Hematologic Diseases and the Brain
Andreas H. Kramer
RED BLOOD CELL DISORDERS
Anemia is a common complication of acute, severe neurologic illnesses such as stroke and traumatic brain injury. Maturation of hematopoietic stem cells into red blood cells (RBCs) in bone marrow is regulated by the glycoprotein hormone erythropoietin (EPO), which is released by peritubular cells in the kidneys in response to reductions in oxygen (O2) delivery. Production of RBCs is also dependent on sufficient quantities of bone marrow substrate, including iron, folate, and vitamin B12. RBCs normally have a life span of 100 to 120 days before being removed by the spleen.
ANEMIA
Anemia is defined as a hemoglobin (HB) concentration of less than 12 g/dL in women and 13 g/dL in men. There are numerous possible etiologies for anemia, which are presented in Figure 118.1. Measurement of the reticulocyte count helps determine whether the bone marrow is responding “appropriately” to anemia—if so, it implies that the cause is hemorrhage or hemolysis; if not, there is a problem with RBC production. RBC indices, especially the mean cell volume (MCV), provide further information concerning the differential diagnosis. Microcytosis (MCV <80) implies that there is a cytoplasmic problem with the production of HB and the maturation of RBCs. Specific causes of microcytic anemia include iron deficiency and various hemoglobinopathies. Macrocytosis (MCV > 100) implies that there is a nuclear defect in developing RBCs, which may be due to vitamin B12 and folate deficiency or drug toxicity. Normocytic anemia suggests that there is a pathologic bone marrow process or that there is reduced stimulation for RBC production. This section will focus on the neurologic implications of anemia and on sickle cell disease, which is a major cause of stroke in children and young adults.
 FIGURE 118.1 Approach to determining the etiology of anemia. MVC, mean cell volume; LDH, lactate dehydrogenase; RBC, red blood cell. |
Anemia and Transfusion in Hospitalized and Critically III Neurologic Patients
Anemia is one of the most common medical complications to be encountered among hospitalized patients, especially in the intensive care unit. The development of an HB concentration less than 10 g/dL has been reported in about 40% to 50% of neurocritical care patients with traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). The etiology of anemia in hospitalized patients is multifactorial. RBC production is impaired during systemic inflammation, as cytokines blunt the production of EPO and prevent progenitor cells from incorporating iron. RBC loss is accelerated by the need for frequent phlebotomy, reduced RBC survival, and (in some cases) hemorrhage. Hemodilution produced by administration of large volumes of intravenous fluids or phlebotomy may also contribute.
Optimal care of patients with acute brain injury and various forms of stroke involves the protection of salvageable brain tissue and the prevention of secondary injury. Reduced O2 delivery to ischemic penumbra may produce increasing neurologic damage. The amount of O2 reaching tissues is the product of local blood flow and arterial O2 content, which in turn is dependent on the HB concentration and the degree to which it is saturated with O2.
Anemia is initially well tolerated by most patients for several reasons: systemic O2 delivery exceeds O2 consumption by a large amount, tissues have the capacity to increase O2 extraction in the
setting of reduced delivery, and sympathetic stimulation results in increased cardiac output. In the brain, the normal response to anemia is cerebral vasodilation, with a resulting increment in cerebral blood flow (CBF). Experiments in healthy volunteers demonstrate that neurocognitive impairment begins at an HB concentration below approximately 7 g/dL. It is likely that the HB threshold for neurologic deterioration is higher in brain-injured patients, in whom autoregulatory mechanisms may be impaired.
setting of reduced delivery, and sympathetic stimulation results in increased cardiac output. In the brain, the normal response to anemia is cerebral vasodilation, with a resulting increment in cerebral blood flow (CBF). Experiments in healthy volunteers demonstrate that neurocognitive impairment begins at an HB concentration below approximately 7 g/dL. It is likely that the HB threshold for neurologic deterioration is higher in brain-injured patients, in whom autoregulatory mechanisms may be impaired.
The development of anemia is associated with worsened outcomes in patients with TBI, SAH, and intracerebral hemorrhage (ICH). Studies using invasive multimodal neurologic monitoring have found that anemia is associated with lower brain tissue O2 tension and high cerebral lactate concentrations. Patients with SAH, in particular, are vulnerable to delayed cerebral ischemia. Administration of RBC transfusions improves O2 delivery to the brain and increases physiologic “reserve” in regions of the brain with a high O2 extraction fraction.
