Clinical manifestations

Presentation and course

Most commonly, leukemia directly involves the nervous system by way of meningeal metastasis. Patients may present with a nonlocalizing encephalopathy, cranial neuropathy, radiculopathy, or myelopathy (43; 10). Symptoms of increased intracranial pressure, including headache, nausea or vomiting, mental status decline, gait disturbance, or incontinence may also be indicative of hydrocephalus (15).

Much less frequently, leukemia may be associated with the formation of intraparenchymal mass lesions. The cerebral hemispheres are the most common sites of involvement, though the brainstem, cerebellum, or spinal cord may also be involved. Symptoms depend on the location and the rate of growth and may include headache, focal neurologic signs, nonlocalizing encephalopathy, seizures, or visual disturbances (43).

Chloroma (granulocytic sarcoma) is a subset of parenchymal metastasis seen in the setting of myeloid leukemias. Chloroma is defined as an extramedullary manifestation of acute myeloid leukemia that can occur in any organ, including the brain (05). Although often occurring in the setting of relapsed disease, it may be seen as an initial manifestation of acute leukemia, particularly in the setting of preexisting myelodysplastic syndrome or myeloproliferative syndromes such as polycythemia vera, essential thrombocytosis, or myelofibrosis (29; 01). Skull-base disease may result in cranial or optic neuropathies (08; 30; 04). The eyes may be directly infiltrated with leukemic cells (41). Chloromas or other masses may arise outside the nervous system, such as in the skull or epidural region, and extrinsically compress the brain or spinal cord (26).

Cerebrovascular complications of leukemia consist of hemorrhagic and nonhemorrhagic stroke. Clinical manifestations are based on the site of involvement and may include hemiparesis, aphasia, visual disturbances, headache, abrupt loss of consciousness, or seizures (20; 39). Intracranial hemorrhage may be related to tumor-related or treatment-related coagulopathy (46). Central nervous system vasculitis has been reported to occur in the setting of systemic vasculitis associated with hairy cell leukemia. Leukemia may also be associated with paraneoplastic or drug-induced vasculitis (36).

Posterior reversible encephalopathy syndrome has been associated with leukemia, particularly in children (33). Posterior reversible encephalopathy syndrome is a syndrome of reversible ischemia localized to the posterior hemispheres and is associated with a variety of diseases, including hypertension, eclampsia, renal disease, and cancer as well as cancer treatment and immunosuppressive agents (particularly cyclosporin and tacrolimus) (45; 47). Symptoms include visual disturbances, confusion, seizures, encephalopathy, and headache. Despite its implied reversibility, patients may be left with neurologic sequelae (24; 27).

Infection is another cause of neurologic morbidity in the setting of leukemia. Patients who have undergone splenectomy are at risk for bacterial meningitis. All patients are at risk for a variety of opportunistic infections, including cryptococcal meningitis, listeria monocytogenes, aspergillosis, nocardia, mucormycosis, toxoplasmosis, herpes simplex, varicella zoster, and JC virus (progressive multifocal leukoencephalopathy) (48; 09; 28; 27).

Iatrogenic complications often result from the treatment of leukemia. The complications of a variety of chemotherapeutic agents are detailed in Table 1. The incidence of radiation-induced brain tumors has been reduced by the elimination of prophylactic whole brain radiation in favor of other strategies for CNS prophylaxis, such as intrathecal chemotherapy (40; 03).

Table 1. Complications From Chemotherapeutic Agents

(32; 48; 09; 28; 13; 42; 07; 44)

Prognosis and complications

At the time of central nervous system relapse, prognosis is poor, with a median survival of approximately 6 months (43).

The prognosis of cerebrovascular complications of leukemia is based on clinical presentation, etiology, and effective treatment (39).

The prognosis of posterior reversible encephalopathy syndrome is generally good with resolution of symptoms and neurologic signs with successful treatment. Despite its implied reversibility, patients may be left with neurologic sequelae (24; 47).

The prognosis of central nervous system infections is based on clinical presentation, etiology, and effective treatment (13).

The prognosis of paraneoplastic necrotizing myelopathy is poor. No treatment is known; symptoms will generally progress and are not reversible (18; 21).

Clinical vignette

A 52-year-old woman was receiving chemotherapy for recurrent acute lymphoblastic leukemia. During chemotherapy, she experienced a seizure. A brain MRI was performed.

