Introduction

Primary central nervous system lymphoma (PCNSL) is defined as lymphoma confined to the central nervous system (CNS) at presentation. By contrast, secondary CNS lymphoma represents a systemic lymphoma (i.e., outside the CNS) that has metastasized to the CNS (e.g., secondary site) either as part of the initial presentation or at relapse. Secondary CNS lymphoma can also manifest as isolated CNS relapse despite systemic remission. Although this chapter focuses on PCNSL, secondary CNS lymphoma shares many similarities in the approach and management.

PCNSL is a rare, aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the CNS with no evidence of prior or current systemic disease. It may involve the brain, eyes, leptomeninges, or the spinal cord. Of note, eye involvement in this context refers to involvement of the vitreous and retina—i.e., ocular lymphoma. In contrast, orbital lymphoma refers to a non-CNS site of extranodal lymphoma; as such, it is not germane to the discussion of CNS lymphoma. PCNSL accounts for 2 to 3% of all primary CNS tumors. The median age of patients with PCNSL is approximately 60 years. Over 90% of cases of PCNSL are classified histologically as diffuse large B-cell lymphoma (DLBCL).

Patients present with progressive and relatively rapid progression of focal neurological symptoms. Over two-thirds of patients present with a focal neurological deficit and over 40% have neuropsychiatric symptoms. Other presenting symptoms include increased intracranial pressure, seizures, and visual disturbances.

Clinical case

Case 13.1

Primary CNS Lymphoma

Case. A 61-year-old female presented in 2009 to an outside hospital with confusion, word-finding difficulties, and absence episodes. MRI of the brain demonstrated a 1.8 cm × 1.4 cm diffusely enhancing mass in the left frontal lobe ( Fig. 13.1A–C ). The patient received corticosteroids. A lumbar puncture (LP) yielded cerebrospinal fluid (CSF) that was abnormal but nondiagnostic by cytology and flow cytometry. A brain biopsy was performed and the specimen was read as suspicious but nondiagnostic for lymphoma. The mass gradually shrunk, the corticosteroids were tapered off, and the patient felt well for 2 years. In 2011, the patient developed floaters; a vitrectomy showed scattered atypical cells but was nondiagnostic. Six months later, a brain mass appeared. A second brain biopsy demonstrated chronic inflammatory cells. The patient came off corticosteroids and was monitored until 2014, when the lesion grew ( Fig. 13.2A–C ). A brain biopsy demonstrated DLBCL. Systemic staging including CT chest, abdomen, and pelvis was negative for systemic involvement. Ocular examination did not reveal involvement of the vitreous. A diagnosis of primary CNS DLBCL was made and the patient enrolled in a clinical trial of high-dose methotrexate (HD-MTX)–based combination chemotherapy. She completed the 6-month regimen and achieved a complete response (CR) that lasted for 3 years. In 2017, the patient had a relapse. She was re-challenged with HD-MTX and again achieved a CR. In 2018, she developed an isolated ocular recurrence and received intravitreal chemotherapy. She continues with stable ocular disease on intravitreal therapy without relapse in the brain or CSF.

MRI of the brain including (A) axial diffusion-weighted imaging showing an area of restricted diffusion in the left insular cortex (arrow), (B) axial T2-weighted imaging showing a central round mass lesion (arrow) with surrounding cerebral edema (arrowhead), and (C) axial T1-weighted homogeneously gadolinium-enhanced lesion (arrow) measuring 1.4 × 1.8 cm ² .

MRI of the brain including (A) axial diffusion-weighted imaging showing a large area of restricted diffusion in the insular cortex (arrow) , (B) axial T2-weighted imaging showing an enlarged lesion (arrow) with surrounding mass effect, expansion into the region of the Sylvian fissure and surrounding cerebral edema with left to right midline shift, and (C) axial T1-weighted imaging showing a large homogeneous enhancing 3.6 × 4.6 cm ² lesion (arrow).

Teaching Points: Approach to Evaluation and Management of PCNSL. This patient’s case illustrates several important aspects of the evaluation and management of PCNSL. At presentation, she received corticosteroids, which likely contributed to the initial nondiagnostic pathological specimens. Because of this nondiagnostic pathology, she underwent an LP, vitrectomy, and three brain biopsies before her PCNSL was able to be diagnosed, 5 years after her initial symptoms. Thus, corticosteroids should be withheld in any patient for whom PCNSL (or any lymphoma) is suspected but not yet diagnosed.

