Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 69

Neurologic aspects of lymphoma and leukemias MATTHEW McCOYD1*, GREGORY GRUENER1,2, AND PATRICK FOY3 Department of Neurology, Loyola University Medical Center, Maywood, IL, USA

1 2

Leischner Institute for Medical Education, Loyola University Medical Center, Maywood, IL, USA 3

Department of Hematology, Medical College of Wisconsin, Milwaukee, WI, USA

INTRODUCTION Lymphoma and leukemia include a heterogenous group of blood malignancies arising from hematopoietic stem cells (Fig. 69.1). Historically, the two entities have been considered separately. Leukemia has been used to describe a cancerous change in the hemopoietic stem cells and their progenitors, usually with widespread involvement of the bone marrow and peripheral blood (Mughal et al., 2006; Kumar et al., 2009a). Lymphoma has been used for proliferations of lymphoid cells that arise as discrete tissue masses, most commonly within lymphoid tissue including nodes (Kumar et al., 2009a). However, with improved diagnostic tools including immunophenotyping, genetics, and cytochemistry, the juxtaposition of leukemia and lymphoma has blurred as the same entity can present in either fashion (Ottensmeier, 2001). Multiple classification systems for the leukemias and lymphomas have been proposed since Thomas Hodgkin’s paper “On some morbid experiences of the absorbent glands and spleen,” published in 1832 (Jaffe et al., 2008), and the first description of leukemia in 1845 (Goldman and Velo, 2003). The leukemias can be considered neoplasms of myeloid and lymphoid precursors (Glass, 2006). They are broadly considered as “acute” or “chronic” and are classified by the salient features of the aberrant hematopoietic cell populations (Mughal et al., 2006). The lymphomas are lymphoid tissue tumors and historically were divided into Hodgkin lymphoma or the larger, non-Hodgkin group (Glass, 2006). However, the current and most broadly accepted classification is the World Health Organization (WHO) classification of myeloid and lymphoid neoplasms. Under constant revision, it is a consensus classification based not only on morphology, genetics, and immunophenotype, but

clinical features. Table 69.1 is representative of the current classification of lymphoid neoplasms (Ottensmeier, 2001; Vardiman et al., 2009; Vardiman, 2010). Early and late neurologic complications of leukemia and lymphoma have long been recognized as both a result of the disease and its treatment. This review will highlight the most frequent lymphomas and leukemias, or those with the greatest neurologic significance. Complications of treatment are considered within separate contributions of this handbook and elsewhere (Dropcho, 2011). This review should begin to address delays in referral when patients with hematologic disorders present first to a neurologist (Abel et al., 2008).

LYMPHOMAS The lymphomas can be conceptualized as two broad categories of disorders: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) (Fig. 69.2). Further classification relies on clinical features and histopathology that is further defined by immunophenotype and cytogenetic characterization. While the clinical presentation can hint at classification, tissue characterization is always necessary as symptoms cannot be relied on accurately to identify the specific type of lymphoma. The vast majority of lymphomas are of B cell origin with the remainder T cell. Non-Hodgkin lymphoma cells tend to circulate within the vascular system and are often widely dispersed at the time of diagnosis, while Hodgkin lymphoma tends to spread contiguously from their site of origin. Lymphomas arise from a clonal expansion of a malignant lymphoid hematopoietic stem cell. Each malignant cell expresses a conserved set of aberrant genes, transcription products, and proteins that can be detected through morphologic, immunohistochemistry,

*Corresponding author: Matthew McCoyd, M.D., Loyola University Medical Center, Building 105, room 2700, 2160 South First Ave; Maywood, IL 60153, USA. Tel: þ1-708-216-2127, Fax: þ1-708-216-5617, E-mail: [email protected]

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Fig. 69.1. Differentiation of hematopoietic cells.

chromosomal, and cytometric methods to prove origination from a primary malignant stem. These markers can help to identify these cells as an abnormal monoclonal population, rather than the expected polyclonal expansion of hematologic and immunologic cells seen in a reactive lymphoid process.

