Neurological Syndromes and Emergencies in the Cancer Patient: Differential Diagnosis, Assessment Protocols, and Targeted Clinical Interventions
Authors: Herbert B. Newton, MD, Associate Professor of Neurology and Director, Division of Neuro-Oncology, Department of Neurology, Ohio State University Hospitals and James Cancer Hospital, Columbus, OH.
Sid M. Shah, MD, Assistant Clinical Professor, Michigan State University College of Human Medicine; Department of Emergency Medicine, Michigan Capital Medical Center, Lansing, MI.
Peer Reviewers: David Kramer, MD,Associate Professor, Residency Program Director, Emory University School of Medicine, Atlanta, GA.
Jonathan A. Edlow, MD, Clinical Director, Beth Israel and Deaconess Medical Center, Boston, MA; Instructor in Medicine, Harvard Medical School, Cambridge, MA.
Although cancer-related complications produce life-threatening syndromes and consequences in any age group, adults and the elderly are most often affected. Due in part to the aging of our society, the incidence of cancer is on the rise, and these demographic changes are bringing more emergency encounters related to malignancy and its various complications, particularly those affecting the central nervous system (CNS). For example, it is estimated that nearly one out of three Americans will suffer from a tumor sometime during their life. Finally, EDs are also seeing an increase in malignancy-related visits because of current trends toward shorter hospitalizations in cancer patients and an emphasis on outpatient therapy.
Although any malignancy has the potential to involve the peripheral or central nervous system, some tumorsparticularly those affecting the lung and breast as well as lymphomasare more likely to produce life-threatening complications that require emergency intervention. In this regard, neuro-oncologic emergencies are most often seen in the setting of therapeutic failure for systemic cancers that recur after unsuccessful chemotherapy.
Among cancer-related neurological conditions that require a high index of suspicion on the part of the emergency practitioner are primary and metastatic tumors of the CNS, leptomeningeal metastases, infectious and metabolic complications of cancer and immunodeficiency states, and the toxic effects of cancer therapy.1 More often than not, prompt diagnosis and emergency intervention are required because neurological complications of malignancy are associated with significant morbidity and mortality.
With these clinical concerns in mind, the purpose of this review is to identify both common and challenging presentations of neurological emergencies that occur in patients with malignant disorders. Strategies for evaluation are outlined and complication-specific treatment protocols are highlighted.
The Editor
Introduction
Many patients with neurological complications related to cancer present to the ED de novo (i.e., before a specific cancer diagnosis is made.) Often, the presentation is part of a constellation of neurologic symptoms and signs that have developed acutely or subacutely, whereas, in other cases, signs and symptoms have progressed over several weeks to months.
Presentation Syndromes. n the case of primary and metastatic brain tumors, the most common presenting symptoms in the ED include headaches, seizures, mental status changes, and focal weakness.2,3 Typically, spinal cord tumors cause back pain, lower extremity weakness, loss of sensation, and urinary incontinence,4 a combination that should always alert the clinician to malignant invasion of the spinal cord. Focal neurologic signs and symptoms are especially common in patients with primary brain and spinal cord tumors but also occur as complications of metastatic disease associated with non-CNS tumors.
At the time of presentation, more than 50% of patients with primary brain tumors will have hemiparesis, cranial nerve palsies, and/or papilledema.2 Focal deficits occur not only as a result of tumor invasion, but as a result of cerebrovascular emergencies, leptomeningeal metastases, and treatment-related neurotoxicity.5-8 For patients with established neuro-oncologic disease, focal signs can worsen as a result of tumor progression, recurrence of the malignancy, and as a result of metabolic derangements.
In particular, the clinical presentation of leptomeningeal metastases can be quite variable.7 In the majority of patients, this complication presents in a subtle, subacute fashion and is characterized by multifocal symptoms and deficits. On occasion, the presentation can be more fulminant and acute and mimic infectious meningitis. Metabolic and toxic derangements, either from the primary malignant process or resulting from cancer therapy, can present as mental status changes, seizures, or a variety of other systemic complaints.1,2,5,8
This detailed review is based on a symptoms-oriented approach to neuro-oncologic emergencies. Accordingly, the five most common ED presentations associated with neurological complications of cancer will be reviewed. They include: alteration of mental status; seizures and status epilepticus; cerebrovascular emergencies; back pain and spinal cord compression; and acute treatment of cancer-related pain.
Alteration of Mental Status: Spectrum and Presentation
Mental status changes are the most common ED presentation of patients with neuro-oncologic emergencies.1 The spectrum of mental status changes can range from minimal lethargy or confusion to encephalopathy or coma. Mental status changes in these various neuro-oncologic conditions can be caused by structural abnormalities within the brain such as tumor, abscess, or hydrocephalus; de novo or treatment-related infections; seizure activity; metabolic encephalopathy; treatment-related encephalopathy; and toxic encephalopathy. (See Table 1.) any of these conditions can also elevate intracranial pressure, which may further contribute to the alteration of mental status.
