Neurologic Complications of Cancer

ORIGINAL ARTICLE
Neurologic Complications of Cancer

Part 2: Vascular, Infectious, Paraneoplastic, Neuromuscular, and Treatment-Related Complications
Erol Tasdemiroglu, MD,* Ahmet Hilmi Kaya, MD,* Sirzat Bek, MD, Canan Bolcu Emir, MD, Ahmet Sengoz, MD,* Ozgur Kilickesmez, MD, and Ilknur Mansuroglu, MD*
Abstract: Neurologic complications related to cancer and its

therapy are increasing because of increasing survival and therapeutic modalities in patients with cancer. To deal with such complications requires familiarity with them and knowledge of pathophysiologic events underlying cancer. The vascular, infectious, paraneoplastic, neuromuscular, and treatment-related neurologic complications of cancer are discussed in this article. Key Words: cancer, cerebrovascular, infectious, neurological complications (Neurosurg Q 2004;14:133153)
CEREBROVASCULAR COMPLICATIONS OF CANCER

Cerebrovascular events are well-known complications of cancer during its progression and therapy. Pathologic processes underlying cancer such as coagulopathy, tumoral or infectious emboli, tumoral infiltration, infectious vasculitis, and mycotic aneurysm, as well as cerebrovascular events related to surgical intervention, radiotherapy, and chemotherapy may occur,1,2 and these processes, in turn, are likely to cause hemorrhagic and ischemic insults to the central nervous system (CNS).
Pathophysiologic Considerations
Susceptibility of patients with cancer to systemic coagulopathy is proven and is mostly related to the complex influences of tumoral procoagulant substances, immature neoplastic blood vessels, hematopoietic growth factors, hormones, chemotherapy, and surgical intervention.3,4 Acute dissemiFrom the *Neurosurgery Clinic, Institute of Social Security, Istanbul Hospital, Istanbul, Turkey; Neurosurgery Clinic, Institute of Social Security, Okmeydani Hospital, Istanbul, Turkey; Neurology Clinic, Institute of Social Security, Okmeydani Hospital, Istanbul, Turkey; and Radiology Clinic, Institute of Social Security, Istanbul Hospital, Istanbul, Turkey. Reprints: Erol Tasdemiroglu, MD, Incirli Caddesi, Deniz Apartment 74/7, Bakirkoy, Istanbul 34740, Turkey (e-mail: ahmethilmikaya@yahoo.com). Copyright 2004 by Lippincott Williams & Wilkins
nated intravascular coagulation (DIC) is usually reported with cancer and occurs symptomatically in up to 68% of solid tumors.5 DIC is mainly caused by excessive thrombin production and secondary consumption of platelets, coagulation factors, and inhibitors of coagulation. It is relatively common in acute leukemia, and the predisposing factors are administration of chemotherapy (increased tumor cell lysis), liver metastasis (decrease in clotting factor), and thrombocytopenia (bone marrow infiltration, chemotherapy, and radiotherapy).1 Clinical signs are usually acute but may be gradual in onset and include headache, vomiting, and encephalopathy. Computerized tomography (CT) and magnetic resonance imaging (MRI) are precise diagnostic tools. Multiple hemorrhages are characteristically associated with severe thrombocytopenia, whereas solitary hemorrhages occur with DIC.1 Laboratory findings of DIC include low platelet and fibrinogen levels, elevated prothrombin and activated partial thromboplastin time, increased fibrin split products, and D-dimer. Peripheral schistocytes are another valuable finding. Treatment of acute DIC is controversial and includes treatment of underlying tumor; management of underlying infection; and replacement of clotting factors with freshfrozen plasma, cryoprecipitate, and platelets. Heparin administration is another choice, especially to stop the thrombotic process. The evacuation of hematoma is usually not possible because of uncontrollable bleeding, and conservative measures take precedence.6 Nonbacterial thrombotic endocarditis is a specific manifestation of systemic coagulopathy and is characterized by the occurrence of sterile plateletthrombin vegetations on cardiac valves. The effects of these cardiac vegetations on cerebral infarction are well established in postmortem studies7,8 and are mostly seen in patients with carcinoma of the lung and gastrointestinal tract and lymphoma.9 Isolated cerebral intravascular coagulation of small vessels in the brain is relatively well described with breast cancer, leukemia, and lymphoma, and widespread metastasis is another manifestation of clinically silent thrombotic coagulopathy, which is diagnosed mainly at autopsy.8,10 Another striking pathologic finding related to co-
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agulopathy in patients with cancer is occlusion of the cerebral venous system, mostly the superior sagittal sinus, which is common in leukemia.11 The main pathologic finding in sinus occlusion is venous infarction, and this may lead to severe parenchymal hemorrhage. The tumor itself may infiltrate or compress the vascular structures. Compression of the superior sagittal sinus by a metastatic tumor or encasement of the carotid artery by a malignant tumor may lead to venous and arterial infarction, respectively.12 Leptomeningeal metastasis of cancer typically obliterates Virchow-Robin perivascular spaces and causes cerebral infarction.13 Intratumoral hemorrhage is reported as 14.6% in the literature,14 and brain metastasis of melanoma, germ cell tumors, thyroid tumor, hepatocellular tumor, and lung cancer are most concordant with intratumoral hemorrhage.15 Immature blood vessels that are susceptible to rupture, rapid tumor necrosis, and the invasion of vascular territory by tumor are all predisposing factors for intracerebral hemorrhage. Rarely, tumor emboli may invade the cerebral vasculature and lead to a neoplastic aneurysm that is located in distal arterial branches and may cause subarachnoid hemorrhage.16 Just as a dural metastasis may result in a subdural hemorrhage, a spinal tumor may result in a subarachnoid hemorrhage. Interestingly, cerebral arterial embolization of a large tumoral piece such as cardiac sarcoma or lung cancer may lead to cerebral infarction or transient ischemic attack.17,18 Infection is another typical cause of neurologic complications in patients with cancer. Immunosuppression related to tumor and therapy (eg, steroids, chemotherapy, antibiotics) renders these patients susceptible to systemic opportunistic infections, and, in turn, fatal septic fungal and bacterial embolization to the brain may ensue.19 A mycotic aneurysm of the cerebral arterial territory may also lead to fatal subarachnoid hemorrhage. Chemotherapy leads to systemic and cerebral thrombosis by means of endothelial injury, activation of clotting pathways, vasospasm, and vasculitis.4 It may induce fibrinolysis and lead to parenchymal hemorrhage in the brain.20 Radiation therapy is clearly responsible for stenosis of cerebral arterial territories of all sizes, ranging from carotid to small-sized distal vessels, in a slowly progressive manner.21,22 Rarely, some vascular malformations such as cavernomas are prone to hemorrhage after radiotherapy.23 Lastly, surgical interventions in patients with cancer may also lead to cerebrovascular complications such as vascular injury, traumatic aneurysms, and intracerebral hemorrhage.
Clinical Considerations
Almost the final representation of the various pathologic processes underlying the cerebrovascular complications of cancer is infarction or hemorrhage. The clinical picture ranges from focal neurologic signs such as aphasia and hemiparesis to general problems such as intractable seizures and coma.
Transient ischemic attack or infarction encountered in patients with cancer may be strongly associated with nonbacterial thrombotic endocarditis or a large metastatic embolus. As the first presenting sign of cancer, nonbacterial thrombotic endocarditis is usually encountered in advanced cancer and is more common after allogenic bone marrow transplantation (BMT).24 If the vascular occlusion is multifocal, progressive encephalopathy is more likely than the localized signs (eg, aphasia, hemiparesis) that are seen in focal occlusions.8 The most commonly seen cardiac tumor, sarcoma, may present with cerebral infarction, and early postthoracotomy cerebral infarction in lung cancer may signal tumoral embolism caused by manipulation of the lung.17,25 Rarely, cerebral embolization caused by mural thrombus as a result of doxorubicin-induced cardiomyopathy is also reported.26 CT and MRI are the best diagnostic tools in cerebral infarction, and echocardiography can be diagnostic for cardiac tumors. Anticoagulation therapy is the treatment of choice in these ischemic pathologic conditions, but treatment targeted to underlying cancer is the best approach with nonbacterial thrombotic endocarditis or tumoral embolization. Cerebral venous occlusion is not unusual in patients with cancer and is mostly associated with hematologic malignancies such as leukemia.11 The venous infarction may be accompanied by parenchymal or subarachnoid hemorrhage, and the clinical findings include headache, seizure, focal signs, and encephalopathy. Leptomeningeal metastasis, tumoral infiltration, or compression to the superior sagittal sinus and chemotherapy with L-asparaginase are also responsible for cerebral venous thrombosis. The clinical findings in L-asparaginase related occlusion characteristically occur in the third and fourth weeks of therapy.27,28 Contrast-enhanced CT may detect venous sinus thrombosis with the empty delta sign, which is a triangle of decreased density seen in the posterior portion of the affected sinus, or MRI may show a flow defect within the sinus.29 Treatment in tumor-related venous occlusion is usually radiation therapy, but surgical resection is preferred in some cases. Fungal sepsis leading to septic embolization to the brain is rather common, especially in patients with leukemia or in those who have undergone BMT.19 Aspergillus and Candida are usually the responsible agents, and seizure, focal neurologic signs, and encephalopathy are typical clinical findings. Signs of meningitis are not always present, and multiple brain infarctions with or without hemorrhage are frequent on neuroradiologic examination. The clinical course depends on the response to antifungal therapy but is usually progressive and fatal. The increased risk of stroke in patients undergoing radiation therapy is well known, and Doppler ultrasound is a good screening method for these patients.22,30 Endarterectomy and stenting may be satisfactory treatments for radiation 2004 Lippincott Williams & Wilkins
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induced carotid stenosis, but preventive measures are unknown.31 Intracranial hemorrhage, including parenchymal, ventricular, subdural, and subarachnoid spaces, are other complications of cancer. These hemorrhagic coagulopathies usually present with an abrupt onset and are fulminant and fatal. DIC is one of the leading causes of such hemorrhagic events. Its symptomatic prevalence in patients with solid tumors is reported as 6.8%.5 Other causes of bleeding diathesis in cancer patients such as liver metastasis, bone marrow infiltration, thrombocytopenia, and infection also aggravate DIC. Intracranial hemorrhages are more common in leukemia, especially of the myelogenous type, than in solid tumors and lymphoma. Intratumoral bleeding in brain metastasis, especially of melanoma, germ cell tumors, thyroid tumor, hepatocellular tumor, and lung cancer, is possible, and the enhancement adjacent to hemorrhage in neuroradiologic examination is an important diagnostic finding.14 Steroid therapy and surgical intervention are major treatment modalities in this circumstance. Tumoral and infectious embolic aneurysms are other important lesions having the potential risk of subarachnoid hemorrhage in patients with cancer.16 These aneurysms are generally located in more distal parts of the cerebral arterial territory, and angiography is the gold standard in their diagnosis. Carcinoma of the breast, prostate, and gastrointestinal tract as well as lymphoma and leukemia have an affinity for dural metastasis, and subdural hemorrhage is possible in these circumstances.1 Surgical resection or drainage of subdural hematoma, followed by irradiation, is the preferred treatment modality at this time. In conclusion, patients with cancer are likely candidates for major cerebrovascular complications such as cerebral infarction and cerebral hemorrhage. The prompt diagnosis and treatment of complications depend on familiarity with these pathologic processes and close follow-up of the patients.
