Epidural cord compression from metastatic breast cancer.
Nodular meningeal (arrows) and nerve root enhancement due to leptomeningeal breast cancer.
Graber JJ, Nolan CP. Myelopathies in Patients With Cancer. Arch Neurol. 2010;67(3):298-304. doi:10.1001/archneurol.2010.20
DAVID E.PLEASUREMDAuthor Affiliations:Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Myelopathy is a devastating neurologic complication of cancer. The resulting pain, paralysis, and incontinence can turn a patient with cancer from a functioning individual to one who is confined to a chair or bed. Early diagnosis and appropriate therapy can prevent or ameliorate these symptoms and improve both duration of survival and quality of life. Accurate neurologic assessment of patients is crucial for early diagnosis and correct therapy. Myelopathy in patients with cancer is not rare. Epidural spinal cord compression (SCC) affects an estimated 5% of patients with cancer; other disorders such as intramedullary spinal cord metastases, adverse effects of therapy, and paraneoplastic spinal cord syndromes, although less common, are equally devastating. Because of space limitations, this review addresses the pathophysiology, clinical findings, diagnosis, and treatment of only some of the myelopathies that affect patients with cancer (Table 1). Because of new data, epidural SCC and paraneoplastic syndromes are emphasized.
Spinal cord compression occurs in approximately 5% of patients with cancer (approximately 80 000 patients per year), mostly prostate, breast, or lung cancer. In 20% of patients, SCC precedes the cancer diagnosis, especially in patients with lung cancer.1The tumor usually reaches the vertebral body via arterial embolization but may also spread by the Batson plexus. Extension of paravertebral tumor through the neural foramina may compress the cord without vertebral involvement. Rarely, tumor spreads directly to the epidural space itself.2In keeping with relative size and blood flow, metastases to the thoracic cord are most common, followed by the lumbar and cervical regions.2Symptom onset may be gradual in the case of a slowly expanding mass or rapid in the case of a vertebral fracture with herniation of bone or disc elements into the epidural space. The resulting SCC causes initially reversible edema followed by eventually irreversible vascular occlusion, lending urgency to the evaluation.3Back pain is the presenting symptom in more than 80% of patients.4,5Weakness is present in 35% to 75% of patients at diagnosis, with one-half unable to walk.4Functional status at diagnosis is the strongest prognostic factor, with inability to ambulate or sphincter dysfunction suggesting poor neurologic outcomes.3,4Urgent evaluation of new or worsening back pain or any other neurologic symptom is essential in any patient with cancer. Magnetic resonance imaging (MRI) of the entire spine is the initial study of choice with greater than 93% sensitivity and specificity (Figure 1).6One-third of patients have multiple sites of compression at initial diagnosis.1,5,6Treatment with high-dose corticosteroids should be initiated urgently in patients with neurologic dysfunction as they may reduce edema and preserve neurologic function until definitive therapy can be performed. One randomized trial7showed a benefit of dexamethasone, 96 mg, given intravenously prior to radiosurgery; however, the optimal dose, route, and schedule remain unclear.7- 9Most experts advocate higher doses of dexamethasone in patients with rapidly worsening weakness or autonomic dysfunction. Steroids should be followed by definitive treatment with radiotherapy or surgery as soon as possible.4,10A large randomized trial11showed the benefit of surgery prior to radiotherapy for ambulation, continence, and survival in patients with solitary compressive sites by radioresistant tumors. These results may not apply to all patients because those with recurrent SCC, symptoms lasting longer than 48 hours, multiple sites of compression, cauda equina lesions, radiosensitive tumors, symptomatic brain lesions, or high surgical risk were excluded.11Unfortunately, this means that a substantial proportion of patients with SCC would have been excluded from this trial. Therefore, the decision of whether to treat with radiation or surgery first remains a clinical one. Neurosurgical intervention prior to radiotherapy is indicated in patients with rapidly evolving neurologic deficits from vertebral bone compression, as opposed to soft-tissue tumor, and with mechanical instability (indicated by pain provoked by positional changes). Radiotherapy should be considered after surgical treatment or in patients who are not surgical candidates. While no randomized controlled trials have directly compared radiotherapy with placebo, radiotherapy clearly benefits most patients by resulting in improved pain and functional ability.4,10,11Newer techniques of image-guided intensity-modulated radiotherapy allow higher doses to be precisely delivered to tumor with less spinal cord exposure and have been shown to provide long-lasting local tumor control and symptom relief with minimal toxic effects.12,13Image-guided intensity-modulated radiotherapy also allows for re-treatment of recurrent lesions and may permit prevention or delay of surgery in both radiosensitive tumors as well as those thought traditionally to be radioresistant.12,13Chemotherapy also improves symptoms and survival for chemosensitive tumors such as lymphoma and breast cancer.14,15Given the consequences of SCC, prevention would be ideal. Bisphosphonates have been shown to decrease the incidence of vertebral metastases and fracture but not SCC, although a meta-analysis found a trend for decreased incidence of SCC.16- 18The effects of calcium and vitamin D remain unstudied, but they are commonly prescribed.