In terms of management, she was enrolled in a clinical trial at diagnosis. Although she eventually relapsed, participation in a well-designed clinical trial is the treatment of choice for aggressive primary CNS malignancies including CNS lymphoma. She had a good initial response to HD-MTX–based chemotherapy and when her disease recurred 3 years later, she was able to be re-challenged with methotrexate with good response. Thus, for a patient with a durable response to chemotherapy, re-challenge with the same regimen is a reasonable option.

Her isolated ocular relapse was treated with isolated ocular therapy while her brain and CSF remained disease free. For a patient with isolated ocular disease, local therapy to the eyes is a reasonable option.

This case raises several important clinical questions for consultants evaluating and managing these patients. The remainder of the chapter will address each of these clinical questions:

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  Is lymphoma in the differential diagnosis for this new brain lesion?

  
  
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  In biopsied-confirmed CNS lymphoma, is this primary or secondary CNS lymphoma?

  
  
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  Is the patient immune competent or immunocompromised?

  
  
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  What is the approach to management of immunocompetent PCNSL?

  
  
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  What is the approach to management of immunocompromised PCNSL?

  
  
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  What is the approach to management of relapsed or refractory PCNSL?

Approach to the initial diagnosis of CNS lymphoma

About two-thirds of immunocompetent patients with PCNSL initially present with a solitary brain mass. Involvement of the brain hemispheres is the most common localization (38%), followed by thalamus and basal ganglia (16%), corpus callosum and related structures (14%), periventricular loci (12%), and the cerebellum (9%). MRI of the brain typically demonstrates periventricular homogenous contrast enhancement with well-defined borders, low signal on T2-weighted imaging, and restricted diffusion on diffusion-weighted imaging. Less typical presentations such as an intraventricular mass, cranial or radicular nerve enhancement, or isolated meningeal enhancement have been described. In patients who are immunocompromised, imaging findings may be atypical with multiple, ring-enhancing, or patchy enhancing lesions being observed.

Suggestive imaging must be followed by histopathologic confirmation. Tissue diagnosis is essential as the differential diagnosis on MRI of the brain includes multiple sclerosis, sarcoidosis, and occasionally gliomas. Like lymphoma, these entities may demonstrate a transient response to corticosteroids. Therefore, unless the patient is deteriorating, one must avoid corticosteroid administration prior to the proper evaluation of the patient with suspected PCNSL. The potent lympholytic property of corticosteroids will commonly lead to necrosis of lymphoma, rendering tissue nondiagnostic as occurred in the patient described above.

Differentiating primary and secondary CNS lymphoma

For a patient presenting with a possible CNS lymphoma on imaging, the initial decision on the site of tissue diagnosis will also depend on imaging of the chest, abdomen, and pelvis, typically with CT. Some centers use positron emission tomography (PET) CT scan with fluorodeoxyglucose (FDG) (PET-CT). Imaging of these sites accomplishes two purposes: (1) It distinguishes primary from secondary CNS lymphoma and, (2) if suggestive of systemic lymphoma, it determines a site for biopsy. If systemic lymphadenopathy is present, a lymph node biopsy is the biopsy site of choice, as it will reveal the lymph node architecture that informs the subtype of lymphoma and allows comprehensive molecular analysis, which in turn oftentimes will guide therapy. Men with negative systemic imaging should have a testicular ultrasound (US) to rule out primary testicular lymphoma, which, though uncommon as a primary site, has a significant risk of CNS metastasis. Bone marrow aspirate and biopsy have been recommended in some guidelines as part of the evaluation for systemic lymphoma. If the described staging is negative, however, the likelihood of finding isolated bone marrow lymphoma as a source of CNS involvement is 2.5%, calling into question the utility of this procedure.

Once the CT of chest, abdomen, and pelvis and, in men, testicular US are confirmed negative, three options exist for tissue diagnosis and should be pursued in order from least to most invasive.

• 1.
  

  Lumbar puncture. If not contraindicated by elevated intracranial pressure, the least invasive method to diagnose PCNSL is an LP. Importantly, the CSF analysis should be of high volume (>10 mL) and must include flow cytometry and ideally reviewed by a hematopathologist, in addition to routine analysis and cytology. CSF cultures are not necessary in the absence of symptoms or signs of infection and allows for prioritizing CSF to more relevant tests. MRI should be performed prior to the LP to avoid nonspecific meningeal enhancement caused by the procedure. This enhancement can mimic leptomeningeal disease. For patients with immunocompromised PCNSL, the presence of positive CSF Epstein-Barr virus (EBV)-polymerase chain reaction (PCR) in the setting of typical imaging of CNS lymphoma is diagnostic and can mitigate the need for brain biopsy.