Pathophysiologic Considerations
Because the infections are related to the attenuated immunologic status in patients with cancer, the infectious agents include many organisms normally having low pathogenicity in the intact host, and infection with more than 1 agent is not unusual. Up to 40% of patients with cancer having CNS infection were reported as having extraneural infection with an organism different from that infecting the CNS.36 Infection in patients having cancer may be subclinical because of a diminished inflammatory response and coexisting metabolic abnormalities obscuring the clinical picture. Therapy in CNS infection is challenging because of the many factors affecting efficacy such as the bloodbrain barrier, lipid solubility, and the neurotoxicity of anti-infectious agents. These characteristics of cancer and the CNS constitute the major problems to curative therapy.37 Surgical intervention, radiation therapy, a central line, and monitoring devices all breach the natural skin barrier. Chemotherapeutic agents may easily disrupt the mucous membrane. These initial therapeutic maneuvers can easily supply a port of entry for common infectious agents such as Staphylococcus aureus and Staphylococcus pneumoniae in patients with cancer.38 The single most important determinant of a patients susceptibility to bacterial and fungal pathogens is the absolute granulocyte count (AGC).2 A deficit in neutrophil function or number, especially below 500 neutrophils/mm3, renders a patient susceptible to bacteria derived from the skin and gastrointestinal and respiratory tracts as well as to Aspergillus and Candida fungal infections.2,37 Patients with leukemia usually have a risk of neutropenia because of bone marrow invasion, intensive chemotherapy, and radiation therapy. Impaired B-lymphocyte and immunoglobulin capacity in patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and other blood dyscrasias may easily result in infection with encapsulated bacterial organisms such as Haemophilus influenzae and S. pneumoniae. Lymphoreticular malignancies, chronic corticosteroid therapy, and cytotoxic drugs may lead to severe CNS infections by impairing T-cell mediated immunity; these are usually viral infections, fungal infections (Cryptococcus neoformans), and infection related to intracellular pathogens (Listeria monocytogenes).37 Another potential risk of infection in patients with cancer is BMT.39 Patients who undergo BMT are severely granulocytopenic for approximately 1 month until the new marrow begins to function, and additional immunosuppressive therapy in these patients multiplies the risk. Three major periods for posttransplantation infections are categorized.35,38 During the first posttransplantation month, the patient is exposed to infection with common bacterial pathogens and opportunistic infections such as Aspergillus, Mycobacterium tuberculosis, and S. stercoralis; from 1 to 6 months after transplantation, the pa-
INFECTIOUS COMPLICATIONS OF CANCER IN THE CENTRAL NERVOUS SYSTEM

Infection is one of the leading causes of morbidity and mortality in patients with cancer.32 In cancer, compromised mechanical barriers, quality and quantity of neutropenia, impaired cellular and humoral immunity, and splenic dysfunction are the main causes of increased susceptibility of patients to infectious complications.33 Moreover, treatment modalities used in cancer such as corticosteroids, antimetabolites, alkylating agents, radiation therapy and prolonged hospitalization, broad-spectrum antibiotic therapy, and BMT are other factors either suppressing polymorphonuclear, humoral, and cellmediated immunity or predisposing the patient to opportunistic infectious pathogens.34 The CNS is one of the major areas for these infectious complications, and one sixth of patients with CNS infection are reported as having an underlying malignancy.35
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tient is exposed to infection with Epstein-Barr virus (EBV), cytomegalovirus (CMV), Listeria, Aspergillus, and Nocardia because of intense immunosuppressive therapy; and after more than 6 months after transplantation, patient infections are common with Listeria, Nocardia, cryptococcal meningitis, and progressive multifocal leukoencephalopathy (PML) because of high-dose immunosuppressive maintenance therapy such as OKT-3 and antilymphocyte globulin. Some specific infections unique to BMT are also described.7,40,41 These include a fatal adenovirus meningoencephalitis possibly acquired from the infused marrow and human herpesvirus-6 variant B, which selectively involves the hippocampus, with clinical findings of short-term memory dysfunction, confusion, insomnia, and partial complex seizures. Posttransplantation lymphoproliferative disorders (PTLDs) may complicate BMT and are characterized by polyclonal B-cell infiltration of multiple organs, including the CNS, in 25% of cases.42 These disorders are believed to be triggered by infection of B lymphocytes with EBV and later aggravated by immunosuppressive agents such as cyclosporine and corticosteroids.
Clinical Considerations
Identification of the major immune deficiency and predicting the possible periods and possible causes of infection in patients with cancer are the main considerations in CNS infection. During cancer and its therapy, as infection becomes likely, the immunologic responses become blunted because of immunosuppressive regimens. Thus, familiarity with clinical findings of infections in patients with cancer is the most important step in diagnosis and therapy. The three most common syndromes of CNS infection are acute meningitis syndrome, progressive focal or multifocal deficits, and an aseptic meningitis syndrome.37 The presence of focal neurologic deficits with ring enhancement in the radiologic examination discloses a brain abscess possibly associated with conventional bacterial pathogens or Aspergillus, Toxoplasma, tuberculosis, or Nocardia. Extraneural infection sites may help to eliminate the responsible pathogen; a patient with a CNS mass lesion with pulmonary abnormalities may have Aspergillus or Nocardia infection, whereas a patient with meningitis and pulmonary abnormalities is likely to have cryptococcal meningitis. Single or multifocal progressive deficits without radiologic enhancement are usually consistent with PML. A stroke-like syndrome in cancer may be caused by infections such as endocarditis, Listeria, or vasculitis associated with varicella-zoster virus (VZV) infection.37 Aseptic meningitis syndrome can be caused by many agents ranging from viruses (eg, enterovirus, herpes virus, VZV, EBV) to partially treated bacterial meningitis and specific agents (eg, S. pneumoniae, M. tuberculosis, Borrelia burgdorferi, Treponema pallidum, C. neoformans, H. capsulatum, C. immitis, Toxoplasma gondii) and is generally characterized by mild headache, meningismus, change in mental status, mild lymphocytic
pleocytosis with normal glucose, and mild to moderate elevation of protein in cerebrospinal fluid (CSF). L. monocytogenes is one of the leading cause of meningitis, especially in patients with a solid or hematologic malignancy who received immunosuppressive therapy.43 Febrile syndrome associated with gastroenteritis in 16% of cases is a common presentation,44 and brainstem rhombencephalitis with pontine and medullary signs may occur in 9% of patients.45 A CNS abscess in listeriosis was also described, but contrary to the case with a bacterial abscess, antibiotic therapy was reported as successful without surgical intervention. In case of suspicion of this organism, penicillin must be part of initial coverage, and trimethoprim sulfamethoxazole is another choice of therapy. Nocardial infection of the CNS originates from a pulmonary source and is characterized by a single or small number of brain abscesses. Conservative treatment with trimethoprim sulfamethoxazole is usually successful.46 Cryptococcal infection was reported as responsible for one third of CNS infections in cases of cell-mediated immunity defects, mostly related to immunosuppressive therapy of more than 6 weeks duration.36 C. neoformans especially occurs in immunocompromised hosts such as patients with HIV infection or those receiving long-standing corticosteroid therapy.47 The usual symptoms are headache, meningeal symptoms, and, rarely, focal infarctions. Diagnosis is easily made by detection of cryptococcal antigen, and high titers strongly correlate with the prognosis. A triple-therapy regimen, including an induction phase with amphotericin B or AmBisome, with or without flucytosine, for 2 weeks, followed by fluconazole or itraconazole for 8 to 10 weeks and then fluconazole for an additional 6 months, is used for cryptococcal meningitis, and it improves survival, although morbidity remains high.48 Neutrophil and macrophage deficits, high-dose corticosteroid therapy, chemotherapy, broad-spectrum antibiotics, and concurrent CMV infections are all risk factors for susceptibility to spores and hyphae of Aspergillus, and CNS infection with this agent is almost always associated with invasive pulmonary disease.37 Affinity for the blood vessels at the circle of Willis leading to multiple small hemorrhagic infarctions and subarachnoid hemorrhages is typical, but antemortem diagnosis is difficult in this instance. Amphotericin B and flucytosine therapy with surgical intervention for infectious masses is possible, but the prognosis remains poor.48 Candida species, especially Candida albicans, are part of normal human microbial flora, and infection is usually related to catheters (particularly the parenteral type), operations (mostly gastrointestinal), and several weeks of antibiotherapy.37 The most common manifestation is meningitis, sometimes with skull infiltration and cranial nerve palsies. Removal of risk factors such as catheters, drains, and shunts is an important part of the therapy.
