Neuromuscular Complications of Cancer

Disease/Disorder

Definition

Cancer and its treatments can produce a wide variety of neuromuscular disorders which may affect the motor and/or sensory neurons of the peripheral nervous system, autonomic nerves or their fibers, nerve roots, plexuses, single nerves (i.e., mononeuropathies or entrapment neuropathies), multiple nerves (i.e., polyneuropathies), the neuromuscular junction disorders, and/or damage of the muscles themselves.¹

Etiology

• Direct effects of cancer on the peripheral nervous system may include mechanical compression, as well as endoneurial/perineural, hematogenous, lymphatic, and leptomeningeal spread.²
• Cancer treatments, including chemotherapy, radiation, and surgery, can cause direct and/or indirect damage to the peripheral nervous system (i.e., plexopathy, mononeuropathies, peripheral neuropathy) and muscles (i.e., 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 cancer pain syndromes, and the limited prospective population-based studies to estimate the probability that a particular cancer, treatment, or patient may be affected by a neuromuscular disorder.
• Prominent neuromuscular manifestations include:
  • 69% of cancer patients develop chemotherapy-induced peripheral neurotoxicity ⁴
  • Incidence of chemotherapy induced peripheral neuropathy varies tremendously based on the kind of chemotherapeutic agents used with higher incidences noted in platinum-based agents, taxanes, vinca alkaloids, and bortezomib.⁵
  • Brachial plexopathies may affect up to 12.5% of cancer patients⁴
  • 50% of patients with the rare osteosclerotic myeloma have a peripheral neuropathy as part of the POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, skin changes).
  • 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
• There is currently no evidence to suggest that these neuromuscular complications of cancer and cancer treatment can be prevented. However, the guidelines state clearly that the use of acetyl-L-carnitine should be discouraged.⁵

Patho-anatomy/physiology

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 (i.e., 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

Nerve tumors

• 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

Peripheral neuropathies

• Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 69% of cancer survivors.⁴ The pathophysiologic mechanism by which these drugs affect the neuromuscular system is poorly understood but is likely a result of their effects on normal cellular components as they would affect tumor cells. 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 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 neuropathies

• Cranial nerves (CNs) have a cerebral parenchymal and intracavitary course in the skull prior to having a set exit from the skull. Extracranially, CN’s either travel within cavities or soft tissue of the head and neck or even further, like CN X.
• 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 CN V and CN VII, can be the site of antero- and retro-grade spread from skin, head, and neck tumors. Nasopharyngeal tumors can affect CN IX and CN XII.¹

Muscles

• Muscles can be directly affected by metastases or indirectly affected as a paraneoplastic phenomenon.
• 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 (i.e., 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
• Patients on Immune check point inhibitors (ICIs) were shown to cause a wide range of ICI associated myopathies (ICIAM) including dermatomyositis, polymyositis, necrotizing myopathy and non-specific myopathy. Usually occurs within the first 3 months of ICI administration and nearly half of all patients were found to have predominant oculobulbar weakness with varying proximal limb involvement. Regardless it is recommended all ICI-treated patient with oculobulbar weakness, axial or limb weakness undergo EMG screening regardless of CK level^18,19,20

Other

• 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, ICIs are associated with immune-related adverse events (irAEs), including peripheral neuropathies, myasthenia gravis, myositis and myopathies, and are twice as likely to affect the PNS compared to the CNS.^18,19,20
• With the rising use of Immune Checkpoint Inhibitors (ICI), the incidence of immune-related adverse events (irAEs) has been increasing. These complications include ICI-Induced Myasthenia Gravis (MG). Studies have shown an increased risk of ICI-induced MG in patients being treated with ICI and an underlying autoimmune disorder, along with an increased predilection for males when compared to females. Additionally there is evidence showing that ICI-Induced MG has a higher rate of life-threatening complication such as myasthenic seizures needing respiratory support^18,19,20
• The literature documents concurrent overlap between ICI-induced MG and myopathy/myocarditis which is important to recognize early as there is rapid decline in function and increased mortality rates.  Studies have estimated incidence of myocarditis between 16.1-40% in the setting of ICI-Induced MG with complications including cardiovascular death, cardiogenic shock, cardiac arrest, or life-threatening arrythmia. It has been observed that the elevated Creatine Kinase (CK) levels in patients with ICI-Induced MG has been attributed to co-existing myopathy or myocarditis and clinicians should consider further testing and diagnostic work up.^18,19,20

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

History

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. When evaluating patients presenting with potential cancer-related syndromes with or without a past history of cancer associated with constitutional symptoms such as fever, night sweats, and weight loss, cancer should be suspected as a possible diagnosis. 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.

Physical examination

It is important to perform a thorough musculoskeletal, neurological (including Cranial Nerves), and functional exam of each patient. Though many patients may have new onset weakness or pain related to a disc herniation or peripheral nerve entrapment, it is important to consider malignancy as a potential etiology when patients present with new onset pain and/or weakness.

