Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Lerner, D. M. Articles by Rosenstein, D. L. Search for Related Content PubMed Citation Articles by Lerner, D. M. Articles by Rosenstein, D. L. Other Treatment Other Neuroscience

Neuropsychiatric Toxicity Associated With Cytokine Therapies

Received December 12, 1998; accepted January 11, 1999. From the Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, MD. Address correspondence and reprint requests to Dr. Lerner, Experimental Therapeutics Branch, Building 10, Room 3N218, 10 Center Drive, MSC 1274, National Institute of Mental Health, Bethesda, MD 20892–1274.

ABSTRACT

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
The cytokines interleukin-2 and interferon- are potent biological agents used to treat malignancy, infectious diseases, and neurodegenerative disorders. While these medications show substantial therapeutic promise, the neuropsychiatric toxicity associated with these agents is often treatment-limiting. The pathophysiology of this toxicity is not well delineated, and adverse effects to the central nervous system are often misdiagnosed by clinicians. This report reviews the preclinical and clinical literature describing the morbidity associated with these agents and suggests appropriate clinical management strategies and future directions for research.

Key Words: Neuropsychiatric Toxicity • Cytokines • Immunity

INTRODUCTION

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
Immunomodulating therapies using cytokines such as interleukin (IL)-2 and interferon (IFN)- are rapidly becoming part of the standard medical armamentarium. The neuropsychiatric toxicity associated with these agents is poorly understood and poses substantial management problems for clinicians. In this article, we review the literature on the etiology, clinical presentation, and management of the neurotoxicity induced by IL-2 and IFN-. The correct diagnosis and treatment of these adverse events are essential, given the treatment-limiting morbidity that can occur. Moreover, controlled trials of medical prophylaxis are indicated and there is a clinical need to identify persons at high risk for developing this central nervous system (CNS) toxicity from these agents.

Cytokines, soluble mediators secreted by immune tissues, are promising medications for a wide variety of malignancies, infectious diseases, and neurodegenerative diseases. Cytokines have been used successfully to treat malignancies such as renal cell cancer, malignant melanoma, and leukemias by promoting an immune response against cancer cells or by altering biochemical events in the cell-replication cycle. Similarly, cytokines may disrupt biochemical pathways essential for viral replication in infectious diseases such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. The process of neural degeneration observed in multiple sclerosis and amyotrophic lateral sclerosis (ALS) may also be susceptible to cytokine therapy, as these may be immunologically mediated disorders. Analogous to the treatment-limiting systemic toxicity associated with conventional chemotherapy, the adverse effects of cytokine biotherapy frequently present substantial clinical management problems.

IL-2

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
IL-2 is a 15–16 kDa protein produced mainly by peripheral CD4 positive helper T-cells in response to stimulation by antigens, allogens, and mitogens.¹ Through a cascade effect, IL-2 activates resting T-cells to initiate deoxyribonucleic acid synthesis and cell division, resulting in the proliferation and clonal expansion of T-cells.¹ The magnitude and duration of this response is determined by the interaction between IL-2 and its high-affinity receptor (which is found on T-cells, B-cells, natural killer cells [NK], monocytes, and macrophages). In this manner, IL-2 can regulate its own expression and that of other cytokines, notably interleukin-1 (IL-1), tumor necrosing factor (TNF), and interferon- (IFN-).¹

Clinical trials of recombinant IL-2 have targeted malignancies with low response rates to traditional chemotherapy. For example, metastatic malignant melanoma and renal cell cancer show limited or no therapeutic benefit from standard combination-chemotherapy regimens.² These malignancies are significantly more responsive to IL-2, with tumor suppression rates of up to 60% for melanoma and 40% for renal cell cancer.¹ No direct cytotoxic effect on tumor cells by IL-2 itself has been detected; rather, IL-2 is thought to mediate tumor regression by stimulating the proliferation and activation of cytotoxic cells such as NK cells and tumor-specific T-cells. In addition, IL-2 may act indirectly by stimulating other cytokines or hormones.¹