The T1-weighted images showed evidence of an area of hyperintense signal without contrast enhancement in the bilateral occipital lobes and possibly in the right thalamus. Hyperintense signal was evident in these areas on FLAIR images. Diffusion-weighted images revealed no obvious abnormality with the exception of a subtle, hyperintense signal along the cortex of the right occipital and temporal lobes and left occipital lobe. A lumbar puncture was performed and was negative. She was hypertensive and was treated with the belief that this may have represented posterior reversible encephalopathy syndrome. Seven days later, the patient underwent a repeat brain MRI because of a progressive decline in mental status and possible cortical blindness.

Again, there was no evidence of enhancement on pre- and postcontrast T1-weighted images, though there was evidence of increased hypointense signal surrounding the sulci. On FLAIR, there was increased signal in the right and left occipital lobes and left temporal lobe. This correlated with an area restricted to diffusion on diffusion-weighted images. Because of progressive neurologic decline, she underwent a repeat brain MRI approximately 4 days later.

Hypodensity was increased on T1-weighted images, and sulcal and meningeal enhancement was evident. There was evidence of worsening of the abnormalities previously noted on FLAIR and diffusion-weighted imaging and a new area of restricted diffusion in the left thalamus. A lumbar puncture was performed and was positive for leukemia.

This clinical vignette characterizes the presence of meningeal disease and resulting stroke. In this case, the patient was initially believed to have posterior reversible encephalopathy syndrome based on the initial MRI findings and the lack of any significant abnormality on FLAIR testing. However, subsequent evidence of ischemia and local enhancement indicated that this patient was experiencing progressive meningeal disease resulting in infarction. She was treated with radiation therapy but did not recover any neurologic function.

Biological basis

Etiology and pathogenesis

Leukemic cells reach the meninges either by hematological spread or by extension from bone marrow. The pathogenesis of parenchymal mass lesions is most likely hematological spread (02). Meningeal metastasis is most commonly seen in the setting of acute lymphocytic leukemia and less commonly in the setting of acute myelogenous leukemias or chronic leukemias. A number of risk factors for central nervous system relapse have been identified and include young age, leukocytosis, extramedullary disease, a high proliferation rate, elevated serum LDH level, mature B-cell phenotype, Philadelphia chromosome positivity, CD56 expression, and an elevated serum beta-2 microglobulin level. Kantarjian and colleagues identified 3 specific risk factors (elevated serum LDH, elevated beta-2 microglobulin, high proliferation rate) and determined that the risk of meningeal metastasis at 1 year is over 13% in those patients with 1 risk factor and over 20% if 2 or more risk factors are present (25). Parenchymal metastases are much less common and tend to occur in the setting of acute myeloid leukemias. No risk factors have been identified. Communicating hydrocephalus may result from blockage of the arachnoid villi, preventing resorption of cerebral spinal fluid. Noncommunicating hydrocephalus may also occur from direct blockage of cerebrospinal fluid flow.

Leukemia and its treatment are associated with coagulopathies. Many factors in the coagulation cascade, including factors V, VII, X, and XIII as well as plasminogen, antithrombin III, and platelets may decrease as a direct result of disease and as a result of treatment, increasing the risk for hemorrhage. Hemorrhage is often associated with fulminant leukocytosis; patients in blast crisis may develop thrombi within small blood vessels, which can result in vascular disruption and hemorrhage (17; 16). Hemorrhage may also be seen in the setting of other forms of coagulopathy, such as disseminated intravascular coagulation. Hemorrhage may also occur as a result of venous sinus thrombosis that is either a direct result of leukemia or associated with L-asparaginase chemotherapy (31; 34). Ischemic stroke in the setting of leukemia may have both direct and indirect causes. Direct causes include thrombosis related to leukocytosis, vascular occlusion by masses of leukemic cells, extrinsic vascular compression by parenchymal masses or meningeal disease, or by venous sinus thrombosis. Meningeal metastases may infiltrate Virchow-Robin spaces and extrinsically compress small penetrating vessels, resulting in ischemic stroke (20).

Indirect causes of ischemic stroke include septic emboli, nonseptic embolic disease (nonbacterial thrombotic endocarditis), venous sinus thrombosis (from tumor or L-asparaginase chemotherapy), or disseminated intravascular coagulation (14; 06).