Non-Hodgkin’s lymphomas This group comprises up to two-thirds of lymphomas and is classified based on pathologic, immunophenotypic, and clinical presentation. Many subtypes exist (Table 69.1). This discussion will first focus on two subtypes of peripheral B cell lymphoma, primary CNS lymphoma (PCL) and Burkitt lymphoma, because of their high rate of involvement and relapse within the central nervous system (CNS). Multiple myeloma, its variants, and Waldenstr€ om’s macroglobulinemia will be described as a group. Finally, we will also discuss complications

of an infrequent extranodal subtype of peripheral B cell lymphoma, intravascular large B cell lymphoma, because of its frequent presentation with CNS or skin manifestations and delay in diagnosis.

PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA Perhaps 90% of the cases of primary CNS lymphoma (PCL) demonstrate diffuse large B cell lymphoma morphology that while confined, can involve any level of the neuraxis, brain, spinal cord, leptomeninges, or eyes. Upon diagnosis, searching for evidence of occult systemic disease is recommended. The remaining 10% of cases of PCL represent Burkitt lymphoma, T cell lymphoma, or poorly characterized low-grade lymphomas and is more often identified in younger patients (Kim et al., 2011). As a group, PCL comprise between 1% and 6% of primary brain tumors, but are much more common in immunodeficiency syndromes including

NEUROLOGIC ASPECTS OF LYMPHOMA AND LEUKEMIAS Table 69.1 World Health Organization classification of lymphoid neoplasms (representative) Precursor lymphoid neoplasms B lymphoblastic leukemia/lymphoma T lymphoblastic leukemia/lymphoma Mature B cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B cell prolymphocytic leukemia Hairy cell leukemia Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Mantle cell lymphoma Diffuse large B cell lymphoma Intravascular large B cell lymphoma Burkitt lymphoma Mature T cell and NK cell neoplasms T-cell prolymphocytic leukemia Chronic lymphoproliferative disorder of NK cells Aggressive NK cell leukemia Adult T cell leukemia/lymphoma Enteropathy-associated T cell lymphoma Mycosis fungoides Se´zary syndrome Primary cutaneous T cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Primary cutaneous CD4 positive small/medium T cell lymphoma Angioimmunoblastic T cell lymphoma Hodgkin lymphoma Histiocytic lymphoma Langerhans cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumor Histiocytic and dendritic cell neoplasm Classic subtypes Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depletion Post-transplant lymphoproliferative disorders (PTLD)

human immune deficiency (HIV) infection and posttransplant settings, and the frequency of PCL increased at the same time as the appearance of individuals with HIV infection. While the institution of more effective therapy for HIV has been associated with a concomitant decline in the incidence of PCNSL their prognosis remains worse than HIV-negative patients and HIV testing is still recommended in all cases of PCL (Gerstner and Batchelor, 2010; Bayraktar et al., 2011).