Structural Abnormalities.The most common structural conditions causing mental status changes in cancer patients are the presence of a primary (less common) or metastatic (more common) brain tumor.1-3 Depending on the location of the tumor or tumors, the alteration can vary from subtle personality changes to lethargy, marked confusion, or frank coma. The changes in mental status are gradual when caused by tumor growth and associated edema formation but can be rapid in the presence of intra-tumoral hemorrhage or acute hydrocephalus.1
Intra-tumoral hemorrhage typically causes sudden headache, systemic hypertension, and mental status changes, a syndrome that mimics the presentation of hypertensive intracerebral hemorrhage. In fact, 3% of patients with intracranial hemorrhage are subsequently found to have an underlying brain tumor.2,3 In the ED setting, the presentation of a brain tumor is linked to its anatomic location and rate of growth. Many metastatic brain tumors produce the classic triad of headache, seizures, and hemiparesis, similar to primary brain tumors. However, metastatic tumors are less likely to develop hydrocephalus and more often present with hemorrhage.3
Symptoms such as headache, nausea, and vomiting suggest elevated intracranial pressure (ICP), which is frequently present in patients with hydrocephalus prior to the onset of mental status changes.1 Hydrocephalus is most often produced by tumors blocking the CSF outflow tracts, as well as by other cancer-related neurological conditions, such as leptomeningeal tumor, meningitis, and subarachnoid hemorrhage. In addition to hemorrhage, other cerebrovascular disorders may also cause alterations of mental status through structural damage unrelated to hydrocephalus.5,6 Leptomeningeal metastases often cause mild mental status changes such as lethargy and confusion in addition to symptoms such as headache, weakness, and gait disturbance.7
Central Nervous System Infections. NS infections, including abscess formation, can cause alterations of mental status in cancer patients. Meningitis associated with opportunistic organisms (e.g., fungus, mycobacteria, listeria) are common in the immunocompromised cancer patient. These infections may present with lethargy, confusion, seizures, meningismus, and cranial neuropathies.1,9 Viral encephalitis, possibly the result of herpes zoster or cytomegalovirus infection, usually presents with seizures, confusion, encephalopathy, fever, and headache.1-9 In addition, sepsis resulting from treatment-related neutropenia can also be associated with mental status changes that, in some cases, may precede the fever spike by 12-24 hours.1 Aspiration pneumonia from clinically silent dysphagia is reported in patients with primary malignancies of the brain as well as in patients with leptomeningeal tumor and cancers of the head and neck.10
Metabolic Encephalopathy. etabolic encephalopathy most often results from electrolyte imbalances such as hyponatremia. When kidney or liver failure accompanies malignant disease, uremia, hyperammonemia and hypercalcemia should also be considered.1 Wernicke’s encephalopathy, seen in nutritionally-compromised cancer patients (i.e., those with low thiamine intake), presents with confusion, nystagmus, ophthalmoplegia, and ataxia. In many cases, only one aspect of the syndrome (e.g., mental status changes) is clinically apparent at the time of presentation.
Toxic Encephalopathy. ot infrequently, mental status alterations in cancer patients are the result of side effects caused by normal, elevated, or unambiguously toxic levels of commonly prescribed medications, notably anticonvulsants, antidepressants, analgesics, and steroids.1 Overuse of narcotics can lead to sedation, pulmonary edema, and encephalopathy. Other medications that are frequently responsible for toxic encephalopathy in cancer patients include neuroleptics, antiemetics, and sedative hypnotics. Toxic medication levels occur more frequently in patients with extensive liver metastases and abnormal hepatic metabolism.
Treatment-Related Encephalopathy.Chemotherapeutic agents such as 5-fluorouracil and methotrexate are well-documented causes of encephalopathy.1,8 Radiation encephalopathy is most frequently seen as a complication of treatment for primary brain tumors. In these cases, radiation causes encephalopathy by exacerbating peri-tumoral edema, which produces a mass effect that leads to further elevation of ICP.
Seizures. n the ED, patients with seizures secondary to cancer present in a post-ictal state or have subclinicalnonconvulsivestatus epilepticus. Seizures commonly result from both primary and metastatic brain tumors.2,3 Cancer patients with metabolic disturbances and infection can also present with seizure activity.1,9
Alteration of Mental Status: Evaluation and Management
Initial Evaluation and Intervention. nitial evaluation of these patients should focus on answering the key question of whether the alteration of mental status is secondary to a toxic/metabolic disorder or a structural abnormality of the CNS. Assessment, diagnostic investigation, and protocol-driven treatments that address coma should be implemented simultaneously. Airway, breathing, and circulation (i.e., the ABCs) should be assessed and attended to immediately in order to stabilize the patient for a more in-depth examination. Cervical spine precautions should be taken not only when there is a history of a fall, but also when no reliable history is available and trauma is suspected. Prehospital care providers can describe critical findings from the "scene survey."
