Pathophysiology of spinal cord compression

Epidural tumor is found both anterior and posterior to the spinal cord in almost 50% of patients; in approximately 20%, the tumor is circumferential. Histologic studies show that the most common abnormalities are demyelination with infiltration by lipid laden macrophages, interstitial edema, and focal axonal swelling, but infarction is rare, even in patients who develop the sudden onset of paraplegia. Compression of the epidural venous plexus (possibly contributing to spinal cord edema) occurs early in SCC, whereas decreased spinal cord blood flow takes place much later; therefore, venous infarction may contribute to the acute paraplegia, which can happen unpredictably, making SCC a neurologic emergency. The release of potentially neurotoxic substances, including prostaglandins and serotonin, by compressed neural tissue may also play a role in neurologic disability.

Clinical findings and diagnosis

The symptoms and signs depend on the level of compression (e.g., cervical vs thoracic). Back pain is the first symptom of SCC in virtually all patients (Table 4).⁵ The pain may be local (at the involved area of the spine), radicular (radiating into arm, trunk, or leg), or both. Local pain is dull, aching, and progressive and usually localizes to the involved area of the spine. Local pain aggravated by movement implies spinal instability. In the cervical and lumbosacral regions, radicular pain is often unilateral, but in the trunk, it is usually bilateral (band-like), a finding highly suggestive of epidural disease. Pain from SCC is typically worse when the patient is supine, which helps to distinguish SCC from a herniated disc where the pain improves with recumbancy. The pain of SCC is exacerbated by coughing, straining, or valsalva. Pain may be absent in patients whose SCC is identified incidentally on chest or abdominal CT or MRI done to evaluate the patient’s primary cancer.

Weakness is the second most common feature of epidural SCC; it usually follows the onset of pain by weeks to months and is most obvious in proximal muscles of the legs. By the time weakness occurs, tone in the lower extremities is usually increased, reflexes are hyperactive, and the plantar responses are extensor. If the SCC occurs below the cord involving the cauda equina, hyporeflexia or areflexia is found. If pain limits strength testing, analgesics should be administered to permit adequate evaluation.

Bowel and bladder dysfunction usually occur late in SCC. However, when the conus medullaris is the site of compression (vertebral lesions from T-10 to L-1), bladder dysfunction may be the first and only sign. The patient may be unaware of urinary retention because bladder sensation is lost; examination reveals a distended bladder, and a postvoid ultrasound reveals urinary retention. The anal sphincter is usually flaccid. Sensory symptoms include numbness and paresthesias that begin in the toes and spread proximally. Except in conus compression, the sacral segments may be spared, even when a sensory level is found on the trunk. In a few patients, gait or truncal ataxia mimicking cerebellar disease may be the only neurologic finding although back pain usually precedes the ataxia. Varicella-zoster eruption may occur at the dermatomal level of epidural metastasis. If it precedes the diagnosis of the spinal metastasis, it can delay recognition of SCC.

None of the clinical symptoms or signs of epidural SCC are specific (Table 5). Some disorders that mimic SCC such as herniated disc or spinal stenosis are common and may confuse the initial evaluation of an individual cancer patient. Others, such as epidural hematomas and abscesses, may be directly related to the cancer or its treatment.

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging; RT, radiation therapy.

Source: Adapted from DeAngelis and Posner, 2008.1 Reproduced with permission from Oxford University Press.

Patients with cancer who develop back pain have SCC until proved otherwise. Evaluation should proceed urgently because high-grade compression may cause abrupt compromise of the spinal cord and severe neurologic dysfunction. The only necessary diagnostic test for spinal lesions caused by cancer is an MRI (Figure 2). The entire spine should be imaged, but contrast is not necessary to detect spine metastasis or epidural tumor. However, contrast is essential to identify intramedullary or leptomeningeal metastasis (LM). Patients unable to have an MRI (e.g., pacemaker) should be imaged by CT-myelography where full reconstructed images can provide excellent views of the spine in all dimensions.

Treatment

SCC requires urgent therapy directed at reduction of tumor mass and prevention of regrowth.^{1, 4} Radiation therapy (RT) is the primary treatment for most patients, but surgery and chemotherapy are important modalities in individual patients. The initial treatment for all patients is corticosteroids, which can have an oncolytic effect relieving SCC by shrinking tumors, especially lymphoma, but in most instances, their salutary effects result from the reduction of spinal cord edema. Other treatment is usually started concurrently so the effect of corticosteroids is difficult to evaluate, and the optimal dose has not been determined.

For patients with pain only, dexamethasone at 16 mg every 24 h can be started increasing the dose if pain persists or new symptoms develop. For patients with severe pain, or evidence of myelopathy, an intravenous bolus of 100 mg of dexamethasone should be administered, followed by 100 mg every 24 h in divided doses. The drug should be tapered as the patient is treated with more definitive modalities. Corticosteroids cause side effects, and some may be more prominent in patients with epidural SCC. Perforation of the gastrointestinal (GI) tract may occur in as many as 1% of patients; constipation, a frequent complication of SCC, appears to increase the risk of GI rupture. Thus, a rapid taper, particularly of high initial doses, is essential.