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In non-HIV-related cases of PCL it is just as likely at presentation to suggest a focal CNS lesion as a more diffuse neurologic process, with clinical signs at presentation including focal deficit (70%), neuropsychiatric symptoms (43%), increased intracranial pressure (33%), seizures (14%), and vitreous involvement (4%). Systemic symptoms such as weight loss, night sweats, or fever are less common at presentation (Bataille et al., 2000). Contrast-enhanced magnetic resonance (MR) imaging of the brain is the preferred diagnostic imaging study. Spinal cord involvement is rare so empiric spinal cord neuroimaging is not routinely recommended. Cerebrospinal fluid (CSF) examination is the most sensitive technique to evaluate for leptomeningeal disease. Characteristic radiologic features include a superficial location, contrast enhancement, and absence of necrosis. In the majority of immunocompetent cases a single uniformly enhancing lesion is identified. The most common sites of involvement include cerebral hemisphere (38%), thalamus/basal ganglia (16%), corpus callosum (14%; bulky infiltration of the corpus callosum is considered the most characteristic sign of PCL), periventricular (12%), and cerebellum (9%) (Haldorsen et al., 2011). In HIV-related PCL the lesion may appear ring enhancing. New imaging modalities that include fludeoxyglucose (18 F) (FDG), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are increasingly used to aid in differential diagnosis, but as of yet no imaging modality is diagnostic and histology is still required (Tang et al., 2011). There is no clear consensus in regard to treatment protocols for PCL, but methotrexate appears to be the most effective chemotherapeutic drug. However, it necessitates high doses in order to penetrate the blood–brain barrier (BBB) and the eyes (which can be a potential reservoir for partly treated lymphoma) as well as treat leptomeningeal involvement (perhaps in up to 42% of people at diagnosis), and often part of a multidrug regimen. Rituximab, a monoclonal antibody targeted against CD20, is incorporated into most treatment regimens as most PCL express CD20, but data suggesting benefit are limited to case series. Wholebrain radiation therapy produces an initial radiographic response and control of disease in 90% of patients, relapse occurs within the first few months, and delayed neurotoxicity in those older than 60 years is common. If possible, corticosteroid administration should be withheld until diagnosis since its direct lymphocytolytic effect may impair histologic diagnosis. Like radiation therapy, corticosteroids can also produce a sudden response, but relapse also occurs quickly and alternative therapies are required (Gerstner and Batchelor, 2010; Roth et al., 2012).

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Fig. 69.2. Origin of lymphoid neoplasms.

The location of PCL and associated treatments are accompanied by significant delayed neurotoxicity, more common in those older than 60 years. Typically there are signs of cognitive impairment and when more severe, subcortical dementia, gait impairment, and incontinence develop. The clinical presentation can be accompanied by MRI changes consistent with periventricular demyelination and cerebral atrophy, while pathologically there is evidence of demyelination, neuronal loss, and gliosis (Gerstner and Batchelor, 2010). One unique and rare manifestation of PCL is a diffuse infiltrating form without evidence of a mass lesion, referred to as lymphomatosis cerebri. Clinically it presents as a rapidly progressive dementia and gait disorder that is accompanied by a characteristic MRI finding of patchy T2-hyperintense areas that do not demonstrate contrast enhancement and are suggestive of a diffuse leukoencephalopathy. These MRI changes are felt to reflect infiltration of the white matter by lymphoma cells. The infrequency of the disorder has not allowed specific recommendations in regards to treatment, but

empirically has been the same as those for typical PCL (Kanai et al., 2008).

BURKITT LYMPHOMA It is convenient to consider three variants of Burkitt lymphoma (BL) distinguished by their geographic distribution, epidemiology, and pathogenesis: endemic, sporadic, and immunodeficiency-associated BL (Perkins and Friedberg, 2008; de Leval and Hasserjian, 2009). All cases share a common characteristic of frequent involvement of the CNS and often are “driven” by Epstein–Barr virus (EBV) viral DNA incorporation into the genome. EBVassociated BL is highest in endemic cases (>90%) and immunodeficiency cases (25–40%), and lowest in sporadic BL (15–30%). Endemic BL occurs with a peak incidence in children (4–7 years), male:female ratio of 2:1, a geographic distribution within equatorial Africa, and Papua, New Guinea, and is commonly extranodal, with jaw and facial bone involvement in 50% of cases. Immunodeficiencyassociated BL is encountered within HIV-infected