Historically, clinicians would give RBC transfusions to maintain HB concentrations greater than 9 to 10 g/dL in brain-injured patients. However, allogeneic RBC transfusions have potential adverse effects, including transfusion-related acute lung injury (TRALI) and immunosuppression with an increased risk of nosocomial infections. Randomized trials in general critical care patients have found no advantage, and possible harm, when RBC transfusions are used to maintain HB concentrations above 10 g/dL compared with a transfusion threshold of 7 g/dL [Level 1].1,2 However, there were few brain-injured patients in these studies and HB concentrations of 7 to 9 g/dL may be too low in some brain-injured patients. There is substantial variability of practice, which will continue until clinical trials are performed specifically in brain-injured patients. Consensus guidelines in the setting of SAH recommend maintaining HB levels greater than 8 to 10 g/dL.
Sickle Cell Disease
Sickle cell disease (SCD) is a group of genetic disorders characterized by the presence of “sickle hemoglobin” (HBS) caused by a mutation in the β-globin gene, whereby the sixth amino acid changes from glutamic acid to valine. The most common and severe form is sickle cell anemia, which occurs in patients homozygous for the HBS allele. There are other SCD variants where HBS is inherited form one parent and another abnormal HB from the other. Stroke is the most common neurologic complication of SCD.
EPIDEMIOLOGY
The global burden of SCD is increasing, especially in Africa and India. About 8% of African-Americans are heterozygous for HBS and 1 in 600 are homozygous. Another 2% to 3% carry the HBC allele, which is attributable to a glutamic acid to lysine substitution. The incidence of stroke in children with SCD is about 300 to 400 times higher than the rate of stroke in other children, such that the chance of having a stroke by 20, 30, and 45 years of age is estimated to be about 11%, 15%, and 24%, respectively. The highest incidence occurs between the ages of 2 and 9 years. Intracranial hemorrhage is less common but increases in incidence between 20 and 30 years of age. Stroke is a major cause of premature death and disability in patients with SCD. Untreated, stroke may recur in as many as two-thirds of patients within 2 years. By far the strongest risk factor for stroke is a previous stroke or transient ischemic attack (TIA). Other risk factors include the degree to which HB is reduced, hypertension, frequent episodes of acute chest pain syndrome, leukocytosis, and lower pulse oximetry values.
Even in patients who have not developed overt stroke, magnetic resonance imaging (MRI) studies demonstrate that silent cerebral infarcts are common, occurring in more than a third of patients. Previous infarcts are seen especially in watershed regions and are associated with cognitive impairment and a higher subsequent risk of overt stroke. Areas of restricted diffusion, suggestive of recent cerebral ischemia, can be detected even when patients are asymptomatic, suggesting that patients are at constant risk. Identified risk factors for silent cerebral infarcts include lower baseline HB concentration, higher systolic blood pressure, and male gender.
PATHOBIOLOGY
O2 is normally transported by adult hemoglobin (HBA) consisting of two α and β polypeptide chains that encircle a heme moiety. Unlike HBA, HBS has a tendency to polymerize when it is deoxygenated, which in turn disrupts the normal architecture and flexibility of RBCs, causing them to take on sickle-shaped morphology. Sickling of RBCs interferes with their transit through capillaries and venules, causes them to adhere to endothelium, and increases blood viscosity, all of which may produce microvascular occlusion and tissue ischemia. Increased hemolysis occurs in the spleen. Most of the clinical manifestations of sickle cell anemia are attributable either to vaso-occlusion or hemolysis.
Multiple factors other than just stasis and sluggish microvascular flow are implicated in causing cerebral ischemia. Adherence of sickled RBCs to vascular endothelium induces a cascade of events that produce leukocyte recruitment, inflammation, intimal hyperplasia, fibrosis, and thrombosis. Intravascular hemolysis and release of free HB scavenges nitric oxide, the production of which may also be impaired by endothelial damage, thereby interfering with maintenance of normal vascular tone. These factors contribute to impaired CBF autoregulation, making the brain vulnerable both to hyperemia and ischemia.