  
  
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  Slit lamp examination (SLE). SLE should be performed to detect cells in the vitreous and/or retinal infiltrates. A suspicious finding on SLE would be followed by a vitrectomy or, in some cases, by a retinal biopsy.

  
  
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  Brain biopsy. If both the LP and SLE are negative, the patient should have a brain biopsy. Although a positive LP or vitrectomy will spare the patient a brain biopsy, the patient who has been diagnosed by brain biopsy first should still undergo an LP and SLE to establish the presence or absence of disease in the CSF and/or ocular compartment, respectively. The latter patient with suspicious findings on SLE would not require a vitrectomy to establish ocular involvement. As mentioned earlier, corticosteroid administration increases the risk of a nondiagnostic biopsy usually characterized by necrosis. In case of a nondiagnostic biopsy after corticosteroid administration, serial imaging after withdrawal of corticosteroid therapy may be performed with repeat biopsy after radiologic evidence of tumor regrowth.

Whereas the vast majority of PCNSL are DLBCL, the finding of Burkitt, low-grade, or T-cell lymphoma will alter the management. Clinically, the most important tumor cell marker is the lymphocyte surface CD20, which predicts therapeutic response to anti-CD20 antibodies such as rituximab.

The pathologic evaluation of CSF should include cell counts, protein, glucose, histology, cytology, and flow cytometry. The latter three tests should also be performed on vitreous fluid. The sensitivity of CSF cytology in diagnosis of PCNSL is only 15%. Flow cytometry is more sensitive. If the initial CSF analysis suggests but does not confirm (e.g., elevated protein concentration or presence of lymphocytes read as “atypical” or “suspicious”) lymphoma, a repeat LP may be diagnostic. If the initial CSF is normal, however, a repeat sample will have a low diagnostic yield. Finally, PCR detection of immunoglobulin (IgH) gene rearrangements in CSF may also be helpful, as it does not require intact cells.

Approach to the immunocompetent patient with PCNSL

Once a diagnosis of PCNSL is established, the immune function of the host is a critical first step in determining the optimal approach to managing the patient. Although immunodeficiency and immunosuppression are the main risk factors for the development of PCNSL, most cases occur in immunocompetent individuals.

PCNSL should be approached as a “whole brain disease.” Pretreatment clinical evaluation should include a detailed history and physical examination with careful assessment of neurologic deficits and lymphadenopathy that may suggest systemic disease. Cognitive function testing with neuropsychologic batteries should be performed at baseline and during follow-up visits to watch for potential treatment toxicities. Often, patients at diagnosis are floridly ill and cannot participate in such testing. Laboratory testing should include HIV and hepatitis serologies, lactate dehydrogenase, and hepatic and renal function tests. Although some guidelines recommend a bone marrow aspirate and biopsy, this procedure has a yield of only 2.5% in detecting isolated bone marrow lymphoma as a source of secondary CNS lymphoma. Therefore, many centers do not perform this procedure as part of the evaluation for CNS lymphoma.

Prognosis . The prognostic significance of the classic Ann Arbor staging system does not apply to PCNSL. Several prognostic scoring systems are used for PCNSL. ^, The simplest prognostic score distinguishes three groups on the basis of age and Karnofsky performance status (KPS)—age <50 years, age >50 years plus KPS >70, or age >50 years plus KPS less than 70—which correlate with median overall survivals of 8.5, 3.2, and 1.1 years, respectively. In daily practice, this system is simple to use and offers at least a rough estimate of prognosis.

Treatment of immunocompetent PCNSL

As with any serious illness, the optimal patient management is entry onto a clinical trial, as was the case in the patient described previously. Unlike most CNS malignancies, the goal of therapy for PCNSL is long-term disease control. Because PCNSL generally responds very well to therapy, most patients, even if severely ill, should be considered for aggressive treatment.