To decide on treatment, one might use the scheme proposed by Bilsky19that addresses 4 factors: (1) neurologic status, (2) nature of the tumor, (3) mechanical state of the spine, and (4) general condition of the patient (performance status, prognosis, and medical comorbidities). Neurologically, high-grade cord compression, particularly with radioresistant tumors, demands early consideration for surgery. With lesser compression, one should consider radiation therapy using image-guided intensity-modulated radiation. The nature of the tumor should also be considered. Radiosensitive lesions such as lymphomas can be successfully treated with radiation. Radioresistant tumor such as renal cell carcinoma can be treated either surgically or with radiosurgery, the higher doses of radiosurgery being more effective against radioresistant tumors. If the spine is mechanically unstable, surgical intervention is required. Burst or compression fractures can often be treated with kyphoplasty; gross instability requires surgery with instrumentation. Patients who are poor candidates for surgery or in whom widely metastatic disease is present should be considered for standard radiation therapy. In patients with good performance status and limited metastatic disease, surgery should be the first consideration.
Intramedullary spinal cord metastases are far less common, affecting fewer than 1% of patients with cancer.20Compared with their vertebral counterparts, intramedullary metastases preferentially affect the cervical cord and conus medullaris and are mostly reported in relation to small cell lung cancer.20Most patients are treated with corticosteroids and conventional radiation therapy. Although these techniques may produce temporary improvement, the median survival is 3 months. In selected patients, particularly those with good performance scores, limited metastatic disease, and radioresistant tumors, surgical removal may be efficacious.21In others, fractionated radiosurgery may be more effective than conventional radiation.22
Leptomeningeal metastases may also cause myelopathic symptoms.23Magnetic resonance imaging and cerebrospinal fluid (CSF) studies usually reveal the diagnosis.23The MRI typically shows enhancing nodular lesions on nerve roots or in the epidural space; in the appropriate clinical situation, this is sufficient for diagnosis (Figure 2). If imaging does not establish the diagnosis, a lumbar puncture with cytologic examination and measurement of tumor markers is required. The cytologic results may be initially negative, but cytologic examination should be repeated when there is a high clinical suspicion as sensitivity improves from 40% to 90% with repeated sampling.23,24Increased opening pressure, increased protein level, and reduced glucose level are suggestive but nonspecific findings. However, an increased CSF pressure suggests obstruction of spinal fluid pathways by the leptomeningeal tumor and obviates treatment with intrathecal agents. Additional testing for tumor markers may reveal strong evidence for leptomeningeal involvement when cytologic results are repeatedly negative (Table 2). Steroids, pain medication, focal radiation, surgery, and systemic or intrathecal chemotherapy may alleviate symptoms, although long-term remission of leptomeningeal metastases is unusual in cancers other than breast cancer or lymphoma that respond to chemotherapy.23,24
Ischemic cord lesions are rare. Ischemia may complicate surgical interventions such as aortic clamping or paravertebral surgery that includes radicular arteries. Thrombotic states, common in patients with cancer, may cause cord ischemia. Patients present with sudden onset of bilateral paraplegia, sometimes with divergent sensory symptoms of posterior column sparing due to the vascular supply of the spinal cord.25Infarcts are usually occult on routine MRI but appear on diffusion imaging or may be suggested by ischemic changes in adjacent vertebral body marrow.25Intravascular lymphomas can present with ischemic cord lesions and may mimic multiple sclerosis.26- 28Normal serum lactate dehydrogenase level, marrow, CSF, and MRI results do not exclude the diagnosis.26
Sudden onset of spinal cord deficits may also signify hemorrhage into a spinal cord tumor.29Spinal epidural and subdural hematomas can occur after lumbar puncture but are rare even in patients with thrombocytopenia (<50 × 103platelets/μL [to convert to ×109platelets/L, multiply by 1.0]).30- 32Hemorrhage may also be a consequence of delayed vascular damage after radiotherapy.33