Imaging studies with digital subtraction or magnetic resonance (MR) angiography demonstrate that many patients have various forms of vasculopathy. By far the most common cerebrovascular abnormality is stenosis of proximal intracranial vessels, especially in the anterior circulation, which may be accompanied by relative hypoperfusion if perfusion imaging is performed. Involvement of extracranial vessels is less common but does occur and may lead to cervical artery dissection and/or embolic strokes. Over time, with persistent severe intracranial stenosis, there may be development of collateral vessels resembling those of Moyamoya disease. The presence of such collaterals is a marker of a greater degree of vasculopathy and has been identified as a major risk factor for future stroke. These friable vessels are also vulnerable to bleeding. Intracranial aneurysms may develop in unusual locations with a possible predilection for the posterior circulation.
CLINICAL MANIFESTATIONS
SCD patients with cerebrovascular disease present most often with TIA or ischemic stroke. Among those with hemorrhage, SAH is more common than ICH or intraventricular hemorrhage. Repeated silent infarcts cause progressive neurologic deterioration. Children in whom previous infarcts are detected on a MRI scan have, on average, lower performance on neurocognitive testing and worse school performance. They are also more likely to have psychological concerns, such as anxiety and depression. Similar observations have been made in adults with sickle cell anemia, in whom the degree of anemia is associated with more severely impaired cognitive function. Neuroimaging reveals that patients with SCD have
a greater degree of thinning of the frontal lobe cortex, as well as reduced basal ganglia and thalamus volumes.
a greater degree of thinning of the frontal lobe cortex, as well as reduced basal ganglia and thalamus volumes.
SCD may rarely cause complications in the spinal cord and peripheral nervous system. There have been numerous case reports of spinal cord infarction, most often involving the cervical cord and causing quadriparesis. Ischemic injury of peripheral nerves presents as mononeuritis multiplex. Functional asplenia is a well-recognized complication of SCD. The resulting immunosuppression predisposes to bacterial infections, including meningitis, with the risk being high enough to justify prophylactic penicillin usage until at least the age of 5 years. Fever should therefore be considered a medical emergency.
DIAGNOSIS
The diagnosis of SCD is confirmed by HB electrophoresis. Quantification of the percentage of HBS, determined by high-performance light chromatography, is important for therapeutic decision making. Ischemic strokes are rare in the absence of detectable abnormalities in the cerebral vasculature. When vasculopathy is present, the risk of stroke can be significantly ameliorated with appropriate therapy. Thus, screening of patients for cerebrovascular disease is important. Cerebral vasculature is best imaged with digital subtraction angiography (DSA), but noninvasive imaging is preferred. Both computed tomography (CT) and MR angiography can be used, although published experience is larger with the latter. Previous concerns that intravenous contrast could precipitate sickling crisis have likely been exaggerated.
In experienced hands, transcranial Doppler (TCD) ultrasonography correlates well with angiography. Increased TCD velocities in the anterior circulation are highly predictive of the risk of subsequent stroke [Level 1].3 In one prospective single-center study, the sensitivity and specificity for subsequent overt stroke exceeded 85% when TCD velocity exceeded 170 cm/s. In children, when TCD velocities in either middle cerebral or intracranial internal carotid artery consistently exceed 200 cm/s, a randomized controlled trial demonstrated that a stroke prevention strategy using RBC transfusions decreased the risk of stroke over the ensuing 2 years from 16% to 2% [Level 1].4 The risk of stroke is even higher if there are elevated velocities in more than one vessel. Annual screening with TCD is recommended for children with SCD beginning at 2 years of age. Implementation of screening has been temporally associated with a reduction in the incidence of stroke in some jurisdictions. Most studies assessing the use of TCD in SCD have been in children. TCD velocities that are associated with vascular stenosis seem to be somewhat lower in adults, and it is unclear whether TCD is as predictive of subsequent stroke risk.
Apart from imaging of the intra- and extracranial cerebral vasculature, patients with SCD who develop ischemic strokes should undergo a similar diagnostic evaluation to that of other patients, including an echocardiogram, lipid panel, and assessment for diabetes mellitus. In patients with SAH or ICH, if CT or MR angiography does not demonstrate a cause, a DSA should be considered to ensure that a small aneurysm or vascular abnormality is not being missed.