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  Surgery. Traditionally, surgery has had no role in the management of PCNSL with the exception of placement of an Ommaya reservoir for the administration of intrathecal therapy. The rapid response to corticosteroids, chemotherapy, and radiation therapy obviate a role for surgical resection. The occasional patient whose brain mass has a radiographic appearance of a glioma may undergo a resection with the unexpected pathologic finding of lymphoma.

  
  
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  Phases of treatment. Therapy for newly diagnosed hematologic malignancies including PCNSL is often divided into three phases: induction, consolidation, and maintenance. Induction refers to the initial therapy, generally with multiagent chemotherapy, with the goal of cure or at least a CR (i.e., no evidence of active cancer detectable on physical examination, CNS imaging, repeat SLE, and, if positive at diagnosis, a repeat LP). Successful induction is then followed by consolidation, which may involve chemotherapy and/or radiation therapy with the goal of consolidating the CR. Thereafter, maintenance therapy may be given with the goal of preventing or delaying disease recurrence, although the efficacy of maintenance therapy in PCNSL is unproven.

Approach to the immunosuppressed patient with PCNSL

Immune suppression either by HIV or immunosuppressive agents allows growth of EBV. Because EBV drives lymphomagenesis, immune suppression increases the risk of NHL and consequently PCNSL. The general strategy for management of these patients involves immune reconstitution with or without cytotoxic therapy.

Iatrogenic immunosuppression-related PCNSL

The population of immunosuppressed individuals is steadily increasing with the wide use of immunosuppressive therapies and the advancements in the field of solid organ or allogeneic hematopoietic stem cell transplantation. Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication of organ transplantation. Although brain involvement occurs in 7–15% of PTLD, isolated CNS disease is rare. ^, For patients with PTLD, reduction of immunosuppressive drugs carries the risk of graft failure, which contributes to the high mortality. As a single strategy, reduction of immunosuppression is not adequate and must be accompanied by chemotherapy. The management of these patients requires close collaboration with the transplant providers in order to decide on how much to reduce the transplant antirejection regimen. The chemotherapy treatment regimens are similar to those used for immunocompetent patients.

Approach to recurrent PCNSL

Despite the significant improvement in the management of PCNSL in the past years, up to 60% of patients experience relapse and one-third of patients have refractory disease (no response to initial therapy). ^, Treatment for PD depends on performance status, site of relapse, prior treatment, and duration of response. In patients with long-lasting remission after initial treatment, re-challenge with a HD-MTX–containing chemotherapy should be considered. ^, If HDC-ASCR was not attempted as a consolidation therapy, it may be offered upon relapse.

Several newer strategies have emerged in recent years. Immunotherapy using single agent PD1 inhibitors or combination immunotherapy using a CD20 inhibitor (e.g., rituximab) and a PD1 inhibitor (e.g., nivolumab, pembrolizumab) is an approach under investigation. ^, The immunomodulatory agents lenalidomide and pomalidomide have activity against progressive PCNSL. ^, Ibrutinib, a Bruton tyrosine kinase inhibitor, also has activity against progressive PCNSL. ^, Other single agents or combinations with modest efficacy include temozolomide (with or without rituximab), topotecan, pemetrexed, bendamustine, ifosfamide/etoposide, cisplatin/cytarabine, buparlisib, and intraarterial carboplatin. Although rituximab has limited penetration across the BBB, intrathecal administration somewhat surprisingly can yield parenchymal responses. Chimeric antigen receptor (CAR) T-cells penetrate the CNS, and responses have been observed in secondary CNS lymphoma patients (see Chapter 30 for discussion of CAR T cells). Trials of this strategy for progressive PCNSL are expected in the near future. Because the efficacy of WBRT at relapse is comparable with that when employed as initial therapy, most experts reserve WBRT for patients in whom medical salvage treatment fails.

Approach to PCNSL with leptomeningeal involvement

Leptomeningeal dissemination occurs in 11–42% of patients with PCNSL. ^, Patients with leptomeningeal PCNSL may present with multifocal symptoms, headaches, cranial nerve palsies, and spinal radiculopathies but often present without localizing symptoms. , Primary leptomeningeal lymphoma (PLML) without synchronous parenchymal brain/spine or systemic disease is rare and constitutes about 7% of PCNSL cases.