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Invasion of the CNS by organisms such as Mucorales or Zygomycetes via the orbit and paranasal sinuses in patients with hematologic malignancies or in those receiving steroid therapy is not rarely encountered and is characterized by nasal discharge, orbital and facial pain, and CNS masses imitating Aspergillus masses.37 Neurosurgical intervention to obtain biopsy tissue is critical for diagnosis, and treatment with amphotericin B is reported as effective in controlling the disease. Viral infections are other offending causes of morbidity and mortality in cancer. Human herpes viruses are the most common among them. As previously mentioned, human herpesvirus-6 variant B is unique for patients undergoing BMT.40,41 Selective involvement of the hippocampus is easily established with hyperintensity on T2-weighted MRI and is clinically characterized by short-term memory dysfunction, confusion, insomnia, and temporal lobe epilepsy. Detection of human herpesvirus-6 DNA in CSF by polymerase chain reaction (PCR) is diagnostic. Aggressive treatment of seizures and antiviral therapy are the only choices. Diagnosis of herpes simplex encephalitis is another problem in patients with malignancy, and differentiation from limbic encephalitis, VZV, CMV, Listeria, and toxoplasmosis is difficult.49 Use of PCR technology is the definite method of diagnosis, and therapy with acyclovir is the only choice. VZV infection may accompany malignancy as a localized condition (shingles or dermatomal VZV), focal segmental motor weakness, or reactivating VZV without rash or may be disseminated to the brain such as in acute necrotizing encephalitis or a multifocal stroke-like picture with little inflammation.37 Brain biopsy is important in the diagnosis, because VZV is a potentially treatable condition, but VZV DNA detection in CSF may also be useful.50 Acyclovir is the choice of therapy. EBV-related PTLDs involve clonal B-cell infiltration of multiorgan systems, including the CNS in 25% of cases, with clinical findings of altered mental status and systemic viral syndrome.42,51 MRI may reveal periventricular and variably enhancing white matter nodules and leptomeningeal spread in 25% of cases. A CSF examination for EBV by PCR may be helpful, but biopsy may be necessary for definitive diagnosis. Reduction of immunosuppression, radiotherapy, or chemotherapy is the choice, but the 2-year survival rate is only 30%. Retinitis with or without associated encephalitis is the most common neurologic manifestation of CMV in patients with cancer.37 Radiculomyelitis involving the cauda equina, cranial nerves, or brachial plexus is another rare manifestation, and extraneural clues for EBV infection are acute monoarticular arthritis, hepatitis, infectious mononucleosis-like syndrome, myocarditis, and pneumonia. Diagnosis by PCR is possible, and significant improvement may occur with ganciclovir and foscarnet therapy. Jacobs-Creutzfeld (JC) virus of the papovavirus family is responsible for PML in patients with cell-mediated immu 2004 Lippincott Williams & Wilkins
nity deficits.52 PML is a subacute demyelinating disease characterized by progressive dementia or slowly progressing focal deficits mimicking a mass lesion. Cortical blindness, anosognosia, and hemianopsias are possible findings, and PCR can be used to detect JC virus genome with a sensitivity of 75%.53 It is usually fatal within months, whereas reduction of immunosuppression may help to control clinical and radiographic regression. Controlled clinical trials are currently evaluating some drugs for therapy for JC virus, and these drugs include inhibitors of DNA topoisomerase activity such as camptothecin.54 In summary, infectious pathogens are more widespread and diagnosis of infection is more difficult in patients with cancer than in normal hosts because of immunosuppression. Thus, consideration of a patients immune status, awareness of infective manifestations, familiarity with the characteristics of malignancy and its therapy, and establishment of laboratory and radiologic studies are important steps in managing infectious complications of cancer.
PARANEOPLASTIC NEUROLOGIC SYNDROMES

Paraneoplastic neurologic syndromes (PNSs) are disorders of nervous system function that cannot be ascribed to metastases or nonmetabolic complications such as coagulopathy and cerebrovascular disorders, infections, metabolic and nutritional deficits, and side effects of cancer treatment.55 Mild PNSs and electrophysiologic abnormalities unrelated to iatrogenic effects of cancer therapy, weight loss, or metabolic abnormalities have been reported in 10% to 50% of cancer patients. The importance of identifying PNS is 3-fold: 1. PNS may involve any part of the CNS or peripheral nervous system and may mimic many cancer-related or -unrelated neurologic complications. 2. In approximately 60% of the patients, the PNS develops before the presence of a tumor is known. Most of these symptoms have a minimal impact on the quality of life of the patient or are overshadowed by tumor-related symptoms or side effects of cancer therapy. The incidence of PNSs with a major impact on the quality of life of the patient is probably less than 3% for all types of cancer and 30% for patients with thymoma.56 Therefore, recognition of a disorder as paraneoplastic avoids unnecessary diagnostic tests and often leads to earlier tumor diagnosis. 3. Prompt diagnosis and treatment of the tumor is the best therapeutic approach to improve or at least stabilize the neurologic syndrome. There is extensive evidence that many PNSs of the nervous system are mediated by immunologic responses against onconeuronal antigens. According to the immunologic mechanisms involved, PNSs can be divided into 4 categories: group 1antibody-mediated disorders (eg, Lambert-Eaton myasthenic syndrome [LEMS], myasthenia gravis, neuromyasthenic disorders), group 2likely mediated by cytotoxic T cells (eg, cerebellar degeneration, encephalomyelitis, Stiff-
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man syndrome, brainstem encephalitis), group 3mediated by direct synthesis of IgM by tumor CNS (peripheral neuropathy), and group 4without specific antibodies (eg, dermatomyositis, acute necrotizing myopathy, vasculitis of the nerve and muscle). For clinicians, a practical implication is that these immunologic disorders frequently are associated with antibodies that are excellent diagnostic markers of paraneoplastic disease (PND) and cancer (Table 2). A second implication is that prompt detection and treatment of the tumor (which initiates the immunoresponse) is the most efficacious therapeutic approach, sometimes leading to stabilization of the PNP.5759 The diagnosis of PNS primarily depends on the system involved. If symptoms involve the muscle, neuromuscular junction, or nerve, the diagnosis of a specific neurologic disorder (ie, LEMS, dermatomyositis) usually is established by clinical, electrophysiologic, or pathologic studies. If symp-
TABLE 1. Paraneoplastic Syndromes of the Nervous System Paraneoplastic syndromes of the brain and cerebellum Focal encephalitis and myelitis Cortical encephalitis Limbic encephalitis Brainstem encephalitis Cerebellitis Encephalomyelitis Cerebellar degeneration Opsoclonus-myoclonus Paraneoplastic syndromes of the spinal cord Stiff-man syndrome Myelitis Acute necrotizing myelopathy Motor neuron disease Subacute motor neuronopathy Paraneoplastic syndromes of the dorsal root ganglia and nerve Sensory neuropathy Peripheral neuropathies Subacute axonal or demyelinating neuropathies Vasculitis of the nerve and muscle Peripheral neuropathies of monoclonal gammopathies Guillain-Barre syndrome and brachial plexitis Neuromyotonia Autonomic neuropathy Paraneoplastic syndromes of the neuromuscular junction Lambert-Eaton myasthenic syndrome Myasthenia gravis Paraneoplastic syndromes of the muscle Polymyositis/dermatomyositis Acute necrotizing myopathy Carcinoid myopathy Myotonia
toms involve the dorsal root ganglia (neuronopathy) or other parts of the CNS (spinal cord or brain), the diagnosis of the neurologic syndrome (ie, myelitis, limbic encephalomyelitis) usually is based on a combination of clinical, radiologic, and CSF studies. MRI studies of the brain and spinal cord are important to rule out cancer-related or -unrelated complications, particularly metastatic disease. CSF studies are important for ruling out other cancer-related or -unrelated complications, including infections and leptomeningeal metastasis. Paraneoplastic syndromes of the brain and cerebellum consist of encephalomyelitis, cerebellar degeneration, and opsoclonus-myoclonus. Encephalomyelitis is characterized by multiple neurologic symptoms as a result of an inflammatory disorder that may involve any part of the CNS, dorsal root ganglia, or autonomic nerves.60 Encephalomyelitis includes any combination of cortical encephalitis, limbic encephalitis, brainstem encephalitis, cerebellitis, and myelitis, with frequent symptoms of autonomic dysfunction and sensory neuropathy. The tumor is usually associated with paraneoplastic encephalomyelitis, and the sensory neuropathy is small cell lung cancer (SCLC). Anti-Hu is the most useful antineuronal antibody for the diagnosis of focal encephalitis or encephalomyelitis associated with SCLC. The treatment of paraneoplastic encephalomyelitis and sensory neuropathy is based on prompt detection and treatment of the tumor, which is usually SCLC. Minimal response to steroids, intravenous immunoglobulin (IVIG), and plasma exchange have been reported.61 In patients with anti-Hu antibodies, neurologic dysfunction is a frequent cause of death.62 Paraneoplastic cerebellar degeneration is the most common paraneoplastic syndrome that affects the brain. The disorder may complicate any malignant tumor, but lung, ovary, or breast cancer and Hodgkin and non-Hodgkin lymphoma are the tumors most frequently involved. The main pathologic findings are loss of Purkinje cells and inflammatory infiltrates in the deep cerebellar nuclei.63 Dizziness, nausea, vomiting, gait and limb ataxia, diplopia, and dysarthria are the most common symptoms and findings. The typical clinical presentation of paraneoplastic cerebellar degeneration is almost pathognomonic. When atypical, the disorder must be distinguished from primary or metastatic cerebellar tumor (by MRI), leptomeningeal metastases (by contrast MRI and CSF examination), nonparaneoplastic cerebellar degenerative disorders, cerebellar hemorrhage, infarction or abscess, demyelinating disorders, and metabolic disorders (eg, alcoholic degeneration).The treatment of this syndrome is similia to that of other PNDs of the CNS, including prompt detection and treatment of the tumor. Immunotherapy has showed limited usefulness. Paraneoplastic opsoclonus is a disorder of ocular motility characterized by involuntary chaotic saccades that occur in all directions of gaze. The disorder is frequently associated
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TABLE 2. Antibodies Associated With Paraneoplastic Syndromes Antibody Anti-Hu Anti-Yo Anti-Ri Anti-Tr Anti-CV2 or anti-CRMPI-5 Anti-Ma proteins Anti-amphysin Anti-VGKC Anti-VGKC Antiacetylcholine receptor Associated Cancer SCLC, other Gynecologic, breast Breast, gynecologic, SCLC Hodgkin lymphoma SCLC, other Testicular germ cell tumors and other cancers Breast, SCLC Thymoma, others SCLC Thymoma Syndrome Focal encephalitis, myelitis, sensory neuronopathy, peripheral neuropathy Cerebellar degeneration Cerebellar ataxia, opsoclonus, brainstem encephalitis Cerebellar degeneration Focal encephalitis, myelitis, cerebellar degeneration, peripheral neuropathy Limbic, brainstem encephalitis, cerebellar degeneration Stiff-man syndrome, encephalomyelitis Neuromyotonia, limbic encephalitis LEMS, cerebellar degeneration Myasthenia gravis Test to Detect the Antibody and Specific Antigens IHC, IB, HuD, HuC, Hel-NI IHC, IB, CDR62 Peripheral neuropathy, NOVA1 IHC, antigen unknown IHC, IB CRMPI-5 IHC, IB Mal-3 IHC, IB amphysin Immunoprecipitation, VGKC Immunoprecipitation, P/Q-type VGCC Immunoprecipitation acetylcholine receptor
IB indicates immunoblot; IHC, immunohistochemistry.