TREATMENT
SCD is a multisystem condition, and the management of neurologic complications occurs in the context of other concomitant treatment considerations. In the management of cerebrovascular complications, therapeutic goals are the primary and secondary prevention of strokes, including those that are silent and may contribute to cognitive decline as well as minimization of brain injury when strokes do occur.
Transfusion Strategies and Stroke Prevention
The Stroke Prevention Trial in Sickle Cell Anemia (STOP) demonstrated that using RBC transfusions to keep the fraction of HBS less than 30% (Table 118.1) significantly reduces the risk of stroke [Level 1].4 Apart from diluting HBS with the addition of HBA, transfusions also temporarily reduce EPO production, thereby reducing the production of new HBS. O2 binds more efficiently to HBA than HBS, such that the O2 saturation is temporarily increased. Although the STOP trial was a primary prevention study, chronic transfusion therapy has also been widely adopted as a secondary prevention strategy. The target HB concentration is generally greater than 9 g/dL. Simple transfusions can be performed when patients are very anemic. Exchange transfusions refer to the transfusion of RBCs together with the removal of the patient’s blood, which is more effective at reducing the concentration of HBS and at lowering stroke incidence.
The need for regular transfusions also has risks, most notably the development of iron overload. Over time, excess iron overwhelms the capacity of reticuloendothelial system to sequester it, and iron begins to accumulate in organs, especially the liver. The consequence of unchecked iron accumulation is hepatic fibrosis and eventually cirrhosis. Rather than performing repeated biopsies, liver iron burden can be accurately monitored noninvasively with annual quantitative MRI scans. Increasing liver iron concentration or serum ferritin (>1,500 µg/L) is an indication to initiate treatment with an iron chelator, most often deferasirox, which has similar efficacy to deferoxamine but is orally available. In an attempt to avoid long-term dependence on blood transfusions, the STOP 2 trial assessed the safety of discontinuing prophylactic transfusions in children whose TCD results had normalized over time. Unfortunately, cessation of transfusions was associated with a clear increment in TCD velocities over time as well as an increased risk of recurrent stroke [Level 1].5
Post hoc analyses of the STOP trials indicated that new silent infarcts were reduced by the use of transfusions and that discontinuation of transfusions led to an increment in the occurrence of new infarcts. However, patients treated with chronic transfusion still commonly develop progressive cerebral vasculopathy. Increased TCD velocities are not necessarily predictive of the development of
silent infarcts. MR angiography may be more predictive, but the relationship between burden of vasculopathy and risk of infarction is imperfect. Until recently, it was unclear whether performing serial MRI scans to document silent infarcts is helpful and should modify the therapeutic approach. However, the Silent Cerebral Infarct trial has demonstrated that regular transfusions to maintain HBS less than 30% and HB greater than 9 g/dL reduces the incidence of subsequent overt or silent infarcts [Level 1].6 Patients should be periodically screened for silent infarcts (the optimal interval has not been defined) and enrolled in a transfusion program if they are present.
silent infarcts. MR angiography may be more predictive, but the relationship between burden of vasculopathy and risk of infarction is imperfect. Until recently, it was unclear whether performing serial MRI scans to document silent infarcts is helpful and should modify the therapeutic approach. However, the Silent Cerebral Infarct trial has demonstrated that regular transfusions to maintain HBS less than 30% and HB greater than 9 g/dL reduces the incidence of subsequent overt or silent infarcts [Level 1].6 Patients should be periodically screened for silent infarcts (the optimal interval has not been defined) and enrolled in a transfusion program if they are present.
