Neurologic complications of chemotherapy agents

PURPOSE OF REVIEW: To review neurologic complications of common and recently developed chemotherapeutic agents, as well as recent research regarding 'chemobrain'. RECENT FINDINGS: Bortezomib, a new anticancer agent, has a propensity toward causing a largely sensory and reversible peripheral neuropathy. Infusion of magnesium and calcium pre and post-oxaliplatin infusion reduces neuropathy but may interfere with clinical response to oxaliplatin. No other measures currently reduce the incidence or severity of neuropathy related to platinum compounds, taxanes, or thalidomide. Chemobrain, cognitive decline attributed to chemotherapy, has garnered research interest. Prevalence and epidemiology of chemobrain are poorly understood. Potential underlying mechanisms are under investigation in animal models and include effects on long-term potentiation and cerebral blood flow. Blood-brain barrier permeability, efficiency of cellular efflux pumps, DNA damage, telomere shortening, alteration of cytokine regulation, defects in neural repair, and oxidative stress may play roles in the effects of chemotherapy on central nervous system function. SUMMARY: Data on prevention and treatment of chemotherapy-induced peripheral neuropathy are limited. Calcium and magnesium infusions for oxaliplatin administration have the most scientific support and are widely used in practice but may interfere with the clinical efficacy of oxaliplatin. Some novel agents, particularly bortezomib, have significant risk of chemotherapy-induced peripheral neuropathy. Animal models are beginning to reveal the mechanisms underlying the impact of individual chemotherapeutic drugs on cognition.     

Neurologic complications of chemotherapy for children with cancer

Survival rates for children with cancer have increased dramatically over the past few decades. Development of new chemotherapeutic agents and the expanded use of older agents have had a major impact on this celebrated improvement. Chemotherapy can have, however, significant toxicity on the nervous system. The most common neurologic complications involve acute alterations in consciousness, leukoencephalopathy, seizures, cerebral infarctions, paralysis, neuropathy, and ototoxicity. Most of the information on toxicity comes from prospective reports and the adult patient population. Methotrexate, cyclosporin, and platinum compounds are the most frequently cited. No prospective studies have been done to evaluate chemotherapyinduced neurotoxicity in the pediatric population, and the exact incidence of such complications is unknown. Such investigation is greatly needed, as it may lead to a better understanding of how chemotherapy affects the nervous system and ultimately help develop more strategies to prevent drug-related neurotoxicity in pediatric cancer patients.     

Neurologic complications of leukemia.

In any patient with leukemia and new neurologic findings, the first entity that must be considered is direct invasion of the nervous system. If that is not a consideration, one must systematically consider cerebrovascular disorders, CNS infections, or metabolic abnormalities as the cause. Finally, one must not overlook radiotoxicity, chemotoxicity, or both in the differential diagnosis. Although some neurologic disorders are stereotyped in their presentation and are relatively easy to recognize, others continue to perplex the physician. Symptoms may be multifactorial in origin, compounding the problem. Leukemia is a systemic disease that may affect the nervous system at any site and at any time during the illness. Now that cure is possible and even to be expected in these diseases, it has become even more important to recognize and alleviate any neurologic morbidity.     

Neurologic complications of alcoholism.

Alcohol is still the most abused drug today and may affect the peripheral, central, and autonomic nervous system in many ways. There are several pathophysiologic mechanisms that include direct effects through intoxication, withdrawal effects, secondary effects from nutritional problems and systemic diseases, and, of course, syndromes of unknown etiology. The alcoholic is also susceptible to trauma to both the central and peripheral nervous system. In many of the clinical entities, multiple factors play a role.     

Neurologic complications in galactosemia.

Two siblings, a 27-year-old man and his 24-year-old sister were diagnosed with classic transferase deficiency galactosemia at birth and were treated with strict lactose restriction. Despite well-documented dietary management, both siblings are mentally retarded and manifest a progressive neurologic condition characterized by hypotonia, hyperreflexia, dysarthria, ataxia, and a postural and kinetic tremor. Magnetic resonance imaging revealed moderate cortical atrophy, a complete lack of normal myelination, and multifocal areas of increased signal in the periventricular white matter on T2-weighting. These patients suggest that even with early diagnosis and treatment, individuals with galactosemia may have significant neurologic morbidity with abnormalities of white matter development. This finding raises the possibility of biochemical heterogeneity within the classic transferase deficiency group, as well as the possibility of a lack of available galactose metabolites necessary for glycolipid synthesis causing a disruption of normal myelin development.     

Neurologic complications of respiratory disease.