NEUROLOGIC ASPECTS OF LYMPHOMA AND LEUKEMIAS individuals as well as those with a congenital or iatrogenic immunodeficiency and is more frequently nodal or involving bone marrow (de Leval and Hasserjian, 2009). The terms endemic or sporadic BL are epidemiologic terms and neither predict the clinical course nor are currently used within a clinical, pathologic, molecular, or pathologic classification scheme. Essentially all cases of BL share a translocation of the c-myc gene on the long arm of chromosome 8 with one of the immunoglobulin heavy or light (k or l) chain loci on chromosome 14, 2 or 22. This translocation brings the c-myc gene, an oncogene that enhances cell proliferation and apoptosis, under the transcriptional control of an immunoglobulin locus. How EBV then contributes or facilitates the development of BL as well as the process where cell proliferation remains enhanced with respect to apoptosis is currently not entirely explained (Bornkamm, 2009). In the US, the sporadic variant of BL is more typically encountered, mainly within adult patients who present with an abdominal mass, B symptoms (fever, weight loss, night sweats) and laboratory evidence of tumor lysis. Extranodal involvement is frequent with bone marrow involvement in 70% and leptomeningeal involvement in 40% of adults at the time of diagnosis. BL exhibits a high rate of mitosis as well as apoptosis with phagocytic, pale-appearing histiocytes on microscopy, dispersed throughout the tumor, taking up the debris and resulting in a “starry-sky” (nonspecific) appearance on low power magnification. The potentially rapid rate of progression necessitates that treatment be instituted as soon as a diagnosis is confirmed. Optimal therapy for an adult patient is not established, although CNS prophylaxis with either high-dose systemic therapy, intrathecal therapy or both is part of all regimens. Treatment regimens used in adults are adapted from treatment protocols that are used in children. In general these include intensive high-dose chemotherapy, similar to those used in ALL with initial “induction therapy” followed by a high-dose chemotherapy consolidation therapy. Both autologous and allogenic hematopoietic stem cell transplantation has been used either as part of a consolidation strategy or upon relapse of disease. Radiation therapy is not part of the therapeutic regimen in BL since the response to chemotherapy is near universal. Prophylaxis against tumor lysis syndrome is essential given the high rate of chemotherapy-associated tumor cell death. Prognosis of BL is excellent when the disease is limited to a single site, and when it occurs in children (5 year survival rates can exceed 90%). There are fewer trials of treatment in adults over the age of 40 years, but outcomes are currently inferior to those reached with children (Perkins and Friedberg, 2008).

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MULTIPLE MYELOMA, PLASMACYTOMA, AND AMYLOIDOSIS

Multiple myeloma (MM) comprises 13% of all hematologic malignances and is second in frequency after nonHodgkin lymphomas. The median age at diagnosis is 70 years with only 2% of cases younger than 40. The frequency of occurrence increases from 1% at age 50 up to 10% in those older than 80 years, and is two- to threefold more common in African- Americans versus whites (Turesson et al., 2010). The typical presentation is with symptoms of fatigue and weakness, anemia, renal failure, or lytic bone lesions; less frequently it presents with a hyperviscosity syndrome, hypercalcemia, or spinal cord compression from epidural tumor or vertebral body collapse. Diagnosis of MM is based on serum and urine electrophoresis (identifies and quantifies M protein), bone marrow evaluation (enumeration and genetic assessment of plasma cells), and skeletal survey (staging of MM, and may identify the characteristic “punched-out” lytic lesions) (Table 69.2) (Lin, 2009; Raab et al., 2009). MM is almost always preceded by a monoclonal gammopathy of undetermined significance (MGUS) of which there is a 1% per year risk of progression to MM and the necessity for long-term follow-up. At times an intervening stage to MM, smoldering myeloma, may be identified. “Smoldering myeloma” is defined by the Table 69.2 World Health Organization diagnostic criteria for MGUS, SM, and MM* Monoclonal gammopathy of undetermined significance (MGUS) Serum monoclonal protein (1 mg/dL above the upper limit of normal) Renal dysfunction (creatinine > 2 g/dL) Anemia (hemoglobin 2 g/dL below lower limit of normal) Bone lesions (lytic lesions or osteoporosis with compression fracture) attributable to the plasma cell disorder Other features include symptomatic hyperviscosity, amyloidosis, and recurrent bacterial infection.