TABLE 118.1 Indications for Chronic Transfusion Program for the Prevention of Stroke in Patients with Sickle Cell Disease | ||||||||
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Management of Acute Stroke
There have been no randomized trials of thrombolysis in the treatment of pediatric stroke. The pathophysiology of acute stroke in the setting of SCD may not be the same as in other settings. Nevertheless, although the risk of iatrogenic hemorrhage may be higher, the presence of SCD is not necessarily a contraindication for the use of thrombolytics, especially if the stroke mechanism involves acute thrombotic or embolic vascular occlusion. CT angiography, performed immediately after an initial noncontrast CT scan, can help clarify the mechanism while concomitantly identifying vascular abnormalities that may constitute a relative contraindication. Urgent transfusion to lower the HBS concentration and raise the total HB concentration to about 10 g/dL is appropriate to maximize O2 delivery to the affected penumbra. Adequate hydration and avoidance of hypotension, hyperglycemia, and fever are other standard measures. Antiplatelet therapy is indicated in adults sustaining acute strokes in other settings but there is no data specifically in patients with SCD. The very high risk of recurrent stroke with SCD justifies the use of chronic transfusion for secondary prevention.
Hydroxyurea as an Alternative to Chronic Transfusion
Fetal hemoglobin (HBF) consists of two gamma, rather than beta, globulins. For this reason, an increased concentration of HBF in the circulation prevents the sickling of RBCs. Hydroxyurea is thought to exert its beneficial effects in SCD by increasing the formation of HBF. A large randomized trial found hydroxyurea to reduce painful vaso-occlusive crises. Long-term follow-up demonstrated a possible mortality benefit [Level 1]. 7 Hydroxyurea is currently recommended in patients older than 24 months with frequent pain crises, acute chest syndrome, or severe symptomatic anemia. There has been interest in using hydroxyurea as an alternative to chronic transfusion in the prevention of cerebrovascular disease. Early data suggested that hydroxyurea might be efficacious. However, the recent Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) trial demonstrated that discontinuing regular transfusions and instead treating patients with hydroxyurea resulted in an increased stroke risk [Level 1].8
 FIGURE 118.2 Approach to determining the etiology of polycythemia. EPO, erythropoietin; O2, oxygen; CO, carbon monoxide. |
Intracranial Hemorrhage and Moyamoya Syndrome
Supportive care of SAH and ICH is not different compared with patients who do not have SCD. Immediate priorities with SAH are cardiopulmonary stabilization and treatment of hydrocephalus. Cerebral angiography (invasive or noninvasive) is required to identify the source of bleeding. Most aneurysms with SCD appear to be saccular and are amenable to clip ligation or coil embolization. Some aneurysms are fusiform and can be treated with endovascular stenting. Nimodipine should be used for prevention of delayed cerebral ischemia.
Moyamoya syndrome, a syndrome of progressive intracranial large-vessel occlusion, is a recognized and relatively common complication of sickle cell vasculopathy that is associated with an increased risk of stroke and cognitive decline (see also Chapter 43). There are no controlled studies assessing the optimal management of moyamoya syndrome in the context of SCD. In the setting of an acute ischemic stroke, physiologic targets (blood pressure, partial pressure of carbon dioxide and O2, core body temperature) should be directed at optimizing cerebral perfusion and protecting vulnerable ischemic penumbra. Surgical revascularization is generally preferred for secondary prevention. Small case series have suggested a reduced risk of ischemic stroke with surgery. In adults, direct revascularization with a superficial temporal artery to middle cerebral artery bypass procedure may be possible. In children or in adults without a suitable target vessel, indirect revascularization procedures (e.g., pial synangiosis) are more often performed.
POLYCYTHEMIA
Polycythemia is present when the HB concentration is greater than 16.5 g/dL in women and 18.5 g/dL in men (or the hematocrit is >48% and 52%, respectively). True polycythemia should not be attributable solely to a reduction in plasma volume (hemoconcentration). “Primary” polycythemia refers to increased production of RBCs without increased release of EPO and occurs as a result of congenital or acquired mutations in RBC progenitors. “Secondary” polycythemia is an appropriate response to increased EPO production (Fig. 118.2). Management of secondary polycythemia should be directed at the underlying cause.
Polycythemia Vera
Polycythemia vera (PV) is of interest to neurologists primarily as a cause of stroke. The median age of diagnosis is about 60 years, but PV can occur across all age categories. In almost all cases, PV is associated with a mutation involving JAK2, a gene located on chromosome 9 that codes for the production of tyrosine kinase, a family of proteins that participate in the regulation of hematopoietic cell proliferation. The same mutation is present in about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis.