Cancer treatment occasionally results in myelopathy (Table 3). Weeks to months after radiation to the spine, a dose-dependent transient myelopathy often with Lhermitte sign occurs in 3.6% to 15% of patients.34,35A progressive myelopathy can develop years after radiation, with risk increasing to 5% with higher doses, prior radiation, older age, and concomitant chemotherapy.35Results on MRI may be normal or show increased T2-weighted signal or enhancement.36Newer intensity-modulated radiotherapy techniques allow more precise targeting to tumor while minimizing exposure to adjacent susceptible spinal cord, although long-term follow-up has not yet been reported.12,13Steroids and hyperbaric oxygen have been reported to be beneficial in some cases.36,37
Intrathecal cytarabine or methotrexate sodium as high-dose monotherapy or in combination can rarely cause a progressive myelopathy, which may respond to steroids.38,39Higher doses and concomitant radiotherapy have been postulated as risk factors, but cases are rare, with one study finding only 1 case among 121 patients treated.40Results on MRI can sometimes show increased T2-weighted signal or enhancement or can be normal.38,39Cases of myelopathy in association with carmustine, cisplatin, and thiotepa treatment have also been reported.41,42
Patients with cancer are often immunocompromised as a result of either the tumor itself (lymphoma) or treatment with chemotherapy. As a result they are susceptible to infection, often with unusual agents. Infections can cause myelopathy (Table 4). Varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus 1 or 2 myelitis have all been reported.43- 45Varicella zoster virus myelitis may occur with or without shingles.46Magnetic resonance imaging usually shows increased T2-weighted signal with enhancement and CSF studies usually reveal lymphocytosis and increased protein level, although normal findings have been reported.43- 46Viral genomic elements can be specifically detected by polymerase chain reaction in CSF, but results may be negative early. Antibody testing may aid diagnosis, especially for varicella zoster virus.47Viral myelitis may respond to steroids, acyclovir sodium, ganciclovir sodium, or foscarnet sodium, the latter two having better CSF penetration.48,49JC virus and human herpesvirus 6 have also been reported to cause spinal lesions.44,50Epstein-Barr virus can cause myelopathy as a consequence of lymphoproliferative disease in patients who have received transplants.45,51A vacuolar myelopathy of unknown etiology similar to that seen in AIDS has been reported in patients with cancer, although whether this is the consequence of an occult infection or metabolic derangements is unknown.52Human T-cell leukemia virus usually causes myelopathy or leukemia separately, but simultaneous cases have occurred.53
Epidural abscess and osteomyelitis are rare causes of myelopathy in patients with cancer.54Such infections can complicate the placement of epidural catheters for pain control. Treatment with appropriate antibiotics is often sufficient, but neurosurgical drainage of an abscess may be required.54Intramedullary abscesses have also been reported with malignant neoplasms.55Cases of syphilis, tuberculosis, aspergillus, and toxoplasmosis causing myelitis have been reported in immunosuppressed patients with cancer.56- 59
Paraneoplastic syndromes can cause myelopathy (Table 5). The pathogenesis is believed to be an autoimmune reaction to antigen shared by the tumor in the nervous system. In some patients, onconeural antibodies are present to establish the diagnosis. The most common antibody in paraneoplastic myelopathy is anti-Hu. The myelopathy is usually part of the syndrome of encephalomyelitis, with the patient having encephalopathy and neuropathy as well. Lung and breast cancers are common causes.60One-quarter of patients with anti-Hu antibody will have symptoms of spinal cord dysfunction, although these symptoms may be overshadowed by symptoms of brain disease.60Antibody against collapsin response-mediator protein 5 is classically associated with retinitis and optic neuritis in patients with lung cancer but can also cause myelitis in 15% of patients.61,62Neuromyelitis optica should be considered a possible paraneoplastic syndrome as 5% of cases of neuromyelitis optica with antibody against aquaporin 4 were associated with cancer in one study.63The neuromyelitis optica antibody and other paraneoplastic antibodies are sometimes found in a small number of patients with cancer (mainly breast and lung cancers) without neurologic symptoms.63Amphiphysin and glutamic acid decarboxylase antibodies have also been reported in cases of myelitis associated with cancer.64,65One case of anti-Ri myelitis was described in a patient suspected of harboring breast cancer.66Findings on MRI are nonspecific or normal in most patients with paraneoplastic myelopathies.
