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 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 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 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 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.     

Neurologic complications of anorexia nervosa

The records of 100 patients with anorexia nervosa were reviewed. Neurologic complications were present in 47 patients. Neuromuscuiar abnormalities were most common and were present in 45% of patients. Generalized muscle weakness was detected in 43% of patients and peripheral neuropathies in 13%. Less common neurologic complications included headaches (6%), seizures (5%), syncope in the absence of orthostatic hypotension (4%), diplopia (4%), and movement disorders (2%). Neurologic problems due to chronic deficiency diseases were rare; only one patient had symptoms directly attributable to a vitamin B₁₂ deficiency and none had evidence of Wernicke's encephalopathy. In most patients, the neurologic complications were reversed completely after correction of nutritional deficiencies and fluid and electrolyte imbalances.     

Neurologic complications of bariatric surgery

With the rapid rise in the number of bariatric surgeries performed for morbid obesity, several short- and long-term neurologic complications of this procedure have been identified. These complications affect various levels of the neuraxis, and most are likely secondary to deficiency of essential minerals and vitamins. We report on 3 patients who developed unusual and severe neurologic deficits after undergoing bariatric surgery, including Wernicke encephalopathy, acute and rapidly progressive polyneuropathy, myelopathy, and visual deficits. Two developed clinical features of Parkinsonism, a complication not previously reported in this patient population. None of our patients had attended a nutrition clinic postoperatively. All 3 had a rapid weight loss and intractable vomiting preceding the development of neurologic symptoms, and all were found to have significant vitamin deficiencies. Replacement of vitamins resulted in a slow and variable degree of neurologic recovery. Patients undergoing bariatric surgery should have close monitoring of their nutritional status postoperatively. Routine supplementation of vitamins and minerals may be a cost-effective strategy for preventing neurologic complications in these 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 liver transplantation

The clinical and neuropathologic findings of 55 adults and 30 children who received liver transplants were reviewed. Encephalopathy was the most common clinical neurologic syndrome and was usually caused by metabolic or anoxic causes. (Alzheimer type astrocytes were present in 73 per cent of patients, and evidence of diffuse hypoxic damage was present in 40 per cent of children and 25 per cent of adults.) Cerebrovascular lesions were a common finding with infarcts or hemorrhages present in 30 per cent of patients. CNS infections were documented in 34 per cent of patients. Seizures were present in a third of patients. Central pontine myelinolysis was present in 12 per cent of patients and was more common in adults than in children. Antemortem diagnosis of neurologic complications was more often based on clinical presentation rather than specific radiologic or laboratory tests.     

Neurologic complications in liver transplantation

A retrospective review is presented of neurologic complications in our first 143 consecutive adult patients (208 liver transplants in 143 adults and 18 children) undergoing liver transplantation. Nineteen (13.2%) of the 143 patients developed neurologic complications in the postoperative period. Immunosuppression was initiated intraoperatively with steroids with the addition of azathioprine on Day 1 and cyclosporine, adjusted by RIA to a level of 400-600 ng/ml, on Day 2 post-transplantation. Azathioprine is discontinued in the third month. Fourteen of the 19 patients (73.6%) presented with CNS complications characterized by: diffuse multifactorial encephalopathy (5 patients); leukoencephalopathy (2 patients) which required temporary (1 case) or permanent (1 case) discontinuation of cyclosporine A; hemorrhage (in 2 cases due to arterial hypertension and coagulopathy and another due to unknown causes); ischemic/anoxic injury secondary to cardiorespiratory arrest (2 patients) or arteriothrombosis (1 patient); and myelopathy (1 patient) due to vertebral compression (T10-T11) secondary to osteoporosis. The diagnostic studies most often employed were computed tomographic (CT) (85.7%) and electroencephalography (EEG) (42.8%). Five of 19 patients (26.3%) suffered peripheral nervous system (PNS) complications: 1 patient with reversible Claude-Bernard-Horner Syndrome caused by central venous catheterization during anesthesia: 2 patients with peroneal nerve palsy due to compression below the knees by operating room table supports; 1 patient with an irreversible lesion of the right recurrent laryngeal nerve secondary to prolonged intubation and central venous catheterization; and 1 patient with a reversible lesion of the left brachial plexus secondary to inadvertant hyperextension of the upper extremity on the O.R. table due to the need for dialysis and catheterization of the axillary vein for veno-venous bypass. Nine of fourteen (9/14, 64.2%) of patients with CNS lesion died. In five of the nine patients (55.5%) who died with CNS lesion, the neurologic lesions (CNS hemorrhage and anoxic-isquemic injury) were directly or indirectly responsable for death. Strict control of patient positioning in the operating room, arterial hypertension and coagulation disturbance in the immediate postoperative period and serum cyclosporine A levels would eliminate the majority of neurologic complications in patients undergoing liver transplantation.     