1032 M. McCOYD ET AL. presence of a monoclonal paraprotein greater than 3 g/ past decade, thalidomide, lenalidomide, pomalidomide, dL or bone marrow involvement by atypical plasma and bortezomib are increasingly used in initial protocols cells > 10%, in the absence of clinical symptoms of mulor regimens for a relapse. These drugs exert their tiple myeloma (hypercalcemia, renal failure, anemia, or effect by disrupting the microenvironment of the MM lytic bone lesions). The majority of patients will evolve cells and also demonstrate characteristic patterns of into MM; median time to progression is 4.8 years and toxicity, with neuropathy (often painful) a frequent the probability of progression to MM (or AL amyloidcomponent (Kumar et al., 2009b). Survival of MM osis) is 54% at 5 years, 66% at 10 years. The percent patients has historically averaged 3–5 years, but has draof clonal bone marrow plasma cells is the strongest prematically improved with development of new pharmacodictor of progression; M protein size, free light chain logic therapies and improvement in transplantation immunoglobulin ratio, immunophenotype and an evolvtechniques. ing type (increasing M protein level over time) are all preThere are several clinical variants of MM that include dictors of progression MM and both of these disorders a primary plasma cell leukemia, diagnosed by absolute are associated with a monoclonal protein, but distinblood plasma cell count and representing an aggressive guished by extent and evidence of end-organ effects disease with a poor prognosis comprising 5% of newly (Table 69.2) (Kumar et al., 2009b). diagnosed MM cases. Solitary extramedullary plasmaMGUS is usually an incidental discovery from routine cytoma usually develops within the head and neck. While laboratory screening or discovered during the evaluation associated with a good prognosis, 15% will later develop of an individual with a polyneuropathy. The M protein is into a typical MM. Solitary plasmacytoma usually usually IgG (70%) or IgM (17%) and k light chains develops within the axial skeleton causing local bone are detected more frequently than l (urinary Bence pain or spinal cord/root compression. Accompanied by Jones protein is usually absent). While MGUS can evolve low levels of M protein, most eventually develop into into a malignant plasma cell proliferative disorder with systemic disease. A nonsecretory myeloma is present approximately a 30% actuarial and 11% real (accounting in 3% of MM cases. Cmposed of plasma cells, confirmafor other causes of death) probability at 25 years of tory diagnosis requires immunophenotyping, immunofollow-up, but 75–90% of MGUS will not progress. At chemistry and detection of cytogenetic alterations. time of detection it is unclear whether the abnormal Polyneuropathy, organomegaly, endocrinopathy, plasma cells in MGUS will proliferate and lead to sysmonoclonal gammopathy, and skin changes (POEMS) temic disease or will remain stable. The combination syndrome (Crow–Fukase syndrome, Takatsuki disease, of a non-IgG MGUS, abnormal free chain ratio, and PEP syndrome, or osteosclerotic myeloma) is a rare varan M protein level  1.5 g/dL identify the greatest risk iant of MM ( 94% of cases of multiple myeloma and in all cases of MGUS. The most common monoclonal paraprotein in myeloma is IgG (52%), IgA (21%) and light chain only (k or l, 16%). POEMS syndrome is typically seen in patients with IgG l or IgA l monoclonal paraproteins. Clinical syndromes typically are slowly progressive distal sensory polyneuropathies and usually axonal in character. However, POEMS produces a more

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prominent/disabling sensorimotor polyneuropathy with ataxia that clinically resembles a chronic inflammatory demyelinating polyneuropathy (CIDP)-like sensorimotor polyneuropathy. Amyloidosis can present as a neuropathy in 15–20% of cases. Characteristically it is a painful, progressive distal sensorimotor process and accompanied by autonomic dysfunction. Prognostic factors for an IgM MGUS includes older age and evidence of demyelination on neurophysiologic studies as negative predictors while the presence of an anti-MAG antibody may decrease the risk of future disability. However, these factors were not clearly shown to be associated with responsiveness to treatments (Niermeijer et al., 2010).