IL-2 is administered either systemically (intravenously or subcutaneously) or locally to specific tumor sites and has been used as monotherapy or as part of adoptive immunotherapy or gene therapy protocols. IL-2 is delivered in intravenous bolus injections, a continuous infusion, or a series of subcutaneous injections. Treatment protocols vary in duration from 3 days to 2 weeks. The cumulative systemic exposure is a critical factor in determining toxicity, with longer exposure conferring greater risk. However, both therapeutic efficacy and toxicity also appear to be dose-related.

NEUROPATHOPHYSIOLOGICAL MECHANISMS

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
While the underlying mechanisms of IL-2–induced CNS toxicity are not known, several potential explanations have emerged from animal and human studies. Increased water content in the gray and white matter has been observed by magnetic resonance imaging (MRI) in IL-2–treated patients.³ It has been suggested that IL-2 can impair the functioning of the blood–brain barrier and lead to capillary-leakage syndrome.¹ Capillary leakage is a prominent aspect of IL-2 toxicity in other organ systems. Water retention may also be increased via a CNS-mediated increase in antidiuretic hormone synthesis.¹ Whether IL-2 is able to readily cross the blood–brain and blood–cerebrospinal fluid barriers, and thereby mediate direct effects on the brain functioning, is unknown. While IL-2–induced brain edema is associated with significant neurotoxicity in the presence of brain metastases, it is uncertain whether IL-2 is etiologically important in those patients without metastases. At least one study revealed no correlation between the severity of CNS symptoms and vasogenic edema.³ However, other authors¹ suggest that capillary-leakage syndrome is likely to be associated with CNS toxicity through the increased access to the brain of neuroactive substances.

Preclinical studies, reported in Hanisch and Quirion in 1996,¹ have localized endogenous IL-2 and IL-2–related molecules to the frontal cortex, septum, striatum, hippocampal formation, hypothalamus, locus coeruleus, cerebellum, pituitary, and fiber tracts of the corpus callosum. Additional studies¹ demonstrate that IL-2 can affect gene expression, neuronal activity, and release of transmitters in brain regions, subserving sleep and arousal, memory and cognition, locomotion, and neuroendocrine function. IL-2 has been characterized as a potent and specific regulator of neurotransmitter release in the frontal cortex, the hippocampus, the striatum, and the hypothalamus. In laboratory animals, neurotransmission by acetylcholine, dopamine, and norepinephrine may be modulated by IL-2 in a dose-dependent, biphasic manner. IL-2 increases acetylcholine, dopamine, and norepinephrine release in various brain tissues in vitro. Furthermore, there is strong evidence of IL–2 interference with neural activity in the hippocampus, suggesting that IL-2 may modulate memory formation.¹

IL-2 modulates the release of several hypothalamic and pituitary peptides and for most pituitary hormones is even more potent in regulating secretion than even the hypothalamic-releasing and -inhibiting factors.¹ IL-2 induces release of corticotropin-releasing factor (CRF), arginine vasopressin, and somatostatin from the hypothalamus and adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin-releasing hormone from the pituitary.¹ In cancer patients experiencing their first reexposure to IL-2 treatment, peak serum ACTH levels were four times higher than in patients with Cushing's disease.⁴ An increase in the release of the opioid ß-endorphin was similarly observed.⁴ IL-2 inhibits growth hormone-releasing factor and lutenizing hormone releasing-hormone release from the hypothalamus and follicle-stimulating hormone, lutenizing hormone, and growth hormone release from the pituitary.¹ In cholinergic neurons, IL-2 stimulates nitric oxide (NO) production. When NO reaches CRF-producing cells, it stimulates CRF release.¹ Hence, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a crucial role in cytokine-induced neurotoxicity.