For patients in which malignancy is already known, physiatrists should be cognizant of the type and location of cancer as well as any known deficits. Range of motion and strength testing may be limited in these patients due to pain and metastases. When a compressive neuropathy is suspected, palpation may reveal cues to the affected area. As with most lower motor neuron disorders, findings may include areflexia, weakness, and sensory impairment. Myopathies will commonly present with proximal muscle weakness.

Functional assessment

Although most oncologists use the Eastern Cooperative Oncology Group (ECOG) 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.

Laboratory studies

• 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 syndrome.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 (i.e., diabetes, thyroid disease, compressive mononeuropathy like carpal tunnel syndrome, etc.) may be present as well and should be considered.

Imaging

• 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 (i.e. when myokymia is seen on needle electromyography), and helps classify peripheral neuropathies as axonal or demyelinating.

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 patients 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 antidepressants, and other SSRI/SNRI antidepressants could be trialed while closely monitoring their potential side effect profiles and potential negative interaction with cancer treatments.⁵
• Radiation-induced neuropathic pain is treated with neuropathic agents such as the anti-epileptics gabapentin and pregabalin, tricyclic antidepressants, and benzodiazepines. Cramps may be treated with quinine. Membrane-stabilizing agents like carbamazepine may reduce nerve hyperexcitability.  Physical therapy to maintain strength and ROM of affected limbs may be helpful to combat radiation-induced fibrosis.^15;16
• Acupuncture is recommended by the National Comprehensive Cancer Network as a useful adjunctive treatment for cancer pain. It has been shown to be associated with reduced cancer pain and reduced opioid doses, when used in conjunction with opioid therapy.²²
• Current first line treatment for immune related adverse events 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, hypertension, alcohol abuse, and avoiding statins may be helpful.
• Rehabilitative methods are similar to those utilized with similar non-malignant 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

Initial diagnosis

• 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, psychological support, and/or smoking cessation.
• 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 radiation therapy, 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.

Recurrence

• Should the cancer return, patients are at an increased risk for cancer and treatment-related toxicity. Focus is on management of early-stage impairments.

Palliation

• 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 and oncologic team will result in improved care coordination.

Patient & family education

• Rehabilitation entails education regarding 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.

Emerging/unique interventions

N/A

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
• 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.
• 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
• Botulinum toxin has been used for various cancer patients to assist with the nociceptive and neuropathic pain pathways in cancer pain. ²⁵
• Capsaicin cream in various over the counter formulations is commonly used to treat painful peripheral neuropathies. Recently, high concentration topical capsaicin 8% film applied with local anesthetic in an office setting has been shown to produce substantial levels of pain relief with low grade evidence.²³ This high dose, office based procedure warrants further investigation as a novel agent to improve neuropathic pain.

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.
• More prospective and retrospective studies are needed to gauge the incidence and prevalence of neuromuscular disorders affecting the rehabilitation of cancer patients.

References

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14. Stubblefield MD. Neuromuscular complications of radiation therapy. Muscle Nerve 2017;56:1031-1040.
15. Reynolds KL, Guidon AC. Diagnosis and management of immune checkpoint inhibitor-associated neurologic toxicity: Illustrative case and review of the literature. Oncologist. 2019;24(4):435-443. doi:10.1634/theoncologist.2018-0359
16. 1. KL; BLMA. A review of neurotoxicities associated with immunotherapy and a framework for evaluation. Neuro-oncology advances. Accessed September 10, 2023. https://pubmed.ncbi.nlm.nih.gov/34859238/.
17. Ruggiero R, Stelitano B, Fraenza F, et al. Neurological manifestations related to immune checkpoint inhibitors: Reverse translational research by using the European real-world safety data. Front Oncol. 2022;12. doi:10.3389/fonc.2022.824511
18. Stubblefield MD. The Underutilization of Rehabilitation to Treat Physical Impairments in Breast Cancer Survivors. PM R 2017;9:S317-S323.
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23. Sheena Derry, Andrew Sc Rice, Peter Cole, Toni Tan, R Andrew Moore. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017 Jan 13;1(1):CD007393
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25. Reyes-Long, S., Alfaro-Rodríguez, A., Cortes-Altamirano, J. L., Lara-Padilla, E., Herrera-Maria, E., Romero-Morelos, P., Salcedo, M., & Bandala, C. (2021). The mechanisms of action of botulinum toxin type A in nociceptive and neuropathic pathways in Cancer pain. Current Medicinal Chemistry, 28(15), 2996–3009.

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, Carl Alex Carrasquer, MD, Steven Papuchis, MD, David Haustein, MD, MBA. Neuromuscular Complications of Cancer. 12/29/2020

Author Disclosure

Megan Bale Nelson, MD
Nothing to Disclose

David Haustein, MD, MBA
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Carl Alexander Carrasquer, MD
Nothing to Disclose

Rebecca Lynn, DO
Nothing to Disclose

Andrew Goldblum, DO, ABIM
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Shelby Sweat, DO
Nothing to Disclose