INFECTIOUS DISEASE While infectious complications are too broad an area to completely address, they are important to mention. In general, patients with cancer have a greater tendency to develop infections, and their illness as well as their treatment places them at a higher probability for complications (Thirumala et al., 2010). Patients with hematologic malignances carry a higher probability of developing severe sepsis (66.4/1000) than those individuals with solid tumors (7.6/1000) and carry a higher mortality. The appearance of neutropenic fever necessitates urgent evaluation and antibiotic administration (half of cases have bacteremia), lack of a clinical response may necessitate consideration of a fungal infection and empiric treatment during evaluation. Treatment is increasingly complicated as the responsible organism is more often Gram positive and resistant nosocomial isolates have begun to restrict treatment options. Most often the source is respiratory and gastrointestinal tract, while genitourinary infections are a less frequent complication. CNS infections often present in a nondescript way and more prominent focal findings or nuchal rigidity can be lacking. In the setting of unexplained malaise, headache, fever, personality change, delirium or seizures a CNS infection must be considered as well as the possibility of CNS metastases (necessitating neuroimaging) or a metabolic abnormality. Lymphoma and stem cell transplantation are risk factors for a CNS infection and an indication for empiric treatment during evaluation. Antimicrobial agents are selected for the clinical setting and in light of underlying immune disorder (T cell dysfunction may necessitate the inclusion of sulfadiazine or TMP/SMZ to cover Nocardia asteroides). In addition, ventricular shunts or Ommaya reservoirs may need to be externalized or removed.

VASCULAR/HEMATOLOGIC The usual risk factors for stroke in patients with or without cancer are the same and can be addressed in a similar

1038 M. McCOYD ET AL. fashion. Chemotherapy-induced risk of stroke appears The deficit does not improve with treatment of the to be small. Cerebral hemorrhage does occur more often Hodgkin disease, but in some studies with early immune in patients with hematologic (and lung) malignancy (25% therapy (IVIg or plasmapheresis) there may be improveversus 14% in one review). The pathophysiologic mechament in the cerebellar deficit and the anti-Tr may disapnism is attributed to a coagulopathy and typically occurs pear in successful treatment. A similar dramatic change in acute disseminated intravascular coagulation (DIC), in anti-Yo antibody titers has not been noted. thrombocytopenia or hyperviscosity. Management of cancer patients with stroke follows general recommendaLEUKEMIAS tions. However, comorbidity and prior treatments may limit some interventions (Fain et al., 2007; Oberndorfer Patients with leukemia often present with signs and et al., 2009). symptoms arising from bone marrow failure and organ Malignancies can be associated with vasculitides, infiltration by leukemic cells. The symptoms of bone more frequently hematologic (myelodysplastic or lymmarrow failure include those arising from anemia, infecphoid). The NHL are more often associated with tions (due lack of white blood cells), bleeding (due to lack some disorders (leukocytoclastic vasculitis, lymphocytic of platelets and coagulopathy), and organomegaly (especially liver and spleen) (Mughal et al., 2006). The diagnocutaneous granulomatous, polyarteritis nodosa, and sis may be suspected on blood studies as patients with Henoch–Sch€ onlein purpura) than HL. Cryoglobulins were found in 22% of patients with vasculitic NHL leukemia frequently have increased white blood cells and assumed to be the etiology. Vasculitis and lym(usually in the range of 20–200  109/L). phoma are diagnosed simultaneously > 70% of the time, Leukemia refers to hematologic neoplasms of myebut response to treatment may differ. Of the disorders loid or lymphoid precursors that present with widespread associated with monoclonal gammopathies, cutaneous involvement of the bone marrow and, usually, the vasculitides (leukocytoclastic, erythema elevatum diutiperipheral blood (Fig. 69.2) (Kumar et al., 2009a). Myeloid precursors give rise to cells of granulocytic (neutronum) are mostly monoclonal IgA in type. phil, eosinophil, basophil), monocytic/macrophage, erythroid, megakaryocytic and mast cell lineages PARANEOPLASTIC (Vardiman et al., 2009). Lymphoid precursors give rise Although rare disorders in patients with cancer (95% but a sensitivity of less than 50% (Cheng et al., 1994). In one study, 41% of patients with autopsy proven leukemic meningitis had negative CSF cytology (Glass et al., 1979). CSF flow cytometry may increase the diagnostic yield. Immunohistochemistry studies can be used to distinguish between reactive and neoplastic lymphocytes in the CSF. The finding of CSF lymphocytes of all B cell lineages is highly suggestive as reactive lymphocytes in the CSF are of T cell lineage (Chamberlain and Marc, 2008). Contrast enhanced brain magnetic resonance imaging is superior to contrast enhanced computerized tomography. Abnormalities include parenchymal volume loss and enhancement; however, both carry a high false positive rate (30% by MRI, 58% by CT) (Chamberlain et al., 2005). MRI findings consistent with leptomeningeal disease are detected in fewer than 50% of patients. Several candidate CSF biomarkers have been identified, but none have been reliably been shown to be diagnostic to date (Chamberlain and Fink, 2009). Early detection may not improve survival. Neither MRI nor CSF analysis is sensitive enough to stand alone as a diagnostic method for leptomeningeal metastases (Clarke et al., 2010). Meningeal biopsy can also be employed in patients in whom there is a high clinical index of suspicion. Biopsy is more likely to be revealing if taken from an area that enhances on MR imaging (Bosch et al., 2005).

