorders:
- Cancer can cause dysfunction through autoantibody-mediated changes at the neuromuscular junction, with antibodies directed against the postsynaptic acetylcholine (ACh) receptors in Myasthenia Gravis (MG) and against the presynaptic P/Q voltage-gated calcium channels in Lambert Eaton myasthenic syndrome (LEMS). Treatment of cancer-related MG is similar to non-tumorous MG, in which first line drugs include pyridostigmine, steroids, and azathioprine, while second-line immunosuppressive agents include mycophenolate mofetil, methotrexate, and cyclosporine and rituximab. As for LEMS, symptoms will typically improve with treatment of cancer. When necessary 3,4-diaminopyridine is the first choice of symptomatic treatment.1;12
- Muscles can be directly affected by metastases or indirectly affected as a paraneoplastic phenomenon.
- Dermatomyositis and polymyositis are immune-mediated inflammatory myopathies that result in muscle fiber atrophy and necrosis.
- A more fulminant necrotizing myopathy has also been described with certain cancers and has been found to be associated with muscle necrosis, myophagocytosis, and the absence of lymphocytic inflammatory cells.
- Myopathic muscles are more prone to muscle spasms, and radiation can induce spasticity (ie Head and neck cancer patients who have received radiation may develop cervical dystonia).13
- Cachexia associated with cancer is also a common cause of muscle weakness.14
- Motor neuron disease and stiff-person syndrome have also rarely been reported to be associated with paraneoplastic phenomena.
- Paraneoplastic syndromes act via immune-mediated damage. Tumor cells express neuronal protein antigens the immune system recognizes as nonself. This activates the immune system to develop plasma cells to produce antibodies against this tumor antigen. These antibodies can then react with normal neuronal tissue, signaling immune-mediated destruction. 6;15
- Radiation therapy (RT) can lead to neuromuscular complications by either direct effect of tissues or neuromuscular compression via radiation-induced fibrosis. Radiation fibrosis (RF) is a poorly understood gradual physiologic response of soft tissue to radiation that causes a subsequent insidious, progressive, pathologic tissue sclerosis. Initially an acute inflammatory response occurs by inflammation and death of rapidly proliferating cell types. Cell death occurs through the induction of apoptosis and free-radical mediated DNA damage. This leads to a vicious cycle of fibroblastic proliferation, extracellular matrix deposition, and the release of pro-inflammatory cytokines and reactive oxygen species (ROS). As fibrosis sets in, further cell-damage and death can occur by microvascular ischemia and hypoxia, leading to further fibroblastic proliferation, ROS, pro-inflammatory cytokines, etc. The last stage may develop over years and decades after RT resulting in tissue that is poorly vascularized, friable, and fragile, that is susceptible to recurrent inflammation. Radiation fibrosis syndrome (RFS) describes the late sequelae of RF and can affect nerve, muscle, bone, fascia, ligament, tendon, skin, and viscera.15;16
- Over the last decade, there has been strong and focused research on how to harness the body’s immune system to fight cancer. “Cancer immunotherapy” was named as 2013’s breakthrough of the year by Science. Recent studies have shown success in using immune checkpoint therapy, blocking antibodies to cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), and by chimeric antigen receptor (CAR) T cells. Unfortunately, immune therapy has also been found to result in a wide range of neurological adverse effects involving the central and peripheral nervous system, including myositis, MG, demyelinating polyradiculopathy, aseptic meningitis, and encephalitis.17;18
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Given the complexity and diversity of the clinical features and presentation of the neuromuscular complications of cancer, it is beyond the scope of this discussion to include the natural history of all disorders. However, in brief, paraneoplastic syndromes often precede the diagnosis of cancer, and can present with progressive, severe pain and relentless progression of deficits. In contrast, compressive neuropathies and plexopathies are usually associated with known cancer, treatment toxicity and/or tumor recurrence, where disease trajectory is impacted by factors such as tumor type, stage, site, and volume.
Essentials of Assessment
Patients should be queried for past and current cancer diagnoses and specific treatments as well as a full neurologic history. Those with radiculopathies and plexopathies usually present with pain, paresthesias, and/or weakness. MG and LEMS are associated with fatigue and proximal weakness. When evaluating patients presenting with potential cancer-related syndromes without a history of cancer, constitutional symptoms, such as fever, night sweats, and weight loss, should be elicited. Questions pertaining to bowel and bladder function, saddle anesthesia, and the time course for the onset of symptoms can help select those patients that require emergent radiologic evaluation.