with myoclonus and ataxia, and the tumors most frequently involved are lung and breast cancer in adults and neuroblastoma in children. Anti-Ri and, less frequently, anti-Hu and anti-Yo are the onconeural antibodies associated with this syndrome. Nearly 50% of children with this syndrome have a neuroblastoma, and approximately 2% of children with this tumor develop opsoclonus.64,65 The two most common PNSs with predominance of the spinal cord include the Stiff-man syndrome and myelitis. Stiffman syndrome is characterized by progressive rigidity and stiffness of the axial musculature, which is associated with painful spasms triggered by sensory and emotional stimuli.66,67 The severity of muscle spasms can result in bone fractures. The main autoantigen of paraneoplastic Stiff-man syndrome is amphiphysin, a protein involved in synaptic vesicle endocytosis. The tumors most frequently involved are cancer of the breast, lung, and colon and Hodgkin lymphoma. Steroids, diazepam, baclofen, sodium valproate, and treatment of the underlying tumor often result in neurologic improvement.
NEUROMUSCULAR COMPLICATIONS OF CANCER

Neuromuscular complications of cancer include disorders of peripheral nerves, the neuromuscular junction, and muscles. These disorders can be classified as a direct or paraneoplastic effect of a primary malignancy or as an iatrogenic effect of treatment. Primary malignancies can cause neuromuscular dysfunction as a result of invasion or compression of nerve roots, plexi, or peripheral nerves. Leptomeningeal car 2004 Lippincott Williams & Wilkins
cinomatosis is one of the most important examples of the direct effects of malignancy. Signs and symptoms of increased intracranial pressure, confusion, and nuchal rigidity can be the presenting features. Compression or invasion of the spreading tumor can result in polyradiculopathies or cranial neuropathies. Radicular pain is a common feature. When leptomeningeal carcinomatosis is suspected, the initial diagnostic procedure must be MRI with gadolinium, followed by lumbar puncture. In general, the prognosis is poor for patients with leptomeningeal carcinomatosis. Treatment includes irradiation and intrathecal chemotherapy. Metastatic tumor or irradiation can be the cause of brachial plexopathies. Breast and lung cancers are the most common responsible tumors. Symptoms include shoulder pain, lymphedema, and Horner syndrome.Upper trunk involvement is unusual and should raise the suspicion of epidural involvement. MRI of the brachial plexus and cervical cord as well as surgical exploration and biopsy is occasionally required for the differential diagnosis. 68 Lumbosacral plexopathy is more likely to result from direct extension of local tumor than from metastatic disease. The most commonly implicated tumors are colorectal cancer, cervical lymphoma, sarcoma, and breast cancer. Symptoms include pain, numbness, weakness, and edema of the lower extremities.69,70 Paraneoplastic sensory neuropathy results from dorsal root ganglionitis and is characterized by inflammatory infiltrates and neuronal degeneration of the spinal cord. The tumor most frequently associated with paraneoplastic sensory neuropathy is SCLC. A study showed that the sensitivity of antiHu antibodies for paraneoplastic sensory neuropathy is 82%, with a specificity of 99.8%. This disorder is associated with
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symmetric or asymmetric deficits of all types of sensory painful dysesthetic pain in any part of the body, including the face and trunk. Paraneoplastic syndromes of the peripheral nerves are divided into 5 groups: 1) subacute axonal or demyelinating peripheral neuropathies; 2) vasculitis of the nerve and muscle; 3) peripheral neuropathies associated with monoclonal gammopathies; 4) Guillain-Barr syndrome and brachial plexitis; and 5) neuromyotonia. Other forms of peripheral neuropathy more rarely complicate cancer. An acute motor polyneuropathy with clinical, pathologic, and CSF features typical of Guillain-Barr syndrome may complicate Hodgkin disease. The management of this disorder should be similar to that of noncancer-related cases, including plasma exchange or IVIG.71 Neuromyotonia (Isaac syndrome) is characterized by spontaneous and continuous muscle fiber activity, resulting in difficulty in muscle relaxation and cramps, motor weakness, and excessive sweating. The tumor most frequently involved is thymoma. Diphenyl-hydantoin, carbamazepine, and plasma exchange are treatment alternatives.72 LEMS and myasthenia gravis are typical examples of the paraneoplastic syndromes of the neuromuscular junction. LEMS is associated with cancer in 50% to 70% of patients. The tumor most commonly involved is SCLC, but lymphoma and other cancers have been reported.73,74 This disorder is characterized by proximal muscle weakness in the upper and lower extremities and autonomic dysfunction. After brief exercise, strength may improve.74 LEMS results from antibodies against the presynaptic P/Q type of voltage gated calcium channel (VGCC) that block the entry of calcium and interfere with the release of acetylcholine vesicles. Myasthenia gravis is a paraneoplastic manifestation of thymoma in approximately 10% of patients, and one third of patients with thymoma develop myasthenia gravis. Fatigue, diplopia, ptosis, dysarthria, neuromuscular respiratory failure, and weakness of the extremities are the symptoms.75 Patients who had a total thymectomy for thymoma can develop myasthenia gravis up to 6 years after surgery.76 Polymyositis and dermatomyositis are 2 different immunomediated inflammatory disorders of the muscle. Myalgias, proximal muscle weakness, dysphagia, neck flexor extensor muscle weakness, and respiratory muscle involvement are the features. There are no specific markers indicating whether or not polymyositis or dermatomyositis is paraneoplastic or idiopathica study found that 11% of patients with polymyositis and 16% of patients with dermatomyositis had cancer. In women, the most common tumors are breast and ovarian cancer; in men, lung and gastrointestinal cancer are the most common tumors. Neuromuscular complications of cancer are common and can affect any component of the peripheral nervous system from the peripheral nerve cell body to the muscle. Perhaps the most common complication is a length-dependent symmetric axonal polyneuropathy that is often multifactorial in cause, re-
sulting from metabolic and treatment effects of the primary malignancy. Neuromuscular disorders may also be the presenting complaint in many conditions, including disorders caused by malignant infiltration of nerve and disorders caused by paraneoplastic syndromes. Although many of the paraneoplastic neurologic conditions are poorly responsive to treatment, not all are, and one hopes that prompt diagnosis of the underlying malignancy will lead to an improved patient outcome. Recognition of iatrogenic neuromuscular complications is also important so as to modify treatment protocols when possible and thus decrease the risk of long-term neurologic disability.