FORMS OF TOXICITY

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
IL-2 is associated with substantial systemic toxicity involving multiple organ systems.^2,5,6 Many patients complain of a flu-like syndrome characterized by decreased energy, fatigue, anorexia, and malaise. Potential cardiovascular complications resulting from the use of high-dose IL–2 include hypotension, arrhythmia, angina, and myocardial infarction.^5,6 The hemodynamic pattern observed is quite similar to that seen in septic shock, and hypotension is typically corrected with intravenous fluid administration and, when indicated, vasopressors. IL-2–associated arrhythmias include sinus bradycardia, atrial fibrillation, and ventricular tachycardia. Supraventricular tachycardias are the most common arrhythmias and are responsive to conventional treatments. In early trials,⁵ ischemia or myocardial injury was found to occur in 2%–10% of patients during the first days of treatment with intravenous IL-2, although some patients with evidence of myocardial infarction had normal coronary arteries, suggesting a direct cardiotoxic effect.⁵ Anemia and thrombocytopenia are common side effects, with other hematological abnormalities occurring more rarely. With high-dose IL-2 therapy, up to 88% of patients may require red blood cell transfusions.⁵ Moderate-to-severe thrombocytopenia, which resolves on IL-2 discontinuation, is observed in up to 63%⁵ of patients, and IL-2 administration is frequently stopped if platelet counts drop below 50,000/µl. Infectious complications, including severe sepsis, may occur, with a mean delay of onset 3 weeks from the start of treatment; Staphylococcus species are the most common pathogens.⁵ While IL-2 does not cause neutropenia, it may lead to decreased neutrophil chemotaxis and thus an increased susceptibility to bacterial infections.² Hepatic symptoms associated with cholestasis and hyperbilirubinemia, such as jaundice and hepatomegaly, may occur infrequently, with serum bilirubin levels returning to normal after IL-2 discontinuation.⁵ Acute renal failure is a possible complication of IL-2 therapy and usually shows rapid resolution following cessation of IL-2.^2,5 Hypophosphatemia without phosphaturia has been described.⁵ Gastrointestinal distress, including diarrhea, nausea, and vomiting, occurs in most IL-2 recipients and quickly resolves.⁵ Pulmonary complications leading to respiratory distress or failure may appear and are thought to be secondary to a general vascular-leak syndrome.⁵ Dose-dependent dermatological complications, including erythema and pruritis, have been observed, and life-threatening bullous eruptions and exfoliative dermatitis have been reported.⁵ A recent report from one group⁶ indicates a progressive reduction in the aforementioned morbidity and mortality associated with systemic administration of high-dose IL-2–based therapies over a 12-year period. This improvement is attributed to better strategies for screening eligible patients and more experienced clinical management.

Hypothyroidism is a frequent complication of IL-2 administration^1,5 and may be associated with psychiatric symptoms. Some patients present with only a marked decline in T₃ or T₄ levels, whereas others present with clinical signs of hypothyroidism such as goiter.⁵ Biological abnormalities usually develop 2 weeks after starting treatment and resolve several weeks after IL-2 therapy stops. Thyroxin replacement may be required in advanced cases. An autoimmune mechanism is suspected to underlie this IL–2–induced thyroid syndrome, but this effect has not been conclusively demonstrated.⁵

Several adverse events related to IL-2 therapy may result from capillary-leakage syndrome, which is thought to occur secondary to endothelial injury, causing increased vascular permeability, and is associated with hypotension, edema, and increased body weight. The accumulation of fluids in multiple body compartments is thought to lead to multiple organ dysfunction and many of the previously mentioned adverse effects.² Patients with significant coronary artery disease are at particular risk because of the hypotension associated with vascular leakage.