Patients with cancer or suspected diagnoses should have a full musculoskeletal, neurologic, and functional examination. When compressive neuropathy is suspected, palpation may reveal cues to the affected area. As with most lower motor neuron disorders, findings are usually of areflexia, weakness, and sensory impairment. In addition to the proximal weakness present in myopathies, patients with dermatomyositis also present with skin abnormalities on the face and extremities, including the typical heliotrope rash.
Although most oncologists use the Eastern Cooperative Oncology Group performance status or the Karnofsky Scale to assess function, these scales are not sensitive enough to identify many patients with functional impairments amenable to rehabilitative methods. A thorough physiatric functional history including work and family dynamics will help direct the treatment plan.
- When suspecting a paraneoplastic syndrome as a cause of neuromuscular disease, serum and cerebrospinal fluid (CSF) antibodies, when present, can help direct the diagnosis of occult cancer.4
- Anti-Hu antibodies are commonly seen with paraneoplastic encephalitis, paraneoplastic sensory neuropathy, and autonomic dysfunction.
- Anti-VGCC (voltage gated calcium channels) and Anti-PCA2 antibodies are associated with Lambert-Eaton myasthenic symdrome.19
- Anti-amphiphysin antibodies are associated with Stiff-person syndrome.3
- ANNA-3 antibodies are associated with paraneoplastic sensory neuropathy
- Anti-VGKC (voltage-gated potassium channels) are associated with neuromyotonia.19
- CSF protein and cytology evaluation can be used to diagnose leptomeningeal disease.
- Serum protein electrophoresis is used to identify monoclonal proteins in paraproteinemia and related neuropathy.
- Non-cancer related causes of neuropathy (ie diabetes, thyroid disease, compressive mononeuropathy like carpal tunnel syndrome, etc.) may be present as well and should be considered.
- Magnetic resonance imaging, usually with gadolinium enhancement, is the study of choice when spine, nerve root, plexus, or peripheral nerve lesions from cancer are suspected.
- Whole body positron emission scanning is considered the best screening method for locating suspected occult cancer.14
Supplemental assessment tools
Electrodiagnosis helps localize peripheral nerve lesions, detect inflammatory or necrotic myopathies, differentiate cancer-related plexopathy from radiation effects when myokymia is seen on electromyography (EMG), and classifies peripheral neuropathies as axonal or demyelinating.
Both MG and LEMS may demonstrate a decremental response with low-frequency repetitive nerve stimulation (RNS). Following exercise, however, RNS produces a smaller 10-50% increase in compound muscle action potential (CMAP) in MG whereas LEMS patients typically show a greater than 100% increase in CMAP amplitude. Single-fiber EMG is the most sensitive test in diagnosing both MG and LEMS.
Early predictions of outcomes
The course of the neurologic symptoms and prognosis is almost always linked to that of the cancer treatment. Early diagnosis and treatment of cancer yields the best outcomes in treating neuromuscular complications of cancer.
Social role and social support system
Psychosocial problems occur with great frequency in patients with cancer. The physical disability that can accompany neuromuscular disorders can further impact emotional well-being and patient’s social role. Individual therapy and support groups can be helpful at all stages of the disease process.
Rehabilitation Management and Treatments
Available or current treatment guidelines
- Treatment of the underlying malignancy is the cornerstone of management and may include surgical excision, chemotherapy, and/or radiation therapy.
- Disorders associated with autoantibodies may benefit from steroids, plasmapheresis, and/or intravenous immunoglobulin.
- There are currently no established agents recommended to prevent chemotherapy-induced peripheral neuropathy. There have been some smaller trials with various agents that have demonstrated some possible benefit, but overall the results are too inconsistent for recommendation at this time.