Contrast-enhanced MRI of the entire neuraxis to define total tumor burden should be performed before initiating treatment. If a patient has already been diagnosed with PCNSL and imaging reveals classic leptomeningeal enhancement, the diagnosis of leptomeningeal lymphoma can be made and CSF sampling can be deferred. Otherwise, histologic confirmation by CSF sampling is essential. CSF should be sent for cytology, flow cytometry, and ideally review of an unfixed, stained sample by a hematopathologist. Repeat sampling with the addition of gene rearrangement studies can be performed if the initial sample is suspicious but nonconfirmatory.

In PLML, the CSF profile is always abnormal, and findings may include leukocytosis, elevated protein concentration, and hypoglycorrhachia. Definitive diagnosis may be established by detection of malignant lymphocytes on cytology, or a monoclonal population by flow cytometry or gene rearrangement studies, which may be more sensitive. Despite the afore mentioned workup, the confirmation of the diagnosis by CSF sampling is sometimes not possible. If the suspicion remains high, diagnosis is sometimes possible with a meningeal biopsy from an enhancing area on MRI.

A high rate of false-positive and false-negative results has been reported in CSF studies in PCNSL with leptomeningeal involvement. ^, False-negative results can be avoided by collection of high volumes (e.g., at least 10 mL), withholding of corticosteroids before the procedure, and prompt transfer of samples to the laboratory for analysis to preserve integrity of the sample. ^, Demonstration of T-cell receptor gene rearrangement may help differentiate true T-cell lymphoma from reactive T lymphocytes, which may accompany a B-cell malignancy. ^,

The impact of leptomeningeal involvement on prognosis has been reported inconsistently in the literature, with some studies associating it with a worse outcomes and other analyses showing no significant differences in prognosis between PCNSL patients who present with or without leptomeningeal dissemination. ^,

Current guidelines of the National Comprehensive Cancer Network (NCCN) recommends treatment with intrathecal MTX, cytarabine, or rituximab in cases of positive CSF studies or meningeal enhancement on MRI. In patients with obvious meningeal enhancement, intrathecal chemotherapy may have limited efficacy due to its very shallow penetration into the meninges. A significant toxicity of intrathecal chemotherapy is leukoencephalopathy (see Chapter 27 , Case 27.5 for further discussion of approach to treatment-induced leukoencephalopathy). Radiation therapy could be considered for the unusual patient in whom deficits and sites of disease are focal and chemotherapy by any route is not an option.

Bing-Neel syndrome

Bing-Neel syndrome (BNS) is a CNS complication of Waldenström macroglobulinemia (WM), a B-cell lymphoproliferative disorder characterized by the presence of a serum IgM paraprotein associated with bone marrow infiltration by lymphoplasmacytic lymphoma. Extranodal involvement of WM is exceedingly uncommon, and in BNS, malignant lymphoplasmacytic cells invade the CNS. In the most common form, lymphocytes invade the leptomeningeal sheaths and perivascular spaces; it thus appears as enhancement and/or thickening of the meninges. A less common tumoral form presents as an intraparenchymal mass.

The clinical symptoms of BNS are diverse and may include headaches, cognitive deficit, cranial nerve palsies, and gait disorders. The diagnosis of BNS is usually made within months after confirming the diagnosis of WM, yet it may be found in patients in whom a diagnosis of WM has not been made on presentation in up to one-third of cases. ^, BNS should be suspected in any WM patient with neurological manifestations. These symptoms and signs, however, could also result from neurological complications of WM caused by IgM deposition centrally leading to hyperviscosity syndrome, or deposition peripherally causing a demyelinating peripheral neuropathy. Some references divide BNS into type A, where the symptoms are caused by lymphoplasmacytic infiltration into the CNS, and type B, where the symptoms are explained by IgM deposition. Patients with either presentation should undergo contrast- enhanced MRI of the brain and spinal cord where BNS typically presents as thickening and enhancement of cranial nerves or the cauda equina. Less commonly, a tumoral form occurs and is most commonly seen in the deep subcortical parenchyma.

Treatment should be offered to symptomatic patients with BNS. Because BNS is an indolent disease, asymptomatic patients may be monitored every 2–3 months off treatment. The goal of therapy is to treat the neurological symptoms. Treatment is guided by the clearance of neurological symptoms even if the disease is detectable by CSF analysis or radiological evidence.