Immediate assessment and intervention should include administration of dextrose (after bedside Dextrostix glucose determination), naloxone if opiate overdose is suspected, supplemental oxygen, and thiamine. The life-threatening causes of altered mental status can be remembered by the mnemonic WHHHIMP and should be carefully considered in the differential diagnosis. (See Table 2.)
Detailed Assessment. n the next step, a more detailed history should be elicited from the patient, accompanying family members, and prehospital personnel. Table 3 ists the most important aspects of the history that should be characterized in any cancer patient with mental status changes. In this regard, characterization of the mental status changes, as well as their rate of onset, may provide clues to the etiology. Subtle personality changes and alterations of mental status can precede the diagnosis of a brain tumor by several months to years.2
The more malignant tumors generally have a more rapid onset and progression of symptoms than benign tumors. Associated symptoms such as headache, nausea, emesis, pain, fever, and focal weakness may direct attention to the underlying condition. Nonspecific complaints, such as nausea and headache, may be due to increased ICP. The patient’s medications should be listed in detail since many drugs can lead to confusion or encephalopathy if taken incorrectly (e.g., narcotic analgesics, antiemetics, sleepers, antidepressants, etc.).1 A brief psychiatric history should be taken as well, to see if the patient has been depressed, a condition that might predispose to intentional overdose with prescribed medications.
Physical Examination. he general physical examination should include inspection for evidence of systemic disease that might be contributing to alterations in the mental status. For example, is there fever, evidence of infection or sepsis, meningismus, or bilateral asterixis or myoclonus? A detailed neurological examination is necessary to evaluate specific alterations in mental status, to document any associated focal findings, and to differentiate structural from metabolic alterations of mental status.1
Patients with mildly abnormal mental status changes should undergo a detailed mental status examination. Obviously, a detailed examination may not be possible in patients with more severe disease. Patients with focal, structural brain disease (e.g., tumor, hemorrhage, stroke) often have localizing signs, such as hemiparesis, facial weakness, sensory loss, and visual field cut. It is important to test the visual fields, since some structural lesions may not demonstrate other focal abnormalities on neurological examination.
Neuro-ophthalmological findings are often critical when examining more severely affected patients.1 Early in the course of mental status changes in patients with structural disease and elevated ICP, the pupils will become sluggish, but remain reactive and symmetric. As the structural disease evolves, mental changes become worse, the patient becomes more obtunded or comatose, the pupils become more sluggish and may develop asymmetric responsiveness in cases of impending herniation. As herniation progresses, the ipsilateral pupil will dilate and become unresponsive. Typically, pupillary responses are quite resistant to metabolic disturbances and, therefore, they do not become asymmetric or unreactive in cases of non-structural disease.
Extraocular movements should also be tested carefully. Once the cervical spine has been cleared, obtunded or comatose patients need oculocephalic (i.e., Doll’s eyes) or caloric testing to assess the integrity of the brainstem connections that mediate extraocular movements. Asymmetric or dysconjugate results indicate structural disease within the brainstem, since these pathways are also quite resistant to metabolic disturbances. The presence of decorticate (arm flexion with leg extension) or decerebrate (arm and leg extension) posturing is a prognostically poor sign that suggests structural damage to the diencephalon or midbrain.
Laboratory and Radiographic Examination. aboratory screening tests include complete blood counts, electrolytes, renal and liver panels (including ammonia), blood cultures, blood gases, glucose, thyroid screen, lactate, coagulation profile, vitamin B12, folate, thiamine, and appropriate medication levels (e.g. anticonvulsants, digoxin). An enhanced CT scan of the brain screens for the presence of (or progression of) primary or metastatic brain tumors and other structural abnormalities.
Lumbar puncture is necessary for cerebrospinal fluid analysis in suspected cases of leptomeningeal metastases (cytology, tumor markers) and CNS infection (gram stain cultures, immunological tests). Metabolic causes of mental status changes should be corrected. (See Table 1.)Seizure activity should be controlled as outlined in the following section. Patients in whom infection is suspected should receive antibiotic coverage immediately after appropriate cultures have been drawn and prior to CT scanning. Patients with toxic encephalopathy will need reduction in dosage or discontinuation of the causative medication. (See Table 1.) n general, medication changes should be made in conjunction with the patient’s primary physician
Stabilization.Patients with elevated ICP due to a space-occupying lesion, as demonstrated by clinical examination and neuro-imaging, require stabilization to prevent further neurological deterioration and brain herniation. The pace of stabilization depends on the clinical status. Immediate measures for impending herniation include intubation, proper oxygenation (100-150 mmHg), and hyperventilation (PCO2 of 25-30 mmHg).1 Further control of raised ICP can be achieved with intravenous dexamethasone (10-20 mg bolus followed by 6 mg q 4-6 h) or mannitol (20-25% solution; 0.75-1.0 g/kg bolus followed by 0.25-0.50 g/kg q 3-5 h). These stabilization measures are most important in cases of large focal lesions (e.g., tumor, abscess) causing severe mass effect and impending herniation. They should be implemented immediately in neurologically unstable patients. In more stable patients, consultation may be obtained before the initiation of these measures.