PATHOBIOLOGY
PV is a myeloproliferative neoplasm characterized by the clonal proliferation of RBC progenitors resulting in an elevated RBC mass. A small proportion of patients with PV will develop leukemic transformation usually after many years. A major concern with PV and other myeloproliferative disorders is a predisposition to thrombosis. It is thought that persistently elevated viscosity produces high shear stress in blood vessels, which in turn is complicated by endothelial dysfunction, as well as platelet and leukocyte activation. Increased levels of thromboxane and other markers of platelet activation can be detected in the blood of patients with PV. High viscosity may reduce CBF to a degree that overall O2 delivery is impaired despite the higher O2-carrying capacity produced by a higher HB concentration. However, other factors must be at play because there is no clear evidence that secondary polycythemia increases the risk of thrombosis.
CLINICAL MANIFESTATIONS
PV is sometimes detected incidentally on routine blood work. However, a sizable proportion of patients have already had thrombotic events by the time they come to medical attention. Arterial thrombosis is more common than venous thrombosis. Patients may also present with transient visual disturbances, headaches, and dizziness attributable to hyperviscosity and sluggish blood flow. Other common complaints include pruritus that is exacerbated by contact with water and erythromelalgia (burning sensation in extremities with erythema or pallor). Physical examination commonly demonstrates hepato- and splenomegaly as well as facial plethora. Apart from an elevated HB concentration, other laboratory findings include thrombocytosis, leukocytosis, high lactate dehydrogenase (LDH), and low EPO levels. Major diagnostic criteria for PV include an elevated HB concentration and the presence of the JAK2 mutation. Minor criteria include characteristic findings on a bone marrow aspirate or biopsy and reduced serum EPO.
TREATMENT
The goal of treatment is to reduce symptoms and the risk of thrombosis while also minimizing long-term complications, especially leukemia. In a multicenter randomized trial involving patients with JAK2-positive PV, treatment with phlebotomy or hydroxyurea to achieve a hematocrit of less than 45% was associated with a significant reduction in thrombotic events. This target hematocrit should therefore be maintained with phlebotomy in essentially all patients [Level 1].9 For patients at especially high risk of thrombosis (those older than the age of 60 years or having had previous thrombotic events), treatment with hydroxyurea is recommended, as it appears to further reduce the risk of thrombosis with a smaller increase in the risk of leukemia over time compared with other myelosuppressive drugs. The addition of low-dose aspirin (80 mg/day) can further reduce thrombotic risk [Level 1].10
WHITE BLOOD CELL DISORDERS
MALIGNANCIES OF LYMPHOID CELLS
Lymphoma and Lymphoblastic Leukemia
Lymphoid malignancies present primarily as mass lesions, which are referred to as lymphoma, or with cancer cells in the blood, referred to as leukemia. They are most often categorized using the World Health Organization classification system. Lymphoma is divided broadly as Hodgkin (HL) and non-Hodgkin (NHL). NHL encompasses a heterogeneous group of malignancies, arising from B lymphocytes in about 85% to 90% of cases, and T lymphocytes in about 10% to 15% of cases. B- and T-cell lymphomas are further subdivided based on whether the malignancy involves proliferation of immature precursor cells or mature cells. Neurologic involvement is rare with HL. However, with NHL and acute lymphoblastic leukemia (ALL), neurologic complications may occur because of direct infiltration of cancer cells into the central nervous system (CNS) (Table 118.2).
EPIDEMIOLOGY
The distribution of NHL subtypes varies by region. In western countries, diffuse large B-cell lymphoma and follicular lymphoma account for more than 50% of cases. CNS involvement is most common with very high-grade lymphomas, especially Burkitt lymphoma and acute lymphoblastic lymphoma, where it may be present at the time of diagnosis in as many as a third. However, CNS involvement also occurs with intermediate- and high-grade
lymphoma subtypes (e.g., diffuse B-cell lymphoma, the most common subtype in North America), especially when there is lymphoma spread to testes, orbits, or the nasopharynx and when there is a high serum LDH concentration. Most cases with neurologic involvement manifest as disease relapses during or after initial treatment, even when there has been a favorable systemic response to treatment, suggesting that subclinical disease was present at the time of diagnosis. The proportion of patients developing CNS relapses may have decreased over time with the addition of rituximab to standard CHOP therapy.
lymphoma subtypes (e.g., diffuse B-cell lymphoma, the most common subtype in North America), especially when there is lymphoma spread to testes, orbits, or the nasopharynx and when there is a high serum LDH concentration. Most cases with neurologic involvement manifest as disease relapses during or after initial treatment, even when there has been a favorable systemic response to treatment, suggesting that subclinical disease was present at the time of diagnosis. The proportion of patients developing CNS relapses may have decreased over time with the addition of rituximab to standard CHOP therapy.