THE LEUKEMIAS
Leukemias are malignant neoplasms of the bloodforming tissues. Although the causes leading to the disease have not been defined clearly, some viruses such as EBV and human T-cell lymphotropic virus, ionizing radiation, and some chemicals are associated with an increased risk of leukemia. Down syndrome and Fanconi anemia are predisposed to leukemia. Clinical and laboratory features of leukemia are caused by suppression of normal blood cell formation and organ infiltration. Inhibitory factors may suppress normal hematopoiesis. Anemia, thrombocytopenia, and granulocytopenia occur. Organ infiltration results in enlargement of the liver, spleen, and lymph nodes. Meningeal infiltration and direct parenchymal involvement are rare and are associated with increasing intracranial pressure. Recent advances in therapy for pediatric hematologic neoplasms have greatly improved the prognosis but have resulted in an increased incidence of associated complications and toxic effects. The main neuroimaging features in pediatric patients with leukemia or lymphoma treated with chemotherapy or radiation therapy were retrospectively reviewed. To simplify the approach and facilitate the differential diagnosis, the neuroimaging features have been classified into 3 main categories: CNS manifestations of primary disease, side effects of therapeutic procedures (radiation therapy, chemotherapy, and BMT), and complications caused by immunosuppression, particularly infections (Table 3). Manifestations of primary disease include cerebrovascular complications (hemorrhage and cerebral infarction) and CNS involvement (infiltration of the meninges, parenchyma, bone marrow, orbit, and spine). Effects of radiation therapy include white matter disease, mineralizing microangiopathy, parenchymal brain volume loss, radiation-induced cryptic vascular malformations, and second neoplasms. Effects of chemotherapy and BMT include hemorrhage, dural venous thrombosis, white matter disease, reversible posterior leukoencephalopathy syndrome, and anterior lumbosacral radiculopathy.77,78 Leukemias can be classified into several subgroups. Chronic myelogenous leukemia is characterized primarily by
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TABLE 3. Neurologic Complications of Leukemia Complications CNS manifestations of primary disease Cerebrovascular complications CNS involvement Results Hemorrhage Cerebral infarction Infiltration of the meninges Parenchymal involvement Bone marrow, orbit, and spine Transverse myeopathy Epilepsy Hydrocephalus White matter disease Mineralizing microangiopathy Parenchymal brain volume loss Radiation-induced cryptic vascular malformations Second neoplasms Hemorrhage Dural venous thrombosis White matter disease Reversible posterior leukoencephalopathy syndrome Anterior lumbosacral radiculopathy Central extrapontine myelinosis Neurotoxicity Second neoplasms Subarachnoid hemorrhage Moya-moyalike vasculopathy Reversible diffuse EEG slowing Psychiatric symptoms Multifocal leukoencephalitis Peripheral neuropathy Meningitis Ventriculitis
Side effects of therapeutic procedures
Radiation therapy
Chemotherapy and BMT
Complications caused by immunosuppression
Infections
an increased number of myeloid cells, typically 100,000 to 300,000 lymphocytes/L at diagnosis. Neurologic complications typically stem from hyperviscosity and intracerebral leukostasis. In chronic myelogenous leukemia after allogenic peripheral hematopoietic progenitor cell transplantation, central and extrapontine myelinosis has been reported.79 Acute leukemias are distinctive disorders characterized by massive and rapid proliferation of clonal immature white blood cells called blasts. Underlying chromosomal abnormalities are typically seen. Complications from acute leukemias, including neurologic ones, stem from anemia, thrombocytopenia, immunodeficiency, and leukostasis. Iatrogenic complications also occur from the intensive treatments used for acute leukemia. Acute myelogenous leukemia is a disease typically of the elderly. CNS complications are caused by hemorrhage, leukostasis, or leukemic infiltration of the CNS. The risk of hemorrhage is increased in patients with thrombocytopenia together with a coagulation disorder such as DIC. Risk of fatal hemorrhage, often intracerebral, is increased by thrombocytopenia, older age, anemia, and high blast counts. Symptoms of CNS leukostasis may occur despite attempts to lower the blast count. Lowering the blast count is most effectively achieved by
prompt treatment with aggressive chemotherapy. Approximately 5% to 7% of patients have cerebrospinal involvement with leukemic blasts at presentation. High blast counts, monocytic morphology, and high leukocyte dehydrogenase (LDH) predispose to CNS involvement. A patient may be asymptomatic, complain of headache, or have cranial neuropathies (typically facial weakness, facial paresthesias, or optic nerve infiltration and acute blindness). Individuals with CNS involvement who have circulating blasts greater than 50,000 lymphocytes/L are at risk for serious events related to hyperviscosity and leukemic small vessel emboli, which may manifest in intracerebral leukostatic hemorrhage. Median survival time after a diagnosis of CNS involvement in acute myeloid leukemia (AML) is 6 months, with death related to bone marrow failure from hematologic relapse. Acute lymphoblastic leukemia (ALL) is a disease typically seen in children. Although the CNS is rarely involved at presentation (less than 5% involvement in children and 15% in adults), without prophylactic treatment, unlike AML, most patients develop CNS disease with associated increased mortality risks. There has been much debate regarding prophylactic cranial irradiation in children with ALL. Radiation can put
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children at later risk for developmental delays as well as neurocognitive disorders and second malignancies. Infants diagnosed with ALL are at a particularly high risk for CNS disease; thus, they are treated with high-dose systemic methotrexate and intrathecal methotrexate and cytarabine. Involvement of the CNS is believed to occur through hematogenous seeding of the meninges. Neurologic involvement may manifest with signs of increased intracranial pressure such as headache, nausea and vomiting, mental status change, depressed level of consciousness, or papilledema. Cranial neuropathy may also be present. The median survival rate after the diagnosis of CNS leukemia in ALL is 8 months. Pagano et al80 describe 3 patients affected by AML in complete remission, who rapidly developed neurologic symptoms leading to death. Neither clinical characteristics nor radiologic or microbiologic procedures allowed a causative diagnosis of the neurologic syndrome. Postmortem examination of the brain showed macroscopic and microscopic findings compatible with acute hemorrhagic leukoencephalitis. CLL is the most common type of leukemia. The leukemic cell of CLL is a mature-appearing B lymphocyte that accumulates gradually without evidence of active proliferation in bone marrow. This is a disease of the elderly. CLL is often discovered incidentally. Leukemic infiltration of the CNS resulting in neurologic manifestations is a rare complication of CLL.81 Although CNS infiltration in CLL may be frequent, it is rarely symptomatic. Although CNS infection must be ruled out, meningeal leukemia should be suspected in patients with CLL who have neurologic symptoms such as confusion, cranial neuropathy, optic nerve involvement with visual disturbances, and cerebellar symptoms. Neurologic symptoms are the first manifestation of this disease. Results of a CT scan of the brain are negative. The diagnosis of leukemic meningitis is made on the basis of examination of the CSF and cytologic and flow cytometry analysis.82 In general, hematologic neoplasms can produce a myriad of neurologic syndromes with different propensities. These complications result from direct invasion or compression by the neoplasm or via an indirect effect (eg, infection, vascular insufficiency, paraneoplasia). Neoplasms in a leukemic phase are more likely to affect the CNS directly. Acute leukemias (especially the lymphoblastic type) have the highest propensity to be present at diagnosis and to relapse solely in the CNS. Recognizing and rapidly treating metastatic complications or avoiding neurotoxic therapies improves outcome, reduces morbidity and mortality, and limits long-term sequelae. Neurologic dysfunction may result from leukemic infiltration of the nervous system or as a consequence of chemotherapy or prophylactic craniospinal irradiation.83 Brito et al84 reported a case of transverse myelopathy in a 31-year-old white man with ALL, subtype L3. This is a severe form of leukemia that affects children more often than adults. Less than 1% of leukemic pa-
tients develop neurologic complications in the spinal cord. The symptoms in the present case started with back pain, flaccid paraplegia, and loss of sensibility and vegetative functions below the lesion. Neurotoxicity is a common complication during cancer chemotherapy. It is estimated that 3% to 10% of children with ALL experience acute transient neurotoxicity during induction chemotherapy. Fatal acute neurotoxicity is rarely encountered. Neurologic evaluation of children with ALL at diagnosis and during treatment is of value to diagnose neurologic complications early so that appropriate interventions can be initiated.85 Because more patients are surviving, late complications occurring after allogeneic BMT are increasingly reported. Among these late complications, solid tumors are of particular clinical concern. Only malignant brain tumors have been reported (eg, astrocytoma, glioblastoma). Meignin et al86 describe 2 cases of meningiomas developing 13 and 15 years after the graft. Occurrence of such benign tumors has been described after treatment of ALL but not after allogeneic BMT. It is important to consider the diagnosis of meningioma in longterm survivors presenting with neurologic symptoms. During the intrathecal colloidal gold application treatment for leukemia, some neurologic complications occur. Therapy with intrathecal colloidal gold has been used in the past as an adjunct in the treatment of childhood neoplasms, including medulloblastoma and leukemia. Nussbaum et al87 describe the long-term follow-up of a series of patients treated with intrathecal colloidal gold and emphasize the high incidence of delayed cerebrovascular complications and their management. In this study, cerebrovascular symptoms related to subarachnoid hemorrhage and moyamoya disease-like vasculopathy were reported. During the treatment of leukemia, especially in the acute lymphoblastic form, application of high-dose methotrexate may cause reversible diffuse electroencephalographic (EEG) slowing and psychiatric symptoms.88,89 Similarly, in the treatment of CLL (B-cell), progressive multifocal leukoencephalitis caused by standard-dose fludarabine has been reported.90 In chronic myeloid leukemia, peripheral neuropathies have been reported after the application of interferon- .91 Allogeneic BMT is frequently associated with neurologic complications, particularly intracerebral bleeding and infections. Cerebral venous sinus thrombosis has only rarely been reported after allogeneic transplants.92 Cerebral venous sinus thrombosis should be considered in the differential diagnosis when neurologic symptoms occur after allogeneic BMT. In leukemia and lymphoma, the coagulopathy is typically acute DIC, which can lead to systemic and brain hemorrhage. It is especially common in acute myelogenous leukemias. The clinical signs of cerebral hemorrhage are fulminant and may be fatal. The bleeding usually occurs in the brain or subdural compartment and rarely in the subarachnoid space. Cerebrovascular disorders can complicate metastatic or pri 2004 Lippincott Williams & Wilkins
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mary tumor in the brain, skull, dura, or leptomeninges. The clinical signs of infarction are indistinguishable from other causes of stroke, except that tumor-related venous occlusion usually first produces signs of increased intracranial pressure. The diagnosis of tumor-related infarction can usually be established by neuroimaging studies that show infarction and may show extracerebral sites of tumor. CSF examination is useful in diagnosing leptomeningeal metastasis. Primary or metastatic tumors in the brain or dura may hemorrhage, producing the initial clinical signs of the brain tumor or a change in chronic signs induced by the tumor. There are helpful clues to a neoplastic hemorrhage on brain CT or MRI scans. The brain hemorrhage may require evacuation, and the underlying tumor usually requires additional antineoplastic treatment. Hyperleukocytosis (extreme elevation of the cell count) in AML is a less common cause of brain hemorrhage in recent years because of improved methods to lower the cell count. Cerebral arterial or venous thrombosis is sometimes the result of cancer therapy.1
TABLE 4. Spinal Cord and Meningeal Complications of Lymphoma Location Extradural deposits Paraneoplastic effect Compressive lesions Result Ischemic myelopathy Acute necrotizing myelopathy Back pain, spastic paraparesis, sensory impairment, sphincter problems, Brown-Sequard syndrome, sensorimotor segmental syndromes
THE LYMPHOMAS