Route of administration also appears to influence toxicity. Compared with intravenous IL-2 therapy, lower dose subcutaneous administration of IL-2 is associated with fewer overall adverse effects, is not associated with capillary-leakage syndrome, and may be administered on an outpatient basis.⁷ Direct intracranial delivery of intraventricular IL-2 for leptomeningeal metastases resulted in subcortical brain damage in one patient. This patient, who had no later evidence of malignancy after treatment, developed a delayed CNS syndrome thought to be secondary to IL-2.¹ Regardless of how IL-2 is administered, adverse effects are frequently treatment-limiting but, in the vast majority of cases, resolve upon the termination of IL-2 delivery.¹

NEUROPSYCHIATRIC TOXICITY

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
Neuropsychiatric symptoms observed in patients receiving IL-2 therapy include behavioral changes and agitation, cognitive impairment and disorientation, and delusions and hallucinations. The first report of clinically significant neuropsychiatric toxicity associated with systemic IL-2 administration appeared in 1987. Denicoff et al.⁸ reported a prospective evaluation of 44 cancer patients treated with IL-2 alone or IL-2 administered with adoptive immunotherapy (lymphokine-activated killer cells). Significant behavioral changes were noted in 15 patients, with symptoms ranging from brief agitation requiring minimal supervision to severe agitation and combativeness lasting several days and requiring the use of neuroleptics and physical restraints. Twenty-two of 44 patients demonstrated severe cognitive changes, as measured by the Mini-Mental State Exam, the Digit-Symbol Test, and the Trail-Making Test. All 22 patients met DSM-III criteria for delirium. Seven patients developed frank delusions during treatment. In this sample, neuropsychiatric symptoms typically appeared at the end of each IL-2 treatment phase and were related to IL-2 doses. Seventeen of 24 patients who received a high dose of IL-2 (100,000 U/kg) showed moderate-to-severe neuropsychiatric changes, whereas only 6 of 19 patients who received the lower dose demonstrated such a response. No specific risk factors were identified by any of the measurement instruments or self-reports used in this study. However, because of the low prevalence of premorbid psychopathology in this sample, the potential contribution of prior psychiatric history was probably not significantly assessed. Additionally, the effect of weight gain (representing vascular leakage and fluid accumulation) was not correlated with the development of a neuropsychiatric syndrome.

While the neuropsychiatric toxicity associated with IL-2 is best characterized as a delirium, several longer-lasting neuroendocrine (e.g., thyroiditis) and memory disturbances (including permanent neurological damage) have been described in humans and animals.¹ Karp et al.⁹ reported eight patients who developed new focal neurological abnormalities while receiving IL-2 therapy for cancer or HIV infection. In these patients, initial delirium evolved into ataxia, hemiparesis, seizures, cortical blindness, and coma. MRI studies revealed multiple white- and gray-matter lesions, particularly in the occipital poles, the centrum semiovale, and cerebellum, which resolved with clinical improvement. Pace et al.¹⁰ reported overall diffuse frontal electroencephalogram slowing in 20 patients treated with IL-2 and also described increased P300 latency in cognitive-evoked potentials.

Consistent with the modulatory effect of IL-2 on the HPA axis, we have observed IL-2 induced mood changes such as depression and hypomania in some cancer patients, although there have been no clinical studies published to date describing these adverse effects. While the depressive and hypomanic symptoms of many patients will decrease or remit following discontinuation IL-2 therapy, other patients will have persistent depressive symptoms requiring antidepressant treatment. In our clinical experience, none of the patients with hypomanic symptoms have required mood-stabilizing therapy.

CLINICAL MANAGEMENT

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
Clinical management of IL-2 toxicity begins with clinician and patient education and early diagnosis. Before treatment, patients and staff should be informed about potential psychiatric adverse effects, such as conceptual disorganization, disorientation, feelings of fear or mistrust, and perceptual distortions or hallucinations. Patients should be reassured that these symptoms almost always resolve completely after treatment and encouraged to communicate symptoms at their first appearance. Even with awareness of these effects, prodromal symptoms of CNS toxicity are frequently missed or misattributed to the effects of the underlying disease, poor psychological adjustment, or a preexisting psychiatric disorder.¹¹