CENTRAL NERVOUS SYSTEM Mass lesions can occur in the brain or spinal cord, though their occurrence is uncommon in the leukemias (Walker, 1991). The cerebral hemispheres are more frequently involved, usually with parenchymal involvement adjacent to blood vessels. Spinal cord compression is rare (1% occurrence) and fortunately highly radiosensitive. There is some controversy as to whether leukemic infiltrates within the brain and spinal cord may represent an extension of meningeal disease rather than a distinct entity. They are rarely hemorrhagic and are more common in ALL than in AML (Glass, 2006).

Chloromas (or granulocytic sarcomas) represent a subset of leukemia-associated solid tumors consisting of myeloid leukemic blast cells (Glass, 2006). The name derives from chloros, the Greek word for green, due to the tumor’s greenish color. Chloromas may be more common in younger patients (mean age 38), though they are uncommon in children (in part due to their association with the myeloid leukemias, AML and CML, which are rare in childhood). The only chloroma more frequently associated with children is the granulocytic sarcoma of the orbit, for unclear reasons. Chloromas are commonly found adjacent to the skull or facial bones, usually with a dural attachment. They are rarely found within the brain parenchyma (accounting for only 1–4% of all chloromas) and spinal canal (they account for 3% of all spinal tumors). The thoracic and lumbar spine are the most commonly involved, with the cauda equina less so (Wiernik, 2001). They can be found in several other non-CNS sites, including the skin, bone, lymph nodes or the liver. There are rare reports of chloromas arising in peripheral nerves (such as the sciatic) and nerve roots. They are usually clinically silent, but are readily apparent on contrast-enhanced imaging studies, appearing similar to meningiomas. Though the tumors themselves are highly radiosensitive, their presence is associated with aggressive systemic disease (Chamberlain and Marc, 2008).

SPINAL CORD Isolated spinal cord disorders are rare in the leukemias. They can be seen in the setting of leptomeningeal disease or with focal masses, as stated above. A more distinct myelopathy syndrome is seen as a complication of treatment. Myelopathic symptoms can arise within 2 days to 2 weeks of injection of intrathecal methotrexate, characterized by typical symptoms including back pain, sensory loss, and weakness. There are no specific predictors of occurrence, no treatment, and variable recovery (Glass, 2006). A paraneoplastic progressive necrotizing myelopathy due to leukemias, and not due to antileukemic agents, has been described in limited case reports. The findings may be nonspecific, including elevated CSF white blood cell count and protein with negative cytology and increased T2 signal changes on MRI (Gieron et al., 1987).