- For cancer patient’s experiencing chemotherapy induced neuropathic pain, duloxetine has been demonstrated to be beneficial. Other neuropathic pain modulating agents have not demonstrated consistent benefit, but given their effectiveness in other neuropathic pain disorders, anti-epileptics such as gabapentin and pregabalin, tricyclic antidepressents, and other SSRI/SNRI antidepressents could be trialed while closely monitoring their potential side effect profiles and potential negative interaction with cancer treatments.5
- Radiation-induced neuropathy is currently treated symptomatically. Pain is treated with neuropathic agents such as the anti-epileptics gabapentin and pregabalin, tricyclic antidepressents, and benzodiazapines. Cramps may be treated with quinine. Membrane-stabilizing agents like carbamazepine may reduce nerve hyperexctability. Physical therapy to maintain strength and ROM of affected limbs may be helpful to combat radiation-induced fibrosis.15;16
- Current first line treatment for immunotherapy-induced neurological adverse effects consists of discontinuation of the immunotherapy and a course of corticosteroids. In cases that remain non-responsive, second-line treatment may include plasmapheresis, intravenous immunoglobulins, as well as other immunosuppressive agents like azathioprine or mycophenalate.18
- Addressing and treating co-morbid factors such as diabetes, HTN, alcohol abuse, and avoiding statins may be helpful.
- Rehabilitative methods are similar to those utilized with similar nonmalignant diagnoses and include therapeutic exercise, use of orthotics, and education in the use of adaptive equipment and compensatory strategies.
- Rehabilitative precautions may be required based on location(s) of tumor burden and/or timing and side effects of oncologic treatment. Examples include but are not limited to metastatic bone involvement, cytopenias, skin integrity, organ dysfunction, and patient access to resources.
- Potential intervention goals include treating the cancer, symptom management, restoration or maintenance of function, and reduction of caregiver burden.
At different disease stages
- Although specific rehabilitative treatment plans depend on the diagnosis, there are overarching concepts in patient management. Symptom relief, particularly pain management in patients with radiculopathy and plexopathy, exercises to maintain/improve strength in both affected and preserved muscle groups, cardiopulmonary conditioning, use of orthotics to provide support and stability, education in compensatory strategies, and use of adaptive equipment all contribute to improvements in functional independence.
- Prehabilitation may help prevent or treat neuromuscular dysfunction through a combination of targeted or whole body exercise, nutrition intervention, psychologic support, and/or smoking cessation. 20
- There is an underutilization of cancer rehabilitation services for a variety of reasons, including a lack of awareness from patients and providers, as well as limited access to cancer rehabilitation programs. As the education of cancer rehabilitation services increases and the number of cancer rehabilitation programs proliferate, the goal of universal accessibility becomes more of a reality.21
Surveillance (a period after initial treatment is complete)
- For most patients this is an indefinite interval characterized by constant vigilance for emerging treatment related toxicities and recurrent cancer.
- As described earlier, late complications related to treatment, including RFS, can have detrimental effects to a multitude of body tissues. A variety of factors including location of RT, amount of radiation, contaminant cancer treatments, and chronic comorbidities must be taken into consideration by the clinician when determining whether the patient’s signs and symptoms are in fact related to radiation. These effects can have severe impairments on function even years after RT.16
- Similar strategies to acute management are employed with a greater emphasis on secondary prevention and disease management including vocational, avocational, and psychosocial counseling.
- Should the cancer return, patients are at an increased risk for cancer and treatment-related toxicity. Focus is on management of early-stage impairments
- If cancer becomes progressive, the focus is on maximizing the patient’s comfort, psychological well-being, and maintaining functional independence with mobility and ADLs as long as feasible.
Coordination of care
- Open communication regarding prognosis and goals with the patient, his or her family/caregivers and the entire healthcare team will result in improved care coordination.
Patient & family education
- Rehabilitation entails education about functional prognosis, self-management of symptoms such as pain and fatigue, prevention and management of secondary complications like edema and joint contractures, and the use of compensatory strategies, particularly for fall prevention.
- Symptoms, such as pain, fatigue, or overall quality of life, can be tracked through a variety of available methods, including visual analog scales or other instruments developed specifically for patients with cancer diagnoses.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
- Early recognition of the disorders and ability to distinguish from nonmalignant causes of neuromuscular disease is a critical first step in management.
- For those clinicians without significant exposure to these diagnoses, early consultation with an oncologist may be helpful in facilitating quick and focused diagnostic testing
- Idiopathic progressive peripheral neuropathy should raise suspicion of occult malignancy, especially paraproteinemias, which commonly present with this symptom.