Lymphomas are a heterogeneous group of neoplasms derived from lymphoreticular tissues.93 The major types are Hodgkin disease and non-Hodgkin lymphoma. Rarer forms include Burkitt lymphoma and mycosis fungoides. Hodgkin disease is a chronic disease with lymphoreticular proliferation of unknown cause that may present in a localized or disseminated form. In the United States, 6,000 to 7,000 new cases are diagnosed annually. Hodgkin disease and nonHodgkin lymphomas affect the nervous system with equal frequency but only rarely. This usually occurs by direct spread from primary nodal and extranodal sites. Occasionally, primary Hodgkin disease and primary non-Hodgkin lymphoma (eg, microglioma, reticulum cell sarcoma, histiocytic lymphoma) of the CNS are seen. The neurologic complications result from compression, leptomeningeal infiltration, intraparenchymal mass lesions, epidural masses, and infiltration of peripheral nerves or from secondary paraneoplastic syndromes. More than 1 complication may be present in an individual patient. Also, lymphomas may metastasize to bone or the epidural space to cause neurologic dysfunction by compressing CNS structures. CNS complications may also occur as an indirect effect of lymphoma. Infections occur secondary to immunosuppression as a result of antineoplastic therapies or true paraneoplastic syndromes.93 Spinal cord involvement and meningeal involvement are relatively common neurologic complications of lymphomas (Table 4). Meningeal involvement (meningeal lymphoma) occurs almost exclusively in non-Hodgkin lymphoma. Infiltration is usually most pronounced at the base of the brain and spinal cord. Any neurologic symptom may be associated with meningeal lymphoma; most commonly, patients present with symptoms of general CNS dysfunction, cranial nerve abnormalities (most commonly, the facial nerve), or spinal cord dys 2004 Lippincott Williams & Wilkins
function. The most definitive diagnosis of meningeal lymphoma is made on identification of neoplastic cells in the CSF. The development of meningeal lymphoma during the course of lymphoma is generally associated with a poor prognosis if untreated; median survival after diagnosis is usually measurable in weeks. Using a combination of focal irradiation and local chemotherapy, neurologic symptoms are controlled in approximately 80% of patients. In approximately 5% of patients with lymphoma, epidural spinal cord compression develops secondary to primary disease. Extradural deposits arise as a result of direct spread from the retroperitoneal or postmediastinal spaces via the intervertebral foramina or by direct invasion from an affected vertebral body. The tumor often extends around the lateral aspect of the spinal cord and may encircle it completely. The tumor can produce an ischemic myelopathy by the compression of segmental arterial supply. Brown-Sequard syndrome secondary to extradural compression has been described. Rarely, an acute necrotizing myelopathy appears as a remote paraneoplastic effect of a lymphoma. Spinal cord segments C5 to T8 are most often implicated. Nerve roots also may be invaded by the lymphoma. Intracranial involvement usually arises via the skull base by direct extension from involved cervical lymph nodes. The tumor is usually extradural, but it may be within the dura or even purely intracerebral. Meningeal lesions produce multiple cranial nerve palsies, headaches, meningism, and papilledema. Non-Hodgkin lymphomas have a high incidence of meningeal involvement. Intracranial deposits produce sign and symptoms of increased intracranial pressure with focal disturbances as a result of infiltration of the cerebral hemispheres, cerebellum, or brainstem. Convulsions may occur. In the patient at risk for meningeal lymphoma, contrast-enhanced CT or MRI should be performed before spinal fluid examination if symptoms or signs suggest a mass lesion.94 When it is not contraindicated, a lumbar puncture should also be performed to assess whether meningeal lymphoma is present. CNS involvement is more frequent in Burkitt lymphoma. The most common complications are paraplegia, cranial neuropathies, and pleocytosis of the CSF.
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Primary intracerebral lymphomas are rare; they represent approximately 1% of all primary brain tumors. There is a clear association between primary cerebral non-Hodgkin lymphoma and the acquired immunodeficiency syndrome (AIDS). In patients with AIDS, CNS invasion by lymphoma occurs even more frequently (in as many as 25% of patients), tends to be more aggressive, and is harder to treat than when it occurs in otherwise normal individuals. These tumors most commonly present as discrete lesions of the cerebral cortex, corpus callosum, basal ganglia, and, to a lesser extent, cerebellum. Despite the fact that these tumors are radiosensitive, late morbidity and mortality may arise from radiation necrosis. Without biopsy confirmation, radiation necrosis is indistinguishable from recurrent tumor. Cerebral radiation necrosis seems to be related to tumor dose and the bulk of residual tumor after diagnostic neurosurgery. Primary lymphoma of the spinal cord is exceptionally rare, as is primary lymphoma of the nerve roots. The paraneoplastic syndromes of peripheral neuropathy, encephalomyelopathy, cerebellar cortical degeneration, polymyositis, PML, and an acute necrotizing myelopathy have been described in association with lymphomas (Table 5). Radiotherapy and chemotherapy may lead to opportunistic infections of the CNS caused by bacteria, fungi, or viruses or to hemorrhage caused by thrombocytopenia. Systemic administration of cytosine arabinoside or methotrexate at high doses can result in neurologic complications. Methotrexate in high doses can produce temporary cerebral dysfunction characterized by behavioral changes and focal sensorimotor signs.95 Intrathecal methotrexate can acutely produce a reversible myelopathy or encephalopathy. Cytosine arabinoside can also result in an acute paraparesis. The combination of radiation and intra-CNS chemotherapy can produce a fatal necrotizing encephalopathy.96
NEUROLOGIC COMPLICATIONS OF RADIATION THERAPY

Radiation therapy is one of the cornerstones of cancer treatment, especially for neuro-oncology patients. Because radiation therapy is nonspecifically cytotoxic like most other cancer treatments, nervous system malignancies together with nonnervous system malignancies, especially those in close proximity to neural structures, are prone to radiation-related nervous system injury. Since 1930, after the first therapeutic use of radiation for brain tumors (starting with cerebral radionecrosis), a group of central and peripheral nervous system injuries has been identified. Because neurologic complications of radiation therapy are related to many factors (eg, individual factors, concurrent chemotherapy, preexisting disease, tumor-related factors, doses and fraction sizes, intentional overdoses), radiation thresholds for safe administration of therapy are not precisely known. The incidence of radiation-related nervous system injury is increasing as conventional radiation therapy techniques are being used more aggressively and patients are surviving longer.
Epidemiology
Many factors related to the treatment, disease, and patient lead to radiation-induced nervous system injury, including high total dose (>5,000 cGy), high fraction size (>200 cGy), increased treatment volume such as the whole-brain radiation delivery technique, concurrent chemotherapy with radiosensitizing agents, proximity of the target tumor to nervous system structures, tumor-associated edema, long survival, age less than 12 years (especially age <5 or >60 years), hypertension, diabetes, hyperlipidemia, intrinsic radiosensitivity of the nervous system structure (eg, hypothalamus, retina > optic nerves, cortex, pituitary > brainstem, other cranial nerves, peripheral nerves), and genetic instability syndromes such as ataxia telangiectasia. As acute complications, fatigue and other nonspecific side effects are seen more frequently in most patients when compared with acute radiation encephalopathy, which was frequently encountered in the past. Meticulous treatment planning and the use of steroids have decreased the incidence of acute radiation encephalopathy. Late effects of radiation are relatively more common when compared with acute and subacute complications. Delayed cerebral radionecrosis is seen in approximately 5% of patients receiving cranial irradiation at a dose greater than 5,000 cGy. Preexisting disease like diabetes and hypertension, concomitant chemotherapy with radiosensitizing agents,97102 and radiation delivery techniques such as stereotactic radiosurgery and interstitial brachytherapy increase the frequency and accelerate the time course of late radiation injury. Symptomatic radionecrosis is seen usually 3 to 12 months after treatment
TABLE 5. Indirect Complications of Lymphoma Paraneoplastic syndromes Peripheral neuropathy Encephalomyelopathy Cerebellar cortical degeneration Polymyositis Progressive multifocal leukoencephalopathy Acute necrotizing myelopathy Opportunistic infections Hemorrhage caused by thrombocytopenia Behavioral changes Focal sensorimotor changes Reversible myelopathy or encephalopathy Acute paraparesis Focal necrotizing encephalopathy
Radiotherapy and chemotherapy
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in 20%103 and 80%104 of patients receiving stereotactic radiosurgery and patients undergoing interstitial brachytherapy, respectively. Radiation-related white matter changes on CT and MRI 105,106 are common findings, and 20% of these patients scans present with radiation-induced dementia.107 In patients receiving whole-brain radiation therapy at a fraction greater than 200 cGy and surviving for longer than 1 year, concurrent chemotherapy with methotrexate or nitrosourea further increases the risk. Nonprogressive personality and cognitive changes are more prominent in children and adults those older than 60 years of age. The incidence of radiation-related endocrine dysfunction is hard to estimate because it is difficult to distinguish from tumor and other treatment factors. We know that at some point after radiation therapy has started, there is a biochemical endocrine abnormality detected in two thirds to three quarters of children and adults.108,109 In a casecontrol study, approximately 30% of the patients had evidence of hypothalamic hypogonadism, hypothalamic hypothyroidism, or hyperprolactinemia.108 Children are more susceptible to radiation-related endocrine dysfunction than adults. Preexisting disease such as neuropathy secondary to diabetes or ischemia and chemotherapy with cisplatin, vincristine, bleomycin, or doxorubicin may predispose patients to radiation-induced cranial neuropathy. The incidence of chronic progressive myelopathy ranges from 0.2% to 5% for spinal cord doses of 45 Gy in 180- to 200-cGy fractions.110 Radiation-induced brachial or lumbar plexopathy is seen in 1% to 9% of conventionally treated patients; approximately 5% of this radiation-induced plexopathy is of a severe form. The frequency of radiation plexopathy may be as high as 19% in patients treated with large fraction sizes or concurrent chemotherapy and in young patients. Effects of radiation on the cerebral vasculature in a study consisting of patients surviving 5 years after therapy revealed some form of carotid disease and/or stroke in 6.9% to 17% of the patients.112 Gliomas, meningiomas, and peripheral nerve sheath tumors can be seen as radiation-induced second primary tumors in those who received a mean dose of 150 cGy for tinea capitis.113 Children with skin hemangiomas and lymphoblastic leukemia and patients with pituitary adenomas are reported to have radiation-induced second primary tumors years after radiotherapy. One large institutional series revealed that 3.7% of 272 patients treated for meningiomas over a 10-year period had a history of treatment with full-dose cranial irradiation for a different primary brain tumor.115 Von Recklinghausen disease or ataxia-telangiectasialike diseases display genetic susceptibility as an important factor for radiation-related second primary brain tumors.118,119
Mechanism
The histopathologic findings of some forms of radiationinduced nervous system injury such as cerebral radionecrosis and radiation myelopathy have been thoroughly described; however, in general, causes remain a mystery in need of further clarification. Acute toxicity is probably related to increased edema, a concept supported by neuroimaging data and steroid responsiveness. Release of excitotoxic neurotransmitters is postulated to be a contributing factor. Subacute damage weeks to months after treatment may reflect demyelination, 120 whereas late damage detected months to years after treatment is thought to be related to multiple causative factors such as neurovascular damage, fibrosis, deletion of oligodendroglial and neural stem cell populations, alterations in cytokine expression, and disruption of cellular DNA.121123
Clinical Presentation
Radiation can affect every level of the nervous system at any time during or months or years after treatment has been completed. Different radiation-related syndromes at different stages during or after treatment can be observed in the same nervous system structures. Therefore, nervous system injury can be classified according to anatomical localization or on a temporal basis as acute, subacute, or late onset. This classification is more appropriate to use when the differential diagnosis and patient approach are considered.