RT is the most common treatment for patients with SCC, many of whom are poor surgical candidates because of advanced cancer or multiple vertebral body metastases.^{1, 5} RT to a total dose of 3000 cGy (300 Gy × 10 fractions) is administered to the site of compression and one or two vertebral bodies above and below that level. Multiple courses of RT for patients who respond initially but then relapse may be helpful and carry only modest risk.⁷ Intensity-modulated stereotactic radiotherapy (IMRT) is effective and safe and can be administered with good results to a previously irradiated site or in place of standard external beam RT. ^8–10

Surgery plays an increasingly important role in SCC treatment. Traditionally, surgery was restricted (1) to patients who developed SCC at sites already irradiated, (2) to patients in whom a diagnosis of cancer had not been established, (3) when epidural defects result from displaced bone or disc fragments, (4) when spinal instability results from bone destruction, and (5) to patients with radio resistant tumors (e.g., renal cancer). However, a prospective phase III trial demonstrated the superiority of surgery plus RT compared to RT alone for SCC.^{11, 12} Tumor resection that usually required resection of the vertebral body had a superior outcome with significantly better neurologic function for longer, including a greater proportion of patients who regained ambulation and continence. Length of survival was not significantly different between the two groups, but there was a trend toward longer survival with surgery (129 days vs 100 days, p = 0.08). These data suggest that surgery should be a consideration in all patients with SCC. However, the patients enrolled in the study were highly selected and it is not clear that the excellent outcome reported can be expected for all patients with SCC. More recently, vertebroplasty and kyphoplasty have proven effective for selected patients with SCC, especially those with vertebral compression fractures and severe pain.¹³

Chemotherapy, with or without RT, is useful in some patients with tumors that are sensitive, especially lymphoma and occasionally other solid tumors.¹⁴ Excellent responses of SCC from chemosensitive tumors to appropriate chemotherapy are seen, but this approach is limited to those who have minimal to no neurologic compromise. If myelopathy is present, RT or surgery must be the primary therapy. Regardless of treatment type, the majority of patients who are ambulatory at the beginning of therapy remain ambulatory. Some paraparetic patients will recover sufficient function to walk again, but only a few who are paraplegic recover useful function.

Pathophysiology

Malignant cells may enter the subarachnoid space by several routes (Figure 3). Subarachnoid invasion can occur via infiltration of the wall of veins and of the marrow trabeculae; malignant cells can attach to leptomeningeal capillaries and move directly into the subarachnoid space. Brain parenchymal lesions can erode into the ventricle or subarachnoid space or be spilled at surgery, causing LM. LM develops in 40% of patients following resection of a cerebellar metastasis, but in only 2–3% of those who had resection of a supratentorial lesion. The choroid plexus is a rare route of entry. Malignant cells may invade the subarachnoid space by direct infiltration along nerve roots, and possibly via epineural lymphatics.

LM causes nervous system dysfunction by several mechanisms:¹ (1) direct infiltration of malignant cells into the brain, spinal cord, cranial nerves, or spinal roots that interferes with neural function, (2) interruption of CSF flow leading to increased intracranial pressure (ICP) with or without hydrocephalus, and (3) infiltration of tumor along the Virchow–Robin spaces may reduce blood supply to the brain causing cerebral infarction.

Symptoms and signs

LM is strongly suggested by the patient having symptoms or signs at multiple sites of the neuraxis.^{1, 2} These include (1) headache, particularly early in the morning or posturally induced headache in the absence of brain metastases; (2) cranial nerve palsies, particularly, diplopia or facial weakness; (3) neck pain in the absence of cervical spine metastases; (4) radicular pain in the arms or legs, particularly when accompanied by weakness but without local spine pain; (5) unexplained constipation, impotence, or urinary incontinence or retention; (6) asymmetric leg weakness and diminished reflexes in the absence of pain or sensory changes; and (7) confusion, memory loss, or other cognitive abnormalities.

Diagnosis

The diagnostic gold standard of LM is the demonstration of malignant cells in the CSF. However, imaging is a much more common means of diagnosis currently.¹⁵ A cranial MRI may reveal enhancing cranial nerves or enhancing tumor in cortical sulci; communicating hydrocephalus may suggest LM. A gadolinium-enhanced spine MRI may demonstrate tumor nodules on spinal roots, particularly in the cauda equina, even when symptoms of nerve root dysfunction are absent (Figure 4). The whole neuraxis should be imaged to identify sites of bulky disease. When characteristic findings are identified, this suffices to establish the diagnosis. MRI is 76% sensitive and 77% specific. Occasionally, FDG-PET imaging may identify LM.¹⁶ However, negative imaging does not exclude the diagnosis in a patient with typical features. A lumbar puncture should be performed and the opening pressure, cell count, protein, glucose, and bacterial and fungal studies should be obtained; the cytology specimen should contain at least 10 mL of CSF optimally and should be processed quickly according to the laboratory’s protocol.

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