Neurologic complications of cardiac transplantation

The neurologic evaluation of an individual cardiac transplant recipient often does not lead to a succinct bedside diagnosis. There are few consistent clinical observations. The onset of seizures in the early postoperative period is associated with embolic cerebral infarction. Seizures occur most commonly, however, as a neurotoxic manifestation of cyclosporine. The onset of an acute delirium or psychosis in the first week after cardiac transplantation usually has multiple causative factors and is reversible. A postoperative brachial plexopathy or mononeuropathy can be identified with a neurologic examination, confirmed by appropriate electrophysiologic testing and is usually reversible. The onset of periorbital inflammation, ophthalmoplegia, and nasal turbinate or sinus invasion and necrosis is consistent with phycomycosis. Most patients, however, present with nonspecific findings of impaired mentation with or without focal neurologic signs. These patients require a fairly systematic search for potentially treatable neurologic complications (see Table 3). In a medically stable patient an aggressive diagnostic approach, at times including stereotaxic brain aspirate or biopsy, is indicated. In the severely ill patient with multiple organ failure, empirical therapy for the most probable treatable disorder is justified.     

Neurologic complications due to catheterization

In our university cardiac center, the incidence of a cohort of children with acute neurologic complications resulting from cardiac catheterization performed for acyanotic or cyanotic congenital heart disease is 0.38% (14 children of a total of 3,648 catheterization procedures). Neurologic complications consisted of convulsion (n = 10), stroke (n = 6), intracranial hemorrhage (n = 2), extrapyramidal features (n = 1), paraplegia (n = 1), visual impairment (n = 1), hearing impairment (n = 1), and brachial plexus injury (n = 1). The main risk factors included prolonged duration of catheterization procedure and interventional manipulation in addition to cardiac catheterization. The possible mechanisms causing brain injury included cerebral embolism from local clots and hypoxia resulting from complications during the procedure. Other complications included intracranial hemorrhage secondary to anticoagulation and peripheral plexopathy because of prolonged fixed posture during anesthesia. The prognosis for the majority of patients with stroke is good. Neurologic sequelae, such as global developmental delay or epilepsy, occurred in those with hypoxic-ischemic encephalopathy.     

Neurologic complications of cardiac catheterization

A retrospective survey was made of neurologic complications of cardiac catheterization. Of 10 patients, only one had a diffuse disorder, with seizures of a type associated with reaction to contrast agents. Disorders in the other nine patients appeared to be embolic in nature. Five of these nine involved deficits indicating damage in the vertebrobasilar territories, suggesting local trauma to vessels as a source of the embolic material.     

Neurologic complications of chemotherapy.

Neurotoxicity is a common and potential dose-limiting complication of cancer chemotherapy. For most agents, high-dose therapy, combination chemotherapy, concomitant cranial radiotherapy, and intracarotid or intrathecal injection are more likely to produce neurologic complications than standard oral or intravenous therapy. Any portion of the nervous system can be damaged. Encephalopathies (either focal or diffuse) are produced by BCNU, cisplatin, cytarabine, 5-fluorouracil, ifosfamide, L-aspariginase, methotrexate, procarbazine, corticosteroids, and some biological response modifiers (interferon, interleukin-2). Cerebellar syndromes may follow the administration of cytarabine, 5-fluorouracil, and procarbazine. Myelopathy may complicate intrathecal methotrexate, cytarabine, thiotepa, and accidental intrathecal vincristine or doxorubicin injection. Peripheral neuropathy occurs from cisplatin, vincristine, and, sometimes, cytarabine or procarbazine. Myopathy is a common complication of corticosteroids. Strokelike syndromes may occur with L-aspariginase, high-dose methotrexate, and intracarotid BCNU or cisplatin. Differentiating the neurologic complications of chemotherapy from other neurologic complications of cancer is often difficult. As cancer patients are treated more aggressively, receive more chemotherapy, and live longer, and as new chemotherapeutic agents are developed and existing agents are used more intensively or in novel ways, neurologic complications of cancer chemotherapy will become more common, serious, and complex. The recognition and treatment of chemotherapy-induced neurotoxicity will become a frequent and important clinical problem for most neurologists.     

Neurologic complications of cardiovascular surgery

With significant advances in surgical technology and methodology, mortality from congenital heart surgery has been significantly reduced in recent decades. Therefore, focus has naturally turned towards predicting, evaluating, and preventing the neurodevelopmental morbidity associated with congenital heart disease and its treatment. This paper reviews recent publications evaluating preoperative neurologic abnormalities and injuries, current neurodevelopmental outcomes of congenital heart repair, and various neuromonitoring modalities that can be used to monitor neurologic function/ dysfunction perioperatively. The rapidly advancing field of clinical neuromonitoring holds the promise of providing modalities that can detect injurious processes acutely to allow for intervention.