Acute Complications
Progressive fatigue or severe tiredness is the most frequently encountered and disturbing acute effect of cranial radiation observed during the course of conventional radiotherapy for primary brain tumors and cerebral metastasis. It starts midway and/or near the end or a few weeks after completion of the shorter course of radiation therapy. Headache, nausea and vomiting, seizures, and worsening of preexisting neurologic deficits may be seen within hours after stereotactic radiosurgery for high-grade primary tumors. Worsening of preexisting neurologic symptoms and deficits such as sphincter dysfunction and new sensory and motor disturbances can be observed similarly in irradiation of epidural spinal cord tumors. Lethargy is the predominant feature of acute radiation encephalopathy. It frequently occurs on the first day or within the first 2 weeks of treatment and may be accompanied by new or worsened preexisting focal deficits, headache, nausea, vomiting, fever, and seizures.125
Subacute Complications
Early delayed encephalopathy in the form of lethargy and cognitive and behavioral changes may develop gradually 1 to 4 months after the completion of radiation therapy.120 Subacute myelopathy, usually after cervical spinal cord radiation,
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is a form of radiation neurotoxicity presenting with a normal neurologic examination and positive Lhermitte sign, with an onset of 4 to 6 months after treatment.126 Transient brachial plexopathy or delayed radiation plexopathy develops within a few weeks to months after the initiation of radiation therapy encompassing the brachial plexus.127
Late Complications
The best-defined late complication of cranial radiation is delayed cerebral radionecrosis. It occurs after intentional or unintentional exposure of intracranial contents (eg, temporal lobes in the treatment of head and neck cancer) to radiation.102,123,125,128 Headache, personality changes, seizures, and focal deficits are seen typically 4 months to 4 years after treatment. Signs of increased intracranial pressure may be present, but acute hemorrhage is a rare complication.129 Radiation-related dementia is another diffuse form of late brain injury observed in patients mainly presenting with a gradual decline in intellectual function and short-term memory loss 6 months to years or even decades after cranial irradiation.120,124,130,131 Together with memory deficits, fine motor disturbances, visual-spatial dysfunction, and psychological disturbances, a significant decline in IQ and academic performance can be observed with relatively low doses of cranial irradiation administered to children with ALL, adults with SCLC, or those patients receiving pituitary irradiation.132134 Children less than 7 years of age and adults older than 60 years of age are particularly susceptible to this form of late radiation injury.135 Radiation-induced endocrine dysfunction is usually observed on a hypothalamic basis.108,109,136 Growth hormone is frequently affected. Spontaneously resolving hyperprolactinemia is common, but diabetes insipidus is rare. Optic nerves are the most sensitive cranial nerves to radiation injury. Postradiation optic neuropathy typically presents as painless, progressive, monocular vision loss or constriction of visual fields with an onset of 3 months to 3 years after irradiation to retinal tumors, the optic nerve, the chiasm, or the pituitary region or even irradiation to structures not directly related to the visual system.137 Radiation-induced cranial neuropathy other than that to the optic nerves can be seen 1 to 37 years after cranial irradiation for head and neck or orbital tumors.138 In order of frequency, cranial nerves XII, XI, X, V, and VI are most commonly affected. Fibrosis of the soft tissues of the neck is a contributing factor to cranial nerve involvement over months and years. Chronic progressive myelopathy is a similar spinal form of corresponding cerebral radionecrosis. IT usually occurs after irradiation of chest tumors, the mediastinum, the cervical region, or the head and neck. Ascending paresthesias, dysesthesias, sensory loss, and weakness as well as signs of myelopathy, transverse myelitis, Brown-Sequard syndrome, and
sphincter dysfunction are the presenting findings seen 3 to 30 months after treatment. Rarely, a gradually progressive syndrome of muscle wasting, fasciculations, weakness, and areflexia develops 2 to 8 months after spinal cord irradiation. This postradiation motor neuropathy most frequently involves the lumbar and sacral spinal cord levels.139 Brachial and lumbar plexopathy after irradiation of head and neck, breast, lung, thyroid, testicular, gynecologic, prostatic, or colorectal cancers or lymphomas was seen in most series with a 5-year median latency for the onset of symptoms. Paresthesia and dysesthesia as well as progressive weakness are common findings. Radiation-induced plexopathy differs in many ways from neoplastic plexopathy. Table 6 summarizes the major features distinguishing neoplastic from radiation plexopathy. Irradiation to the brain, sella, head and neck, or chest leads to damage in cerebral vasculature causing transient ischemia stroke, hemorrhage, or even myocardial infarction depending on the vessels affected and the type of vascular lesion produced.111,140144 Intracranial arterial occlusive disease, thrombotic occlusion, accelerated atherosclerosis, lacunar in-
TABLE 6. Differences Between Radiation-Induced and Neoplastic Plexopathy Neoplastic Brachial plexopathy Latency (median) Pain Ipsilateral lymphedema Horner syndrome Upper plexus involvement Lower plexus involvement CT scan mass lesion Myokymia on EMG Outcome Lumbosacral plexopathy Latency (median) Pain Weakness, numbness Bilateral symptoms Unilateral symptoms Bony erosions Sphincter dysfunction Hydronephrosis CT scan mass lesion Myokymia on EMG Outcome <1 year Yes (80%) ? Frequent (47%) Rare Common Yes Very rare Death <1 year Yes (91%) Rare Rare Yes Yes Yes Yes Yes Death Radiation Induced 5 years Rare Common Rare Common Rare Common (50%70%) Disability 5 years Rare Common Common (79%) Rare Common (50%70%) Disability
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farction, carotid artery rupture, cerebral aneurysms, cryptic vascular malformations, and cavernous angiomas are known forms of radiation-induced cerebral vasculopathies. Radiation-induced tumors after therapeutic, prophylactic, or diagnostic irradiation may arise within the brain (meningiomas, gliomas, and lymphomas), dura (fibrosarcoma and malignant fibrous histiocytoma), cranial bones (osteosarcoma), or spinal and peripheral nerves (malignant peripheral nerve sheath tumor, malignant schwannomas, and neurofibrosarcoma).113,114,145147 Latencies are long, with a range of 5 months to 41 years. Gliomas occur earlier, with a mean of 14 years. Most of the cases described occur after full-dose radiation therapy for pituitary tumors or potentially curable primary brain tumors such as medulloblastomas, germinomas, and meningiomas. Prophylactic cranial irradiation such as that in children with ALL116,117 or even low doses of radiation used for acne, tinea capitis, or dental diagnosis have been linked to the development of tumors. The symptoms of radiation-induced intracranial tumors are identical to those of their nonradiationinduced counterparts, but, typically, the former behave more aggressively clinically and microscopically with their malignant histopathologic findings.