VASCULAR/HEMATOLOGIC CNS leukemic vascular disorders consist of hemorrhagic lesions, arterial and venous thromboses. CNS hemorrhage represents 70% of all cerebrovascular disease in patients with leukemia. It occurs in 20% of all patients with acute leukemia and accounts for 10–20% of leukemic deaths. Hemorrhage is particularly common

NEUROLOGIC ASPECTS OF LYMPHOMA AND LEUKEMIAS in acute promyelocytic leukemia (APL), and patients are increasingly treated with arsenic trioxide and/or all-trans retinoic acid (ATRA) to limit DIC complications associated with APL. Intraparenchymal hemorrhage is the most common while subdural hematoma is relatively uncommon. Predisposing factors include disseminated intravascular coagulation (DIC), disseminated aspergillosis or mucormycosis in the setting of neutropenia, vasculopathy due to leukemic cell invasion of the blood vessel walls, severe thrombocytopenia ( 100 K). Extreme leukocytosis can lead to blood hyperviscosity and sludging of blast cells at the venous end of a capillary bed, causing aneurysmal dilatation of blocked vessels and vessel destruction (Paleologos, 1993). This complication can be prevented by lowering the circulating blast count with oral hydroxyurea or leukapheresis, as well as whole brain radiation. Leukostasis is rarely seen in CLL, ALL, or the chronic phase of CML because the leukemic cells in these disorders do not increase blood viscosity (Wiernik, 2001). Solitary, often massive, ICH is typically seen in the setting of DIC and thrombocytopenia (Chamberlain and Marc, 2008). Multiple hemorrhages are associated with extreme leukocytosis. The most common cause of cerebral infarction at or shortly after diagnosis is venous sinus thrombosis (VST). VST can be due to leukemic infiltration of the superior sagittal sinus, and in children receiving L-asparaginase chemotherapy for ALL (L-asparaginase interferes with fibrinogen). Multiple arterial microinfarcts can lead to a global encephalopathy syndrome, and may be associated with DIC (Glass, 2006). Evaluation for DIC is warranted in any patient with leukemia and encephalopathy. Septic emboli, particularly Aspergillus fungal infarcts, are frequently seen in patients with advanced disease. A mineralizing microangiopathy associated with dystrophic calcifications of the gray matter, basal ganglia, and cerebral cortex following cranial radiation has been well described (Glass, 2006). Symptoms include focal seizures, ataxia, incoordination and behavioral disorders occurring 1 or more years after cranial radiotherapy, particularly in young children.

PERIPHERAL NERVOUS SYSTEM Peripheral nervous system complications are less common than the CNS complications of leukemia (Bosch et al., 2005). One of the more common PNS complications is herpes zoster-related radiculopathies. It is most common in CLL where 7% of patients have at least one infection during the course of their disease (Chamberlain and Marc, 2008).

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Neuropathy due to direct leukemic infiltration is rare, lagging far behind therapy-related neuropathy, even more so if cranial neuropathies associated with leukemic meningitis are excluded. The PNS blood–nerve barrier can theoretically provide a pharmacologic sanctuary for leukemic cells. However, many direct PNS manifestations of leukemia are limited to case reports. Peripheral neuropathy, usually an axonal sensorimotor polyneuropathy, is most commonly seen in CLL, but still occurs in less than 1% of patients (Walker, 1991). By comparison, nerve conduction abnormalities were seen in nearly 30% of children 2 or more years after therapy for ALL. Leukemic infiltration of peripheral nerves and roots may result in an axonal polyradiculoneuropathy or severe sensory ataxic neuropathy. A monoclonal protein is detected in 8% of patients with CLL, and can be associated with chronic demyelinating neuropathies.

CONCLUSION Neurologic complications of the leukemias and lymphomas are multifold. Symptoms can range from generalized, nonspecific features that may not raise the suspicion of a clinician, to readily apparent focal disturbances. While neurologic symptoms are rarely the presenting feature of the hematologic malignancies, the neurologist must be familiar with the common neurologic presentation of these disorders and their treatments.

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