The respiratory system and the central nervous system are interconnected in a delicate balance; disorders in this equilibrium can have devastating consequences. Respiratory dysfunction, whether acute or chronic, may cause neurologic disease, including headache, encephalopathy, and in extreme cases, coma and death. This article will discuss abnormalities in ventilation and gas exchange, their subsequent pathophysiologic effects on the nervous system, and mechanisms of treatment for these disorders.     

Neurologic complications of infective endocarditis.

Neurologic syndromes often complicate the management of infective endocarditis (IE). We retrospectively reviewed 166 episodes of native valve endocarditis to assess the occurrence and implications of nonfocal encephalopathy, meningitis, salient headache, back pain, and brain abscess. Neurologic complications occurred in 35% (58/166) of patients: 41% (54/133) of mitral or aortic valve IE and 12% (4/33) of tricuspid valve IE. Of 133 cases of mitral or aortic valve IE, encephalopathy occurred in 14%, meningitis in 5%, and salient headache in 3%. All neurologic complications occurred more often with Staphylococcus aureus infection (67%) than with viridans streptococci (22%), including encephalopathy (22% versus 7%), meningitis (17% versus 0%), stroke (39% versus 16%), and death (39% versus 9%). Encephalopathy was associated with virulent organisms, increased patient age, and uncontrolled infection. Clinical, radiologic, and neuropathologic data all suggest that infective microemboli are often etiologic in IE-related encephalopathy. There were no macroscopic brain abscesses clinically identified. Meningitis occurred only with virulent organisms. While many clinical aspects of IE have changed in recent years, the frequency and gravity of neurologic complications have not.     

Neurologic complications of systemic lymphoma.

Lymphoma denotes a heterogeneous group of neoplasms derived from lymphoreticular tissues. It can cause neurologic symptoms by infiltrating into the meninges or brain parenchyma. Alternatively, lymphomas may metastasize to bone or infiltrate into the epidural space via intervertebral foramina to cause neurologic dysfunction by compressing adjacent CNS structures. These direct effects can occur at any time during the disease process; most distressingly, meningeal infiltration may be the initial site of relapse after a complete remission. Diffuse and more undifferentiated lymphomas are much more likely to be responsible for producing either meningeal infiltration or intraparenchymal lesions. Direct CNS invasion by lymphoma is associated with significant patient morbidity and short survival despite intensive therapy; whether this manifestation of lymphoma can be prevented by prophylactic CNS treatment remains uncertain. CNS complications may also occur as a result of indirect effects of lymphoma. Therefore, CNS dysfunction may develop as a result of infections that occur secondary to immunosuppression, as a result of antineoplastic therapies, or as a result of true paraneoplastic syndromes. It is important to distinguish between these indirect effects and tumor progression because their recognition permits frequently available appropriate treatment modalities to be administered.     

Neurologic complications of pediatric lung transplantation.

OBJECTIVE: To report neurologic complications in a large population of pediatric lung transplantation patients. METHODS: A retrospective review of the first 135 patients to undergo lung transplantation at St. Louis Children's Hospital from July 1990 to December 1997. RESULTS: Sixty-one (45%) patients had neurologic complications. The most common presenting symptoms were seizures (27%), followed by encephalopathy, headache, depression, and focal neurologic deficits. Cyclosporine toxicity (7%) and hypoxia-ischemia (7%) constituted the most commonly identified etiologies, followed by stroke, metabolic, and infectious causes. Risk factor analysis found that patients with interstitial lung disease had a higher frequency of hypoxic-ischemic events and patients with seizures had significantly elevated trough cyclosporine levels. Patients with stroke and hypoxia had a poor neurologic prognosis, whereas patients with cyclosporine toxicity uniformly had a good outcome. CONCLUSIONS: Neurologic complications occur frequently after lung transplantation in pediatric patients, with seizures being the most common presenting symptom. Except in patients with stroke and hypoxia, prognosis is generally favorable. Seizures not accompanied by an irreversible structural etiology are unlikely to require long-term treatment with antiepileptic medications. Cyclosporine neurotoxicity typically resolves without requiring discontinuation of immunosuppressive therapy.     

Neurologic complications of nonneuronopathic Gaucher's disease.

We describe eight patients with type 1 Gaucher's disease who developed neurologic complications that were secondary to systemic features of the illness. Four patients experienced neurologic difficulties because of coagulopathy, and the other four patients had involvement of the nervous system secondary to skeletal disease. Early recognition of these complications in patients with type 1 Gaucher's disease may lead to improved neurologic outcome.     