Seizures and Status Epilepticus: Spectrum and Presentation
Seizures are a relatively common cause of presentation to the ED. In fact, epilepsy can occur in a diverse group of cancer-related disease states.1 (See Table 4.)Fifty-four percent of patients with primary brain tumors and 15-20% of those with metastatic brain tumors present with seizures.2,3 Following headaches, seizures are the second most common complaint of brain tumor patients. Although presentation to the ED with seizures can be the first sign of a brain tumor, they occur more often in patients with an established diagnosis of CNS malignancy.
A first seizure in an adult older than 40 must be presumed to be caused by a brain tumor until proven otherwise. The frequency of seizure activity often increases with tumor growth. In certain slow-growing tumors (e.g., meningioma, low-grade astrocytoma) the seizures may occur months or even years before the onset of other symptoms. For metastatic tumors, multiple lesions and certain histologic types of cancer (e.g., melanoma, colon) increase the likelihood of seizures. More than 80% of patients who present with brain tumors have focal rather than generalized seizures. This often has localizing value.11 Although rare, status epilepticus does occur in patients with CNS malignancy.
Similar to cerebrovascular events in nononcology patients, hemorrhage and infarction can cause seizure activity via ischemia and irritation of surrounding neural tissues.5,6 Leptomeningeal metastases and CNS infections can induce ictal activity by causing ischemia, acidosis, and other localized metabolic derangements in the underlying cerebral cortex.7,9 Many common metabolic derangements and cancer treatments can also cause seizures; they are listed in Table 4.
Seizures and Status Epilepticus: Evaluation and Treatment
Initial Evaluation. n patients diagnosed with a brain tumor, the most common cause of seizure activity is nontherapeutic or inadequate anticonvulsant levels.2 A thorough history should include past and recent medical illnesses, medications, and compliance issues. A description of the seizure should include the following: duration, aura, focal or generalized, typical or atypical, incontinence, and tongue biting. Pre-ictal symptoms such as fever, headache, nuchal rigidity, somnolence, or confusion should be explored.
Laboratory and Radiographic Evaluation. omplete blood counts, platelets, BUN, creatinine, electrolytes (including magnesium and calcium), glucose, and anticonvulsant drug levels should be assessed. Arterial blood gases and cultures of blood, urine, and sputum should be obtained in appropriate cases. Lumbar puncture is necessary for CSF evaluation if CNS infection (i.e., CSF profile, cultures, gram stain, India ink prep) or leptomeningeal metastases (i.e., CSF profile, cytology, tumor markers) are suspected.
Most of the emergent brain CT image studies ordered through the ED are performed without intravenous contrast. However, in the case of an adult with new onset of seizures (particularly if they are focal), or in patients with a history of cancer, it is important to obtain the scan with intravenous contrast. Enhancement will increase the possibility of finding a focal mass lesion that is the underlying cause of the seizure. A cancer patient with a normal contrast-enhanced brain CT or MRI and a noncontributory metabolic screen should undergo a lumbar puncture to screen for leptomeningeal metastases or CNS infection.2
Treatment. n the ED, continued seizure activity must be controlled as soon as possible with benzodiazepines such as diazepam (3-5 mg/min; total load 0.15-0.25 mg/kg) or lorazepam (1-2 mg/min; total load 0.1 mg/kg).12 Lorazepam is preferred. Aggressive measures such as endotracheal intubation may be necessary to maintain patency of the airway in patients with prolonged seizure activity.
For patients with status epilepticus, intravenous phenytoin (< 50 mg/min; total load 15-20 mg/kg) or phenobarbital (50-100 mg/min; total load 15-20 mg/kg) should be administered simultaneously with the short-acting agents to achieve long-term control.12 If available, fosphenytoin can be substituted for phenytoin (15-20 phenytoin equivalents (PE)/kg infused at 100-150 PE/min). This approach approximates using phenytoin at 50 mg/min; however, fosphenytoin can be administered more rapidly and with less localized toxicity. Versed, a short-acting benzodiazepine, can be used as a continuous intravenous drip to control intractable status epilepticus. Seizures resulting from metabolic derangements are usually brought under control with treatment of the underlying metabolic process; anticonvulsants are unnecessary in most cases. Patients with subtherapeutic anticonvulsant levels need reloading of the medication, either intravenously or orally. The daily dosage of the anticonvulsant may need to be adjusted.
Patients with status epilepticus, a prolonged post-ictal state, or severe neurological deterioration after a seizure need admission to the hospital.