Not all patients with paraneoplastic myelopathy harbor a paraneoplastic antibody, so negative results for described antibodies do not exclude the diagnosis. There are reports of autoimmune myelitis after stem cell transplant, often in association with autoimmune pancytopenia and positive Coomb antibody testing, suggesting a possible common antigen response.67- 69Necrotizing myelopathy occurring in hematologic and lung neoplasms has also been described without a known antibody, although some of these patients also had optic neuritis, suggesting the possibility that these may have been cases of neuromyelitis optica that can induce necrotic pathological changes in the spinal cord due to extensive inflammation.70,71Patients with unexplained myelopathy should be screened for described paraneoplastic antibodies as their presence may prompt thorough investigations and treatment for an occult malignant neoplasm. If the results are negative, these examinations should be repeated at a later interval as treatment of an initially occult tumor may help resolve the neurologic symptoms and prevent widespread neoplasia. Paraneoplastic syndromes respond best to treatment of the underlying tumor; immunosuppression with steroids, intravenous immunoglobulin, or rituximab may also be effective as can symptomatic treatments for pain, bladder and sexual dysfunction, and spasticity.
Stiff person syndrome is a rare but well-described syndrome of axial and proximal limb rigidity with lordosis, usually with antibodies to glutamic acid decarboxylase or amphiphysin.72- 75Cases with amphiphysin antibodies are more likely to harbor malignant neoplasms (usually breast cancer, lung cancer, or lymphoma) and sometimes can be clinically distinguished by a greater propensity to exhibit distal limb involvement.75Ri, gephyrin, and P/Q-type calcium channel antibodies have also been reported in patients with stiff person syndrome and malignant neoplasms.72- 74Results on MRI are usually normal other than straightening of the usual spinal curvature due to muscle stiffness.75Steroids and immunosuppression are beneficial, and benzodiazepines relieve symptoms of spasticity or myoclonus.
Motor neuron disease has been described in association with multiple cancers (lung cancer, breast cancer, lymphoma, ovarian cancer, testicular cancer, and melanoma), and a variety of paraneoplastic antibodies have been found (Hu, Yo, Ma2, myelin-associated glycoprotein, collapsin response-mediator protein 5, spectrin, and GM1).73- 79In association with lymphoma, serum paraprotein and CSF oligoclonal bands have also been described.73,80Some have noted recovery after cancer treatment.80,81
The physician confronted with a patient with cancer who has back pain or a patient with or without cancer who develops myelopathic symptoms must move quickly. After a careful history and examination, the physician should order an MRI of the entire spine with and without contrast. This test usually establishes the diagnosis and dictates treatment. If a mass lesion with cord compression is found, high-dose corticosteroids should be administered and the patient should be assessed for surgical intervention as surgical removal of the lesion, when feasible, usually yields the best palliation and prognosis.
If the MRI does not establish the diagnosis, further urgent testing is necessary (Table 6). A lumbar puncture should be performed with cytologic examination, measurement of cancer tumor markers, and polymerase chain reaction for infectious agents. The serum should be examined for paraneoplastic antibodies; in only rare instances is it necessary to look for antibodies in CSF if they are not present in serum. In patients with advanced cancer, consider vitamin B12deficiency. If the workup results continue to be negative, one should consider a trial of corticosteroids. If there is any evidence to suggest an autoimmune disorder, consider immunosuppression with intravenous immunoglobulin or even rituximab if steroids are ineffective.
Spinal cord complications in patients with cancer are not rare and drastically affect prognosis and quality of life when they occur. Many are amenable to therapy with steroids, radiation, surgery, chemotherapy, and symptomatic treatment. Early recognition and early diagnosis of symptoms are essential for potentially improved neurologic outcome. Astute clinical assessment can help guide appropriate therapy and maximize its benefit to improve patient survival and quality of life.
Correspondence:Craig P. Nolan, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (firstname.lastname@example.org).
Accepted for Publication:October 21, 2009.
Author Contributions:Study concept and design: Graber and Nolan. Acquisition of data: Graber. Analysis and interpretation of data: Graber. Drafting of the manuscript: Graber. Critical revision of the manuscript for important intellectual content: Graber and Nolan. Administrative, technical, and material support: Graber. Study supervision: Graber and Nolan.
Financial Disclosure:None reported.
Additional Contributions:Jerome Posner, MD, provided critical review of the manuscript and helpful advice and Judith Lampron provided editorial assistance.