Posterior reversible encephalopathy syndrome occurs most commonly in the setting of hypertension. It is believed to be mediated by multiple factors, leading to brain-capillary leak syndrome and cytotoxic effects of immunosuppressive agents on vascular endothelium (45; 24; 47).

Immunosuppression directly caused by leukemia is exacerbated by its treatment. Bacterial meningitis may result from primary infection of the central nervous system or by hematological spread from other sites. Nonmyelosuppressed patients who undergo splenectomy as part of their therapeutic regimen are also susceptible to meningitis, particularly from encapsulated bacteria such as pneumococcus, Haemophilus influenzae, and Neiserria meningitidis. Opportunistic infections may occur in T-cell-depleted patients and include cryptococcal meningitis, aspergillosis, nocardia, mucormycosis, toxoplasmosis, and viral encephalitis, such as herpes simplex, varicella zoster, and progressive multifocal leukoencephalopathy (48; 09; 28).

The etiology of hypercalcemia and hyponatremia includes the direct effects of cancer and effects of treatment. Likewise, hepatic encephalopathy may be caused by hepatic infiltration by leukemic cells, though a variety of chemotherapeutic agents can also cause hepatic dysfunction.

The etiology of paraneoplastic necrotizing myelopathy is unknown. Necrotizing myelopathy can also occur outside of the setting of cancer. Overall, nonvascular and vascular types have been identified. Although necrotizing myelopathy in the setting of cancer tends to be the nonvascular type, the vascular type has been seen in the setting of cancer (22; 35; 18; 21).

Prevention

Approximately 5% of patients with acute lymphocytic leukemia will have blast cells in their spinal fluid at the time of diagnosis. Regardless of presentation, approximately 30% of adult patients with acute lymphocytic leukemia will recur without central nervous system prophylaxis despite appropriate treatment for systemic disease. The use of cranial irradiation or intrathecal chemotherapy utilizing methotrexate or cytosine arabinoside (cytarabine, ARA-C) is effective in reducing this incidence to 5% to 10%. However, intrathecal chemotherapeutic protocols are generally utilized because of the incidence of radiation-induced neoplasms in long-term survivors and because of the effects of cognition and, in children, growth associated with cranial irradiation. As with meningeal metastasis, prevention of parenchymal central nervous system relapse consists of appropriate treatment of systemic disease and prophylaxis with intrathecal chemotherapy or with radiation therapy (37).

The prevention of cerebrovascular complications of leukemia is aimed at the detection and prevention of blast crisis and hyperviscosity as well as careful monitoring of platelets and coagulation profiles. The peripheral blast count may be reduced by leukapheresis or chemotherapy, thus, reducing the risk of hemorrhage. Disseminated intravascular coagulation is a risk factor for hemorrhage and stroke and is treated with prophylactic heparin and treatment of the underlying cause (39).

Because posterior reversible encephalopathy syndrome is uncommonly caused by cancer or by therapeutic agents, specific preventative measures are not necessary. Because posterior reversible encephalopathy syndrome may be directly caused by hypertension, treatment of hypertension will reduce risk (45; 24; 47).

Prevention of central nervous system infections is based on careful monitoring of a patient’s hematological parameters. Vaccinations for encapsulated bacteria may be appropriate. Prophylaxis may be provided for certain opportunistic infections, such as herpes viruses, in patients at risk (13).

Other than treating the underlying cancer, no preventative measure is known for paraneoplastic syndromes (12).

Differential diagnosis

Differential diagnosis of meningeal metastasis includes infectious causes of meningitis or benign processes such as postsurgical changes, meningeal fibrosis, intracranial hypotension, or other meningeal tumor such as meningioma. Meningeal leukemia must be differentiated from other causes of meningitis by lumbar puncture or by benign processes such as postsurgical changes, meningeal fibrosis, other meningeal tumors such as meningioma, or intracranial hypotension. The differential diagnosis of parenchymal masses includes metastases from other cancers, primary brain tumors, CNS inflammatory disease, and infection (10).

The differential diagnosis of cerebrovascular complications of leukemia includes parenchymal masses, CNS inflammatory disease, and infection (39).

The differential diagnosis of posterior reversible encephalopathy syndrome includes stroke (basilar artery occlusion) and meningeal disease (24; 47).