Cerebrovascular Emergencies: Spectrum and Evaluation
Cerebrovascular disorders in cancer patients present with conventional syndromes such as transient ischemic attack (TIA) and stroke but also with atypical presentations characterized by a confusional state or encephalopathy.1,5,6 Cerebrovascular complications of systemic malignant disease are quite common and can also occur in patients with brain tumors.1-3,5-7 In fact, approximately 15% of all cancer patients have evidence of cerebrovascular lesions at autopsy, and 50% of this group have antemortem vascular symptoms.5,6 Risk factors for cerebrovascular disease in the general population (e.g., age, hypertension, coronary artery disease, and diabetes mellitus) are not as significant in cancer patients. Large-vessel atherosclerotic thromboembolic disease represents only a small percentage of symptomatic infarction in cancer patients.6
Predisposing Factors.The most important predisposing factors for cerebrovascular emergencies in cancer patients are related to the direct effects of tumors on blood vessels, tumor-induced coagulation disorders, and treatment-related vascular injury.5,6 (See Table 5.) irect effects include mechanisms such as brain tumor encroachment of nearby blood vessels, leptomeningeal tumor invasion of vessels, and hemorrhage. The precise pathophysiology of ischemic cerebrovascular events in patients with brain tumors remains unclear, but is probably due to encasement and stenosis of vessels by neoplasm, arterial "steal" effects associated with the distribution of vessels feeding the tumor, or a combination of these mechanisms.
Hemorrhagic Complications. ntra-tumoral hemorrhage generally occurs in regions of necrosis or arises from structurally damaged blood vessels within the tumor. Leptomeningeal tumor can invade blood vessels within the subarachnoid or Virchow-Robin spaces, causing stenosis and thrombosis.7 Subdural hemorrhage usually follows the rupture of vessels within dural metastases or dural capillaries that are dilated from tumor blockage, or results from coagulopathy. (See following section.) inus occlusion occurs as a direct effect of tumor encroachment on the cerebral sinuses with subsequent venous infarction.
Tumor-induced coagulation disorders generally occur as a consequence of intravascular fibrinolysis and particularly in the presence of diffuse fibrin-platelet clots.1,5,6 This can lead to the production of hemorrhage, emboli, or thrombosis of vessels, depending on the type of disease. (See Table 5.) ntracranial hemorrhages can be subdural, intra-parenchymal, or subarachnoid. Nonbacterial thrombotic endocarditis (NBTE), a distinct coagulation disorder in cancer patients, is characterized by sterile fibrin vegetations on one or more cardiac valves.5,6 An estimated 25% of strokes in cancer patients are caused by NBTE. Approximately 50-60% of patients with NBTE present with focal symptoms suggestive of a classic TIA or stroke. In 20-30% of patients, the presentation is more consistent with an encephalopathy or confusional state, which is common in cases associated with multifocal involvement.
Treatment-related injury to blood vessels is relatively uncommon but can develop during radiation therapy or chemotherapy.5,6 Radiation-induced carotid artery occlusion or rupture is caused by accelerated atherosclerosis within the vessel wall. The antineoplastic agent L-asparaginase appears to cause hemorrhage or thrombosis by inducing a state of fibrinolysis and depleting levels of antithrombin III.6
Cerebrovascular Complications: Evaluation and Management
Initial Evaluation.A concise history obtained from the patient, family members, and pre-hospital care providers should include details of the current neurological problem (i.e., onset, severity, rapidity of evolution), past medical history, and current medications including any chemotherapy agents. A history of fever, rash, bruising, and any areas of pain and swelling should be noted.
A thorough physical examination should attempt to elicit clues that would suggest an etiology for the cerebrovascular event, including new petechiae, heart murmurs, nail-bed splinter hemorrhages, or swelling in the neck. In a patient with confusion or encephalopathy, with or without associated focal findings, cranial intravascular coagulation, NBTE, sinus thrombosis, or subarachnoid hemorrhage should be considered in the differential diagnosis.
Laboratory and Radiographic Evaluation.Laboratory evaluation of a cancer patient suspected of having a cerebrovascular event should include a CBC, chemistry profile, platelet count, coagulation studies, and a diffuse intravascular coagulation (DIC) panel.1,5,6 The latter includes a quantitative fibrinogen level, thrombin time, fibrin degradation products, protamine sulfate gelation, and mixing studies.