Cutting Edge/ Emerging and Unique Concepts and Practice
- Recent findings that patients with paraneoplastic neurologic disorders may have a better prognosis than patients with histologically identical tumors without neurologic symptoms suggest a protective mechanism of this antitumor immune response; it may have a future role in development of successful approaches to tumor immunotherapy.4
- Intraoperative neuromonitoring has improved outcomes in the surgical management of plexus and peripheral nerve tumors.22
- Neuromusculoskeletal ultrasound shows promise as a diagnostic tool in evaluating for increased cross sectional areas of nerves, a prominent finding in both peripheral neuropathy and proximal to nerve entrapment sites.
- Magnetic resonance neurography may lead to better diagnosis of peripheral nerve tumors.23
Gaps in the Evidence- Based Knowledge
- Healthcare professional’s knowledge of tumor type and location as well as cancer treatment(s) rendered can elevate concern for potential neuromuscular complications in a patient; however, the true risk for each individual patient is unable to be predicted prior to symptom(s) onset.
- Current recommendations for exercise in cancer include prescription for aerobic training at least three times per week, for at least 30 minutes, for at least 8 weeks with or without resistance training. Patients with neuromuscular disease may need modification of this regimen depending on their specific comorbidities.24
- Grisold W, Grisold A, Loscher WN. Neuromuscular complications in cancer. J Neurol Sci 2016;367:184-202.
- Sayko O, Dillingham T. Radiculopathy in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;551-563.
- Custodio C. Electrodiagnosis in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;649-667.
- Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist 2010;15 Suppl 2:3-8.
- Hershman DL, Lacchetti C, Dworkin RH et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014;32:1941-1967.
- Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543-1554.
- Ferrante MA. Plexopathy in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;567-589.
- Korfhage J, Lombard DB. Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside. Mol Cancer Res 2019;17:1417-1428.
- Farid M, Demicco EG, Garcia R et al. Malignant peripheral nerve sheath tumors. Oncologist 2014;19:193-201.
- Hoffman-Snyder C, Smith BE. Neuromuscular disorders associated with paraproteinemia. Phys Med Rehabil Clin N Am 2008;19:61-79, vi.
- Weimer LH, Brannagan TH III. Peripheral Neuropathy in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;591-611.
- Etienne M, Gooch C. Neuromuscular Junction Disorders in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;613-625.
- Hojan K, Milecki P. Opportunities for rehabilitation of patients with radiation fibrosis syndrome. Rep Pract Oncol Radiother 2014;19:1-6.
- Cupler EJ, Graf EGultekin SH. Myopathy in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;627-633.
- Delanian S, Lefaix JL, Pradat PF. Radiation-induced neuropathy in cancer survivors. Radiother Oncol 2012;105:273-282.
- Stubblefield MD. Neuromuscular complications of radiation therapy. Muscle Nerve 2017;56:1031-1040.
- Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 2015;125:3335-3337.
- Perrinjaquet C, Desbaillets N, Hottinger AF. Neurotoxicity associated with cancer immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy. Curr Opin Neurol 2019;32:500-510.
- Magda P, Younger D. Autonomic Dysfunction in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;641-647.
- Santa Mina D, Brahmbhatt P, Lopez C et al. The case for prehabilitation prior to breast cancer treatment. PM&R 2017;9:S305-S316.
- Stubblefield MD. The Underutilization of Rehabilitation to Treat Physical Impairments in Breast Cancer Survivors. PM R 2017;9:S317-S323.
- Avila EK, Sandhu SK. Intraoperative Neurophysiologic Monitoring in Cancer. In: Stubblefield MD, O’Dell MW, eds. Cancer Rehabilitation Principles and Practice. New York, NY: Demos Medical Publishing; 2009;669-682.
- Filler AG, Maravilla KR, Tsuruda JS. MR neurography and muscle MR imaging for image diagnosis of disorders affecting the peripheral nerves and musculature. Neurol Clin 2004;22:643-vii.
- Campbell KL, Winters-Stone KM, Wiskemann J et al. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Medicine & Science in Sports & Excercise 2019;51:2375-2390.
Original Version of the Topic
Ayca D. Ozel, MD, Asif Jillani, MD. Neuromuscular Complications of Cancer. 12/28/2012
Previous Revision(s) of the Topic
Megan Nelson, MD, David Haustein, MD, and Steven Papuchis, MD. Neuromuscular Complications of Cancer. 4/4/2017
Megan Bale Nelson, MD
Nothing to Disclose
Carl Alex Carrasquer, MD
Nothing to Disclose
Steven Papuchis, DO
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David Haustein, MD, MBA
Premier Medical Consulting, Employment Part time, Owner