The treatment approach to managing IL-2 neurotoxicity is similar to that for any delirium. With the emergence of neuropsychiatric symptoms, other medical causes of mental status changes, such as electrolyte or endocrine abnormalities, and infectious processes should be investigated, identified, and corrected. It is often necessary to hold or reduce the IL-2 dose to minimize toxicity. As with other nonsedative/hypnotic withdrawal deliria, neuroleptics are the first choice for patients experiencing severe agitation or psychosis. Haloperidol, the most commonly used neuroleptic for delirium, can be instituted at a low dose (0.5 mg po or IV) and increased as needed to manage symptoms. The use of better-tolerated atypical neuroleptics, such as risperidone, olanzapine and quetiapine, for managing IL-2–induced delirium should be considered, whereas drugs with more anticholinergic properties, such as low-potency neuroleptics, might exacerbate a medication-induced delirium. Case reports indicate risperidone has been effective in the treatment of delirium secondary to other medical conditions² Additionally, a recent study demonstrated that olanzapine has comparable efficacy to haloperidol for treating delirium in medial patients.¹³ However, such efficacy has yet to be reported for quetiapine. Sleep disturbance is a frequent complication of IL-2 treatment and is often treated with benzodiazepines. In our experience, benzodiazepines frequently exacerbate the delirium and, thus, we recommend avoiding benzodiazepines, as well as anticholinergics and antihistamines. As with antidepressant treatment in other medically ill patients, SSRI's should be considered first-line treatment of patients with IL-2 associated depression.

IFN-

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
The interferons are comprised of three families of protein molecules: , ß, and . Most cells in the body can be induced to produce these proteins by numerous stimuli.

Interferons were first determined to have properties that render cells resistant to viruses. Later research has established effects on metabolism, cell proliferation, hormone stimulation, immunity, and tumor development. These molecules bind to surface receptors on target cells and induce the synthesis of intracellular proteins. Interferons do not directly inactivate viruses but rather modulate multiple intracellular biochemical pathways that act on the viral-replication cycle. When used as antineoplastic agents, interferons may prevent tumor growth by increasing the length of the cell-multiplication cycle, by depleting essential metabolites such as the amino acid tryptophan, or by promoting tumor cell lysis through activation of immune responses.

IFN-, a 19 kDa protein, has been shown to be an effective therapy for condyloma accuminatum, chronic myelogenous leukemia, hairy cell leukemia, Kaposi's sarcoma, and HCV infection. IFN- is also being investigated as a treatment for malignant melanoma and other tumors.¹⁴ The formulation, dose, and frequency of administration of IFN- varies, depending on the underlying disease state. The typical approach for HCV infection is to administer 3 to 6 million international units (MIU) of IFN- subcutaneously 3 to 6 times per week.

NEUROPATHOPHYSIOLOGICAL MECHANISMS

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
While it is known that IFN- can disrupt the vascular endothelium in tumors, no evidence yet indicates that it can disrupt the blood-brain barrier.¹¹ Several lines of evidence¹⁵ suggest IFN- may mediate neurotoxicity via neuroendocrine, neurotransmitter, cytokine, and free radical pathways.

The neuroendocrine effects of IFN- have been demonstrated within the HPA axis, where IFN- exhibits concentration-dependent biphasic activation or inhibition of the HPA axis. Antigenic and amino acid structural similarities (sharing of a 24-amino-acid sequence at the natriuretic hormone-2 terminal) among human leukocyte interferon, ACTH, and -endorphin suggest that leukocyte interferon may be a precursor or is derived from a common precursor to these hormones.¹⁶ IFN- binds to brain opiate receptors, and its CNS activity may be reversed by opioid antagonists such as naltrexone.¹⁷ Dysregulation of the HPA axis (via increased corticotropin-releasing hormone secretion) and the hypothalamic-pituitary-thyroid axis have been implicated in the pathophysiology of some subtypes of major depression and may be involved in cytokine-induced depression.¹¹ Although not well characterized, IFN- may dysregulate the frontal-subcortical dopamine system through an opiate-associated mechanism.¹⁷ Moreover, the clinical syndrome observed in IFN- neurotoxicity (psychomotor slowing, cognitive dysfunction, and dysphoria) resembles the symptomatology of diseases associated with dopamine depletion; therefore, IFN- CNS pathology could be related to the neurocognitive and executive deficits seen in Parkinson's disease. Alterations of noradrenergic receptor levels and serum tryptophan levels have been observed in both IFN- therapy and in AIDS dementia syndrome.¹⁶ There is speculation that serotonin depletion may be responsible for the dementia and depression seen in both syndromes.¹⁷