Neurologic complications of influenza

Neurologic complications associated with influenza infection represent rare, but often underappreciated, manifestations of both seasonal and global pandemic influenza. Seizures are the most common neurologic complication, occurring as febrile seizures, as exacerbations in patients with epilepsy, or as symptoms of other influenza-induced neurologic disorders. Encephalopathy is the second most common neurologic complication associated with influenza. A wide spectrum of conditions ranging from coma with severe long-term morbidity or mortality and more mild altered mental states that resolve with minimal-to-no sequelae have been reported. Other less common neurologic complications that have been described include stroke, focal neurologic deficits, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and transverse myelitis.     

Neurologic complications of immunization

In the United States and many other developed countries, active immunization of children has virtually eliminated poliomyelitis, measles, rubella, tetanus, and other diseases, such as disease due to Haemophilus influenzae type b. Individual vaccines can produce systemic or neurologic reactions ranging from minor events, such as pain and erythema at the injection site, to major complications, such as seizures, shock, encephalopathy, or death. Immunization programs have also generated considerable controversy, as witnessed by recent concerns regarding the relationship between vaccines or their constituents and autism or multiple sclerosis. This review summarizes current information regarding vaccines, the diseases that they prevent, and the potential relationships between vaccines and neurologic disease.     

Neurologic complications of carcinoid

We reviewed the records of all patients treated for carcinoid tumors at Memorial Sloan-Kettering Cancer Center from 1974 through 1984. Of 219 patients, 90 developed metastatic complications, and of these, 36 developed neurologic complications. Metastases, the most common neurologic complication, included epidural spinal cord compression (14 patients), intracranial metastases (13 patients), leptomeningeal metastases (1 patient), and peripheral nerve lesions (5 patients). Nonmetastatic complications were hepatic encephalopathy (six patients), herpes zoster infection (two patients), cerebral infarction due to septic emboli (one patient), superior sagittal sinus thrombosis (one patient), and carcinoid myopathy (one patient). The carcinoid syndrome was seen in eight patients (4%). Response of neurologic metastases to conventional radiation therapy was usually favorable. We conclude that (1) the frequency and type of neurologic complications associated with carcinoid tumors are similar to those seen with other systemic cancers; (2) CNS metastases are relatively common in patients with metastatic carcinoid (29%); and (3) the carcinoid syndrome is less common than CNS metastasis.     

Neurologic complications of leukemia

PURPOSE OF REVIEW: As treatment of the leukemias improves, patients are surviving longer. Recognizing and rapidly treating metastatic complications or avoiding neurotoxic therapies improves outcome, reduces morbidity and mortality, and limits long-term sequelae. RECENT FINDINGS: Neurologic dysfunction may result from leukemic infiltration of the nervous system or as a consequence of chemotherapy or prophylactic craniospinal irradiation. The present review summarizes common problems in the neurologic complications of leukemia and discusses recent advancements in their diagnosis and treatment. SUMMARY: Topics covered in detail include central nervous system prophylaxis, leptomeningeal metastasis, and common hematologic complications affecting the brain. The findings aid in the clinical management of patients with leukemia.     

Neurologic complications related to cardiac surgery.

Neurologic complications are a major cause of morbidity, complicating open heart surgery, cardiac catheterization, and interventional techniques. Global or focal brain ischemia related to embolism or hypoperfusion predominates. Breakthrough cerebral hemorrhage and infection can complicate cardiac transplantation. Identifying individuals at risk for cerebrovascular complications may lead to more effective preventative and treatment measures.     

Neurologic complications of essential thrombocythemia. 6 cases

Six cases of neurological complications of essential thrombocythemia are reported. Five were ischemic strokes and the clinical expression was heterogenous (transient ischemic attacks or completed strokes), in vertebro-basilar or carotid areas. There was no correlation between the nervous disorders and the severity of the thrombocythemia. In the last case, the patient presented with papillitis and peripheral neuropathy, and the relationship with thrombocythemia was not clear. It is suggested that thrombocythemia may directly induce an arterial or venous thrombosis or increase the severity of ischemic strokes of atheromatous origin.     

Neurologic complications of renal disease

Renal failure and its treatment are associated with a number of neurologic complications that must be differentiated from the nervous system complications of the disease leading to renal failure. Uremic encephalopathy is characterized by clinical signs of depressed brain function coexisting with excitation, often in the form of generalized epileptic seizures. Peripheral neuropathy, due to axonal involvement, is common and is characterized by ascending sensory and motor dysfunction. The treatment of renal failure also may lead to the development of neurologic abnormalities in the form of dialysis disequilibrium characterized by headache, nausea, irritability that may progress to seizures, coma, and death, which is caused by the entry of free water into the brain and swelling. Dialysis dementia, caused by the toxic effects of aluminum, is now rare. Renal transplant recipients may develop cerebrovascular disease, infections by opportunistic organisms, or malignant neoplasms, particularly primary lymphoma of the brain. As transplant recipients live longer and more operations are performed, additional complications may be seen in the future.