Cultures of blood, urine, and sputum are necessary in cases of suspected infection. Transesophageal echocardiography may be necessary to screen for NBTE. CT imaging can reliably detect the majority of intracranial hemorrhage but may not disclose regions of ischemia or infarction early after the event. A follow-up CT scan (e.g., 2-3 days) is more likely to demonstrate the abnormality, although MRI is more sensitive than CT for both hemorrhage and ischemia.5
Management. argeted management of a patient with a cerebrovascular event begins with ensuring patency of the airway and hemodynamic stability and providing supportive care. Delivery of supplemental oxygen and correction of hypoglycemia should proceed as soon as possible. If coagulopathy is present, initial treatment consists of administration of vitamin K, fresh frozen plasma, and platelets.1,5,6 Heparinization may help stabilize neurological progression in patients with DIC and NBTE. Intravenous dexamethasone (4-6 mg q 6 h) is recommended for patients with intra-parenchymal hemorrhage when significant edema and mass effect are noted on CT or MRI imaging of the brain.
Back and Spinal Cord Compression: Spectrum and Clinical Syndromes
Back pain is the second most common complaint for which oncology patients seek medical attention. Overall, 60-90% of the general population will experience back pain at some time in their lives.13,14 Because of its high prevalence, back pain is also a very common presentation in the ED. The majority of non-cancer patients who present to the ED with back pain have a benign and self limited condition (See Table 6.) owever, in patients with systemic or CNS cancer, it is often the first sign of a morbid underlying neurological process.1,15
Compression Syndromes. he structural components of the spinal column are the most common sites for bony metastases, which are more commonly seen in cancer patients with prostate, breast, renal, and lung cancer, as well as melanoma and multiple myeloma.15-17 Epidural spinal cord compression (ESCC) refers to impingement of the spinal cord or cauda equina (i.e., lumbar and sacral spinal nerves traveling within the thecal sac caudal to the level of the spinal cord) from a lesion outside the spinal dura. These metastatic deposits usually occur as a result of hematogenous spread of tumor cells to the vertebral column, with subsequent expansion of the mass into the spinal canal.
Less often, the compressive mass develops by direct spread from paravertebral tumors via the intervertebral foramina or from direct extension from nearby lymph nodes. The tumor is usually confined to the extradural space and demonstrates intradural involvement in only 2-4% of cases. Although ESCC usually develops in patients with an existing diagnosis of cancer and widespread disease, it can be the first manifestation of cancer in up to 25% of patients.15 Approximately 20,000 cancer patients are considered to be at risk each year for developing ESCC because of metastatic deposits in and around the spinal column.15-17
ESCC can affect any level of the spine, although thoracic involvement accounts for 50-60% of all cases. Enlargement of vertebral metastases eventually causes stretching of the periosteum, inducing local or referred pain.15,16 Further growth compresses adjacent neural and vascular structures, evoking neurologic signs and central pain.
Progression of neurologic symptoms can be quite rapid after the development of back pain in patients with ESCC.1,15-17 Consequently, the onset of myelopathy secondary to ESCC is a true neurological emergency. Rapid diagnosis is of paramount importance in these patients because, without treatment, the process will inevitably result in paraplegia, loss of lower extremity sensation, and incontinence. Once paraplegia and incontinence have developed, restoration of neurologic function is uncommon, even with therapeutic intervention.
Assessment.A comprehensive history and physical examination will help the clinician distinguish among the myriad conditions included in the differential diagnoses of back pain. (See Table 6.) t should be stressed that there are many overlapping features among the different categories of back pain and that the distinction between benign causes of back pain and ESCC can be difficult.
Although symptoms of ESCC generally evolve over a period of time, they sometimes progress rapidly. A thorough history, including associated systemic and neurological signs, and a history of a remote or current cancer diagnosis is particularly helpful in distinguishing back pain due to ESCC from other conditions. (See Table 7.) n this regard, special attention should be paid to the quality, location, intensity, and evolution of the back pain. For example, back pain due to ESCC is almost always progressive, although it can begin with mild discomfort, particularly in the thoracic region. Often, the pain is described as a steady, deep ache that can either be axial (mostly in the center of the spine) or radicular (radiating down a limb or around the rib cage anteriorly).
Signs and Symptoms.Manifesting similarities to degenerative disease of the spine, the pain is often exacerbated by movement, Valsalva maneuver, straight leg raising, and neck flexion. In contrast to the back pain caused by degenerative joint disease and other benign causes, which usually improve with recumbency, the back pain of ESCC is frequently aggravated in the supine position.15,16 Patients frequently report sleeping in a "sitting up" position to alleviate the pain. Extremity weakness and autonomic dysfunction are other common symptoms and occur in 75% and 55% of patients with ESCC, respectively.
Weakness is usually symmetric and involves the legs but can also affect the arms. Painless urinary retention is the most frequent type of autonomic complaint. Urinary and bowel incontinence are noted less often. Sensory symptoms include numbness and extremity paresthesias that start in the feet and gradually extend proximally.
Physical Examination. he physical examination often demonstrates localized pain to percussion over the involved vertebral bodies, which are usually thoracic.15,16 This is in contrast to the vertebral tenderness associated with degenerative processes, which typically affects the lumbosacral and cervical regions. The pain is often exacerbated by neck flexion, especially with cervical epidural disease. The straight leg raising maneuver is frequently positive for lower thoracic and lumbar lesions.