TABLE 118.2 Classification of Most Common Subtypes of Non-Hodgkin Lymphoma and Approximate Prevalence of Central Nervous System Involvement | ||||||||||||||||
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More than half of cases of ALL occur in children, with a peak incidence between the ages of 2 and 5 years. CNS infiltration is detected at diagnosis in about 5% to 10% of patients. This is likely to be an underestimate, given that identification of CNS involvement may be challenging and is not routinely pursued. Before routine use of prophylactic therapy, CNS relapses occurred in as many as 80% of cases. CNS involvement was sometimes identified at autopsy in patients previously thought to have had more limited disease. Risk factors for CNS leukemia include younger age, high white blood cell (WBC) count, positive Philadelphia chromosome, and T-cell ALL.
CLINICAL MANIFESTATIONS
The usual location of CNS involvement is the leptomeninges and subarachnoid space. Brain parenchyma involvement is less common. The predilection of certain tumor subtypes for CNS penetration may relate to expression of various surface adhesion molecules. The most frequent manifestations of leptomeningeal involvement include headache, neck pain, and various cranial neuropathies. If there is spread to the lumbar cistern, patients may develop low back pain and radiculopathies. The degree of subarachnoid involvement may occasionally be severe enough to interfere with CSF flow and cause hydrocephalus. With brain parenchymal involvement, there is a risk of developing seizures and focal deficits. Intramedullary spinal cord involvement is rare. In contrast, NHL and multiple myeloma are among the most common malignancies to cause epidural spinal cord compression (see Chapter 16).
DIAGNOSIS
Gadolinium-enhanced MRI can identify leptomeningeal or brain parenchymal spread. There may be enhancement and thickening of the meninges or individual cranial nerves or nerve roots. There are no characteristic MRI features that definitively identify cerebral mass lesions as lymphoma rather than other tumors; surgical biopsy may be required. CSF findings include lymphocytic pleocytosis, elevated protein, reduced glucose, and high opening pressure, although most patients do not have all of these findings. CSF cytology and flow cytometry should both be performed, as they provide complementary information. Sampling CSF more than once may reduce false-negative rate. CNS leukemia is defined by the presence of leukemic blasts in CSF. Blasts may occur regardless of whether or not the CSF WBC count is increased. The presence of CSF blasts predicts a worse prognosis.
TREATMENT
Lymphoma
When NHL is complicated by secondary CNS involvement, the usual treatment approach must be modified. Options include intensification of the chemotherapeutic regimen, with inclusion of higher doses of drugs that cross the blood-brain barrier or delivering chemotherapy directly into the CNS using either an Ommaya reservoir or repeated lumbar puncture. It is unclear which of these approaches is preferred, as they have not been compared in large clinical trials.
When systemic chemotherapy is used, the regimen usually includes high-dose methotrexate. Combining high-dose chemotherapy with autologous stem cell transplantation appears to be a particularly promising approach. Intrathecal therapy consists of methotrexate in combination with cytarabine. Preliminary data suggest that cytarabine is more efficacious when administered as a slow-release liposomal formulation, which has the additional advantage of requiring less frequent administration. Systemic corticosteroids are effective in some patients at temporarily ameliorating neurologic symptoms and providing analgesia. Radiation therapy may be helpful in selected cases where there are radiographically visible lesions that are causing symptoms.
Because the prognosis of NHL is much worse with relapses that involve the CNS, some experts favor administration of prophylactic CNS therapy as a component of the initial chemotherapeutic regimen in patients deemed to be at high risk. The risk of CNS involvement, even if not documented at diagnosis, is sufficiently high with Burkitt lymphoma and lymphoblastic lymphoma to justify CNS prophylaxis. This may also be appropriate other forms of NHL if risk factors for CNS involvement are present.
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