Prognosis, Differential Diagnosis, Treatment, and Prevention

In general, acute and subacute complications of radiation therapy are mild, transient, and easy to treat with corticosteroids, whereas late complications are progressive and severe. Recognition of cancer-related disorders mimicking the symptoms of radiation injury and especially treatable acute and subacute syndromes of radiation injury are important. When mild symptoms develop early over days or weeks, an empirical increase of steroids may be sufficient. Marked deterioration, abrupt changes, or fluctuating symptoms need urgent imaging with CT or MRI for other serious causes such as recurrent tumor, hemorrhage, and obstructive hydrocephalus to be diagnosed. When a patient presents with a mass in the same location as the original tumor within 8 months of the completion of radiation therapy, recurrent tumor is the most probable diagnosis but the possibility of radiation necrosis can be ruled out with the help of positron emission tomography (PET), single photon emission computed tomography (SPECT), or MRI scanning with magnetic resonance spectroscopy.148153 A stereotactic biopsy or second resection must always be considered, because false-positive and false-negative results can be obtained with these imaging techniques.153 The possibility of an abscess, stroke, or demyelinating lesions should not be underestimated, although tumor and radionecrosis are the leading diagnostic possibilities. Diffuse late brain injury clinically (eg, leptomeningeal disease, encephalitis, concurrently administered drugs, metabolic abnormalities, systemic infection, endocrine hypofunc 2004 Lippincott Williams & Wilkins
tion and depression) and radiologically (eg, diffuse cerebral atrophy, ventricular enlargement, white matter abnormalities, periventricular small vessel disease, Alzheimer disease, and other dementias) can be attributed to many causes other than radiation injury. Therefore, a careful search for infection; review of concurrent medications; measurement of serum electrolytes, liver enzymes, and thyroid and adrenal function; and lumbar puncture as well as occasional EEG together with radiologic imaging are necessary to identify all possible causes. Radiation-induced endocrinopathy may be masked by the effects of steroids, chemotherapy, other medications, surgery, vertebral body irradiation, psychological disturbances, nutritional deficiencies, and the tumor itself. Radiationinduced cranial neuropathy can be distinguished from malignant skull base disease by CT or MRI; sometimes, serial scanning over time is needed. Lumbar puncture and paraneoplastic autoantibody testing in selected cases can help to differentiate other causes of cranial neuropathies such as leptomeningeal cancer, basilar meningitis, paraneoplastic encephalomeningitis, Lyme disease, and sarcoidosis. Enhanced MRI scanning and cytologic examination of the CSF and electromyography (EMG) can be used to differentiate other causes of radiation-induced myelopathy-like situations and conditions mimicking postradiation motor neuropathy. Conventional causes of cerebrovascular disease and other causes of vascular compromise can be diagnosed with the help of MRI scanning and magnetic resonance angiography. There is no specific intervention for radiation-related fatigue apart from adequate rest and proper scheduling of activities. In case of previous tapering of corticosteroids, a return to higher doses may be beneficial. No treatment is needed for subacute myelopathy or transient brachial plexopathy, both of which are self-limiting. Most forms of delayed radiation injury to the nervous system cannot be treated satisfactorily, and the symptoms are rarely self-limiting. Corticosteroids, resection, neurolysis (in radiation plexopathy),154 shunting (in diffuse radiation injury and dementia),131 hyperbaric oxygen (in children with delayed cerebral radionecrosis),155 and anticoagulation therapy with heparin followed by wartarin sodium (Coumadin) (in patients with delayed cerebral radionecrosis, chronic radiation myelopathy, and radiation plexopathy)156 are forms of treatment used for radiation-related injuries. Treatment of radiation-induced tumors is just like treatment of their nonradiation-induced counterparts but is rarely successful. Prevention, which is more important than treatment, by means of a reduction in overall radiation dose, fraction size, and treatment volume; control of increased intracranial pressure; modifications in radiation dose with concurrent chemotherapy; and exploration of alternatives for young and old pa-
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tients is not easily achievable. Many drugs and agents proposed need to be clarified by prospective trials. Benefits of the proposed interventions in clinical practice and their potential effects on tumor control necessitate further research.
NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY

Cancer patients take multiple medications directed at neoplasms or at secondary symptoms such as cerebral edema or seizures. Many of these drugs have some form of adverse effect on the CNS. Because causes of neurologic symptoms in patients with cancer are numerous (eg, disease progression, metastasis, paraneoplastic syndrome, seizures, infection, radiation effects, other neurologic and medical illnesses such as stroke and renal failure), observed neurologic findings cannot be attributed to a single factor most of the time. In this review, only serious, debilitating, fatal, or life-threatening forms of neurotoxicity related to medications used for cancer patients are mentioned briefly. Mild transient effects and the effects of overdoses are not discussed. Because the differential diagnosis of a neurologic complaint in a cancer patient is extensive, chemotherapy-based neurotoxicity can only be considered after exclusion of other possible causes, careful review of the drug administered and the neurologic complaint observed, and consideration of the route of administration, temporal relation between drug administration and neurologic complications, and the known side effects of these specific agents.
binoside (cytarabine, Ara-C) can produce aseptic meningitis and, rarely, myeloencephalopathy or seizures ending with good recovery or death.169172 Acute and subacute toxicity related to methotrexate is usually transient and reversible, whereas late neurotoxicity developing more 6 months after treatment with intravenous or intrathecal administration may lead to a syndrome characterized by leukoencephalopathy on neuroimaging and progressive dementia, gait ataxia, and urinary incontinence with a significant decline in Karnofsky Performance Scale score.173 Incidence is increased if methotrexate is given concomitantly with or after radiation therapy.174
Platinum Complexes
Cisplatin (cis-dichlorodiamine platinum II, DDP) preferentially affects the peripheral nervous system. Sensory neuropathy is the most common complication. Painful paresthesias, gradually disappearing deep tendon reflexes with the preservation of motor function, ototoxicity with hearing loss (in 20% of patients treated for testicular cancer),175 rare cases of myocardial infarction and stroke caused by injury to the vascular endothelium, activation of clotting mechanisms, and thrombosis176179 are seen. Thrombotic angiopathic hemolytic anemia presenting as multifocal neurologic deficits with encephalopathy180 and blindness181 has been reported with the use of carboplatin.
Antineoplastic Antibiotics
Antineoplastic antibiotics include the anthracycline antibioticsdoxorubicin, daunorubicin, and mitoxantrone. Cardiomyopathy, ventricular thrombus, transient cerebral ischemia, and strokes caused by doxorubicin are reported. Intrathecal administration of mitoxantrone is discouraged because it causes permanent myelopathy in human beings and animals.182,183
Alkylating Agents
Intra-arterial BCNU leads to vision loss160,189 (in the ipsilateral eye in 15% of patients) and progressive subacute encephalopathy100,188,189 characterized by seizures, confusion, and contralateral hemiparesis in 10% of patients developing 1 to 6 months after treatment. Estramustine has rarely been associated with stroke.190,191 Diplopia and bilateral retinal hemorrhages have been reported with the use of chlorambucil.160 Intracarotid injection of mechlorethamine(nitrogen mustard, mustargen) can cause serious ophthalmologic problems such as ipsilateral necrotizing uveitis; ophthalmoplegia; and even necrotizing encephalopathy, coma, and death.158160 Rarely, ifosfamide can lead to encephalopathy that progresses to coma and death, but encephalopathy is usually estimated to occur in 10% to 25% of the patients in the form of a transient preventable or treatable complication with the administration of diazepam and methylene blue.161166
Plant Alkaloids
Encephalopathy, seizures, and blindness suggesting posterior leukoencephalopathy may occur with vincristine.184,185 Accidental administration of vincristine into the CSF may produce an encephalopathy that is usually fatal, even with rapid CSF drainage.186,187
Other Agents
L-asparaginase (Elspar) produces deficiencies of antithrombin III, plasminogen, and fibrinogen, predisposing patients to cerebrovascular disease, particularly venous sinus thrombosis.157,158 Suramin leads to a demyelinating polyneuropathy similar to the Guillain-Barr syndrome developing 1 to 2 months after delivery in 10% to 20% of patients. Progression to quadriparesis, ventilatory support, and death has been reported.192194
Antimetabolites
Cladribine (2-chlorodeoxyadenosine, CdA)-related neutropenia in approximately one third of patients may lead to opportunistic infections as well as Neisseria meningoencephalitis by prolonged suppression of CD4- and CD8-positive lymphocytes.167,168 Intrathecal administration of cytosine ara-
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Hormonal Therapy
Tamoxifen has been associated with an increased risk of arterial and venous thrombosis; however, the increased risk of stroke remains small (1.45 events per 1,000 women per year).195,196 Corticosteroids are used commonly in chemotherapy regimens for their cytotoxic effects to reduce peritumoral edema in primary and metastatic CNS tumors, to relieve painand chemotherapy-induced nausea, and to improve appetite. Complications of steroid therapy have been well known since the 1950s. One of the most common complications is myopathy (10%60% incidence),197,198 with proximal weakness interfering with the quality of life. Neuropsychiatric symptoms with mild/moderate (27%) and severe (5%) affective disease were reported.199,200 Depression and mania are common, and psychosis and delirium are less frequent. Steroid withdrawal can also precipitate psychosis.157 Other common complications of steroid therapy include vision blurring, tremor, insomnia, and cerebral atrophy.158,201
7. 8. 9. 10. 11. 12. 13. 14.
15. 16.
Biologic Agents
Interferon- causes cognitive deficits consistent with frontal-cortical dysfunction.202 Depression, psychosis, and suicidal ideation can be seen in up to 25% of patients.202,203 Spastic diplegia may occasionally be seen in children receiving interferon- .204,205 Interleukin-2 (IL-2) may occasionally lead to a chronic subcortical dementia when administered intraventricularly.206 Systemic IL-2 may also rarely lead to hemiparesis, ataxia, seizures, aphasia, or cortical blindness. Most patients improve after withdrawal, but death may occur.207
17. 18. 19.
20.
21. 22.
Growth Factors
Erythropoietin may cause venous sinus thrombosis associated with polycythemia.208
23.
Monoclonal Antibodies
Gemtuzamab ozogamicin (Mylotarg)related severe thrombocytopenia may cause fatal intracranial hemorrhage in up to 4% of patients.209 REFERENCES
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