A rectal examination is mandatory to assess sphincter tone, anal wink, and the ability to perform voluntary contractions, since these functions can be compromised in ESCC by involvement of the conus medullaris or cauda equina. During the early stage of ESCC, mild weakness of the lower extremities may be detected (e.g., iliopsoas, hamstrings, ankle dorsi-flexors). With progression of ESCC, a myelopathy will develop that manifests upper motor neuron (UMN) signs in the lower extremities, which consist of severe limb weakness, spasticity, hyperactive reflexes, Babinski signs, and sensory loss below a distinct sensory level.15,16
In typical cases, muscular atrophy is absent or, if present, it is due to disuse. When ESCC involves the lumbar vertebral processes, a cauda equina syndrome (CES) develops instead of a myelopathy, with compression of lumbar and sacral spinal nerves as they travel caudal to the spinal cord. CES is characterized by the early occurrence of radicular pain in the distribution of lumbar and sacral nerves, areflexia or hyporeflexia, lower extremity weakness and hypotonia, muscle atrophy, and fasciculations. Plantar reflexes will remain normal (i.e., flexor). Depending on the site of the lesion, other diseases in the differential diagnosis of ESCC (e.g., epidural abscesses, spinal cord tumor, epidural hemorrhage) may also present with a similar picture of myelopathy.
Back Pain: Evaluation and Management
Initial management of a patient suspected of having ESCC consists of controlling pain and initiating a targeted diagnostic evaluation using one or more radiographic modalities.1,15,-17 The pain of ESCC is often severe and requires the use of parenteral narcotic medications.
Laboratory and Radiographic Examination. n cases with a history of recent infection or fever, blood tests should include CBC, ESR, and blood cultures. Other laboratory tests should be obtained as indicated by history and physical examination. Plain radiographs of the spine can identify an abnormality in 85-90% of patients with ESCC that is caused by solid tumors.15,16 The most common lesions are vertebral body erosion and collapse, subluxation, and pedicle erosion.
Plain films may also help distinguish other causes of back pain, such as degenerative joint disease and spondylolisthesis. MRI has now mostly replaced myelography as the most sensitive and specific imaging technique for demonstrating the anatomic site of ESCC.15 An MRI imaging study of the complete spine, including both T2 and T1 weighted images (with and without gadolinium contrast enhancement), demonstrates epidural or paravertebral masses, ESCC, primary spinal cord tumors, and most cases of leptomeningeal tumor.
Myelography may be considered in patients who are unable to undergo MRI imaging (e.g., those with a pacemaker or intractable claustrophobia) or when MRI findings are equivocal. Computed tomography of the spine is more sensitive than plain radiographs for epidural tumor or paravertebral masses and can more accurately demonstrate benign causes of back pain. However, it remains inferior to MRI and myelography.
Management. apid evaluation and the institution of definitive treatment measures withing 6-8 hours of onset of neurological deficit are probably the most important aspects of management in the ED for patients suspected of having ESCC. The level of function at the initiation of therapy is the most important prognostic factor for post-treatment neurologic function.15,17
Definitive initial management of ESCC consists of parenteral dexamethasone followed by radiation therapy and/or surgical decompression within 24 hours.1,15,18 The dose of dexamethasone remains controversial. However, most experts agree on a loading dose of 20-100 mg followed by 4-24 mg qid.15,17
Radiation therapy, the most widely used and effective form of treatment for most cases of ESCC, is necessary, even after surgical decompression.15,18 The most common schedule is to administer a total of 3000 cGy in 10 daily 300 cGy fractions. The role of surgical decompression in the management of ESCC remains unclear.15 To date, better outcome has not been proved in controlled trials for patients who receive decompressive surgery plus radiation therapy vs. radiation therapy alone, although several retrospective and prospective trials support an improved outcome using a combined approach in carefully selected patients.1,15,19,20 Radiation therapy and, in carefully selected cases, surgical decompression should be pursued even in patients with severe deficits that have been present for several days or more.
Cancer-Related Pain Management
Pain is one of the most common complications of cancer and can be severe enough to precipitate evaluation and treatment in the ED.21-23 It is estimated that 20-50% of cancer patients have significant pain at presentation or will develop it during active therapy.22 During more advanced stages of the disease, moderate to severe pain will occur in 75-90% of patients. Pain usually is caused by direct involvement of tumor with pain-sensitive structures (e.g., bone, nerves, meninges, blood vessels, visceral organs, mucous membranes, etc.) in more than two-thirds of patients.22,24 In another 20%, the pain is secondary to diagnostic or therapeutic procedures such as bone marrow aspiration, lumbar puncture, irradiation, surgery, and chemotherapy.22 In less than 10-15% of patients, the pain is from cancer-induced syndromes (e.g., decubitus ulcers, constipation, postherpetic neuralgia) or unrelated, benign diagnoses (e.g., migraine).