The differential diagnosis of central nervous system infections is based on clinical presentation. The differential diagnosis of meningitis of infectious etiology includes meningeal metastasis. Likewise, the differential diagnosis of central nervous system infections producing intracranial mass lesions, including herpes encephalitis, consists of parenchymal metastasis or ischemic or hemorrhagic stroke (13).

The differential diagnosis of paraneoplastic necrotizing myelopathy includes meningeal and parenchymal metastatic disease, epidural spinal cord compression, spinal cord ischemia, infectious meningitis, radiation myelopathy, and transverse myelitis. These must be excluded before a diagnosis of paraneoplastic necrotizing myelopathy is made (18; 21).

Diagnostic workup

Meningeal enhancement may be present on MRI, but its absence does not exclude meningeal disease. Diagnosis is ultimately made by lumbar puncture. More than 1 lumbar puncture may be needed to obtain an accurate diagnosis. The diagnosis of parenchymal masses is made by imaging of the central nervous system. Biopsy may be required when diagnosis is unknown or in doubt. In the absence of known leukemia, differentiation from lymphoma may be made utilizing flow cytometry or immunohistochemistry (10; 19).

The diagnosis of cerebrovascular complications of leukemia is made by appropriate clinical suspicion and findings on examination and with CT or MRI. Additional laboratory testing may assist in determining the etiology, such as the presence of thrombocytopenia or extreme leukocytosis (39).

Diagnostic imaging assists in the diagnosis of posterior reversible encephalopathy syndrome. Brain MRI will reveal evidence of abnormalities on T2/FLAIR in the posterior hemispheres, usually bilaterally. MR angiography will fail to reveal large vessel stenosis or occlusion. Diffusion may or may not be restricted. Lumbar puncture will help exclude meningeal metastasis (24; 47).

The diagnosis of central nervous system infections is made based on the appropriate clinical setting. Patients with bacterial meningitis have a fulminant course consisting of fever, nuchal rigidity, headache, and changes in mental status. Diagnosis is made by lumbar puncture. Herpes encephalitis may present with seizures and an acute change in mental status. Diagnosis is made by MRI or computed tomography scan, with the finding of a hemorrhagic mass in either or both temporal lobes, and is also made on the basis of lumbar puncture in which there may be a pleocytosis in addition to an elevated number of red blood cells. Other opportunistic infections may have a more indolent course, and diagnosis must be made on the basis of imaging, lumbar puncture, and brain biopsy if needed (13).

Diagnostic workup for paraneoplastic necrotizing myelopathy involves the exclusion of other etiologies. This includes an MRI of the entire spine and a lumbar puncture. The lumbar puncture may reveal elevated white blood cell count and protein with negative cytology. Imaging will reveal signal changes in the affected areas (18; 21).

Management

Corticosteroids are utilized as symptomatic treatment for meningeal and parenchymal metastases. Meningeal metastasis may be treated by radiation therapy to symptomatic sites (such as skull-base radiation for cranial neuropathy), intrathecal chemotherapy, or systemic chemotherapy with blood-brain barrier permeability. Cranial radiation is most effective in treating symptomatic parenchymal mass lesions (19). Hydrocephalus is managed by cerebrospinal fluid diversion, such as with ventriculoperitoneal shunting.

Management of cerebrovascular complications is based on the type of complication (hemorrhage versus ischemic stroke) and the etiology of the complication. Treatment of the underlying etiology, such as leukocytosis or disseminated intravascular coagulation, is essential (39).

Management of posterior reversible encephalopathy syndrome consists of treatment of any underlying contributory factors, such as hypertension and withdrawal or adjustment of medications that may be contributory. Use of anticonvulsant medication is recommended as seizure prophylaxis because of the high incidence of associated seizures (24; 47).

Management of central nervous system infections consists of prompt diagnosis and treatment with appropriate antibiotics. Initial treatment is based on clinical suspicion and may consist of antibacterial, antifungal, and antiviral agents (13).

No treatment is known for paraneoplastic necrotizing myelopathy other than treatment of the underlying leukemia and symptomatic treatment (18; 21). There has been no evidence in the existing literature that treatment commonly utilized in paraneoplastic syndromes, such as corticosteroids, immunosuppression, intravenous immunoglobulin, or plasmapheresis, are of any benefit.