Like other lymphomas, BNS responds to corticosteroids, yet the effect is short-lasting. Corticosteroids should be reserved for rapid relief of symptoms after histopathologic confirmation of the diagnosis if possible. Overall response to first-line therapy is about 70% according to retrospective data, with no significant difference between different systemic therapeutic agents. ^, Treatment options for BNS are mostly adapted from PCNSL treatment. Patients with isolated meningeal involvement may be treated with intrathecal treatment alone. Other options include HD-MTX, high-dose cytarabine fludarabine, cladribine, bendamustine, or ibrutinib. Rituximab is often added to treatment regimens, with no clear evidence supporting its benefit. Although BNS is radiosensitive, radiation therapy is not recommended as first-line regimen; it may be offered to patients for whom other treatments have failed, or patients with localized symptomatic spinal disease. In case of relapse, challenging with the same therapeutic agent may be considered if the initial response was complete and long standing.

Primary T-cell CNS lymphoma

T-cell primary CNS lymphoma (TPCNSL) is a rare form of PCNSL and comprises 2 to 8.5% of cases, with higher incidences reported in eastern countries such as Japan and Korea. ^,

Of note, B-cell lymphomas are often infiltrated by T-cells, which may complicate the interpretation of immunophenotyping. Therefore, reactive T-cells in a B-cell tumor must be distinguished from a true T-cell lymphoma. This is especially true if a biopsy is collected after corticosteroid treatment, which would cause lysis of B-cells and the collection of reactive T-cells. This distinction can be made with immunohistochemical staining and PCR for TCR gene rearrangement. ^, The clinical picture and treatment modalities for T-cell PCNSL is similar to DLBCL with similar agents used in treatment, with the exception of rituximab, which is used only for B-cell malignancies that express CD20.

Diagnosis and management of neurological complications of treatment for PCNSL

With the improvement in survival of patients with PCNSL, complications of treatment are more commonly observed and require significant attention. Treatment-related neurotoxicity is defined as progressive neurological or cognitive impairment noted on serial examinations in the absence of lymphoma recurrence. Although it is classically considered a late complication of PCNSL treatment, some studies suggest that leukoencephalopathy may begin within weeks after treatment completion.

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  Whole-brain radiation therapy (also see Chapter 25 for discussion of radiation-induced neurocognitive dysfunction). WBRT alone or with systemic chemotherapy is a significant risk factor for the development of late neurotoxicity, with patients over 60 years of age being at higher risk. Common symptoms and signs include deficits in attention, memory, executive function, gait ataxia, and incontinence. The MMSE is commonly used on follow-up to screen for neurotoxicity but has a low sensitivity for the detection of all of the symptoms of neurotoxicity. The actual incidence of neurotoxicity may thus be underestimated. A more detailed assessment such as a neuropsychologic evaluation usually reveals a more significant reduction in cognitive and psychomotor function in addition to a reduction in overall quality of life after early WBRT. Periventricular white matter changes, ventricular enlargement, and cortical atrophy are common radiologic findings. In addition to demyelination and neuronal loss, pathologic studies suggest a possible vascular component. Although reduced-dose WBRT is associated with milder cognitive dysfunction among PCNSL survivors compared with standard-dose WBRT, reduced dose WBRT as consolidation is still associated with impairments of verbal memory and motor speed. ^,

  
  
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  High-dose methotrexate (also see Chapter 27 for discussion of complications of systemic chemotherapy). Neurologic toxicity of HD-MTX can consist of stroke-like symptoms, an acute or subacute encephalopathy, and in the long term, a delayed multifocal leukoencephalopathy. PCNSL patients treated with HD-MTX–based therapies without consolidative WBRT do not appear to exhibit severe cognitive dysfunction as determined by posttreatment neuropsychologic testing but nevertheless score lower than normative control subjects in several cognitive domains.

  
  
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  Other chemotherapeutics (also see Chapter 27 ). Other chemotherapeutic agents can cause neurotoxicity. Rituximab uncommonly causes reactivation of John Cunningham (JC) virus leading to progressive multifocal leukoencephalopathy. Vincristine neurotoxicity most commonly presents as a peripheral neuropathy, which can be severe, necessitating discontinuation of the drug. Vincristine should be stopped at the first manifestation of neuropathy, as this toxicity is cumulative and often permanent. Less common neurological toxicities include autonomic neuropathy, cranial nerve palsies, gait disorders, and encephalopathy. Cytarabine can cause an acute cerebellar ataxia. Unfortunately, there are no known protective measures or treatments for the effects of iatrogenic neurotoxicity in PCNSL, although patients who receive WBRT for brain metastases benefit from the addition of memantine. Memantine could be considered for patients who require WBRT.