Evaluation and Management.It is important to assess cancer-related pain; this always includes a detailed history. The pain should be characterized in terms of intensity, location, areas of radiation, and mitigating factors. The quality (i.e., burning, stabbing, throbbing, etc.) and temporal pattern (i.e., constant, intermittent, etc.) should be elicited. Laboratory data and imaging studies may also be helpful. Implementation of analgesic therapy should proceed simultaneously with the work-up of the pain problem.
Analgesia. ancer-related pain can be effectively ameliorated in more than 80% of patients using conventional analgesics.21-23 In some cases, the medication is used to augment pain relief provided by primary therapy (i.e., surgery, RT, chemotherapy). In others, analgesics form the mainstay of therapy. The three-step "analgesic ladder" provides a systemic approach to alleviating the patient’s pain.22 In step 1, non-opioid analgesics (e.g., aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs) are used, possibly in combination with an adjuvant analgesic (e.g., antidepressants, anticonvulsants, local anesthetics) to treat mild pain.
If this level of analgesia proves ineffective, step 2 proceeds with the use of opioids designed for mild to moderate pain (e.g., codeine, oxycodone, propoxyphene) in combination with non-opioid and adjuvant analgesics. In patients with moderate to severe pain, more potent opioid analgesics are selected (e.g., morphine, fentanyl patch, oxycodone, hydromorphone, meperidine), often in conjunction with non-opioid and adjuvant analgesics. It is uncommon for neuro-oncology patients to have pain that is refractory to the stepwise application of oral agents (in addition to primary treatment and dexamethasone).
Occasionally, patients require more aggressive pharmacological approaches for chronic pain relief, such as continuous infusion intravenous narcotics.25 Invasive analgesic techniques, such as regional anesthesia, sympathetic blockade, somatic neurolysis, or cordotomy are rarely necessary.21,22
Summary
Various neurological syndromes and neuro-oncologic emergencies in patients with malignancy are reviewed in this article. Altered mental status (from minimal lethargy or confusion to encephalopathy or coma) is the most common ED presentation in patients with neuro-oncologic emergencies. The clinical presentation of intra-tumoral hemorrhage mimics the presentation of hypertensive intracerebral hemorrhage. Leptomeningeal metastases can mimic CNS infection, which can be a diagnostic dilemma for the emergency physician. Other presentations include seizures and status epilepticus, cerebrovascular events, back pain and spinal cord compression and cancer-related pain. Rapid evaluation and timely institution of definitive treatment measures such as dexamethasone therapy and radiation therapy are the most important aspects of management for patients suspected of having spinal cord compression.
References
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Physician CME Questions
9. Estimated lifetime incidence of tumor development for an
American is:
A. one in two.
B. one in three.
C. one in four.
10. Common ED presentations of neuro-oncologic emergencies include all of the following except:
A. alteration of mental status.
B. seizure activity.
C. weight loss.
D. cerebrovascular accident.
. With regards to epidural spinal cord compression (ESCC), which of the following is true?
A. Metastatic deposits resulting in ESCC usually occur as a result of hematogenous spread of tumor cells.
B. Back pain due to ESCC is frequently aggravated in recumbency and improves with "sitting up."
C. The thoracic spine is more frequently involved than the lumbar or cervical spine.
D. Extremity weakness and autonomic dysfunction are common symptoms of ESCC.
12. With regard to seizure activity in cancer patients, which of the following is true?
A. More patients with metastatic, rather than primary, brain tumors present with seizures.
B. Seizures occur more often in patients with an established diagnosis of a brain tumor, rather than as the first sign of a brain tumor.
C. Next to seizures, headache is the most common complaint of brain tumor patients.
D. Leptomeningeal metastases cannot induce seizures.
13. Mental status changes resulting form neuro-oncologic emergencies can be caused by all of the following except:
A. intracranial space occupying lesions.
B. CNS infections.
C. seizures.
D. Alzheimer’s dementia.
E. toxic and treatment-related encephalopathies.
14. With regard to the presentation of brain tumors, which of the following is true?
A. The presentation is more a function of the location of the tumor and rate of growth, rather than the underlying histology.
B. Metastatic brain tumors are more likely to develop hydrocephalus.
C. Metastatic tumors are less likely to present with hemorrhage.
D. Primary and metastatic brain tumors are equally prevalent.
. Toxic encephalopathy in cancer patients may be caused by all of the following except:
A. elevated or toxic levels of anticonvulsants.
B. overuse of narcotic analgesics.
C. steroids.
D. hypoammonemia.
E. neuroleptics and antiemetics.
16. Risk or predisposing factors for cerebrovascular emergencies in cancer patients include all of the following except:
A. direct effects of tumor on blood vessels.
B. tumor-induced coagulation disorders.
C. treatment-related vascular injuries.
D. hypertension and diabetes.
E. none of the above.
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