Other cytokine systems, second messengers, and the free radical gas nitric oxide may also mediate the neurotoxicity seen with IFN-.¹⁴ IL-1, TNF-, and IL-2 can be directly or indirectly induced by IFN- in the brain. These cytokines have been implicated in disturbances of memory mechanisms in the hippocampus, neuroendocrine activity in the hypothalamus, or lead to neurodegeneration and neuron apoptosis.^11,14 As discussed before, preclinical evidence indicates that nitric oxide may mediate cytokine neurotoxicity¹⁴ as well as some aspects of alcohol intoxication and withdrawal.¹⁸

FORMS OF TOXICITY

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
Renault et al.¹⁹ described the adverse consequences of IFN- administration in HCV patients and divided these effects into early and late categories. Early effects include a flu-like syndrome, beginning as soon as 2–4 hours following the first IFN- injection, characterized by mild fever, chills, headache, arthralgias, and myalgias. These adverse effects usually attenuate with repeated dosing and are rarely treatment-limiting—except at extremely high doses (i.e., >20 MIU given three times per week).

Other symptoms appear insidiously after 2–6 weeks of therapy and include multiple organ systems. A catabolic state, with a loss of up to 10% of body weight, may develop. Hair loss and decreased libido may be observed. Higher doses may lead to nausea, vomiting, hypotension, tachycardia, and rashes.¹⁹

Hematologic abnormalities resulting from bone marrow suppression are common with sustained IFN- therapy.^20,21 Leukopenia is observed in 69% of patients, thrombocytopenia in 42% of patients, and anemia in 60% of patients. Cytopenias are usually mild, well-tolerated, and self-limiting provided that patients have no preexisting blood cell disorders.²⁰ Cardiac abnormalities appear in 5% to 15% of IFN- recipients and are dose-dependent and usually characterized by either hypotension or hypertension and uncomplicated tachycardia.^20,21 Infectious disease, including urinary tract infections, sinusitis, bronchitis, peritonitis, lung and brain abscesses, and septicemia, may occur more frequently, attributable to immunomodulatory effects of IFN-.¹⁹

Autoimmune phenomena could possibly develop during prolonged IFN- courses, as autoantibody titres have been observed to undergo a significant rise.²⁰ Most frequently, the thyroiditis associated with hypothyroidism or hyperthyroidism is associated with the presence of autoantibodies. Hypothyroidism occurs with 2–3 times the frequency as hyperthyroidism. Clinical symptoms may occur as soon as 2–4 months after the beginning of IFN- therapy but most frequently become apparent after 16 weeks, with the median occurrence of hyperthyroidism at 2–4 months of treatment and the median occurrence of hypothyroidism at 6–12 months of treatment.²⁰ Most patients respond well to thyroid-replacement therapy, with long-term substitutive treatment needed only in those patients with severe and sustained hypothyroidism after IFN- discontinuation.²⁰

In a recent multicenter, randomized clinical trial of various IFN- dose levels (3, 5, or 10 MIU three times per week) in HCV infection,²² 29% of all patients required dose modification because of adverse effects, most of which occurred in the first 12 weeks of treatment. Ten percent of all patients discontinued treatment secondary to adverse effects. Six percent of all patients developed an elevated TSH level following treatment, which may have etiologic significance for IFN-–associated mood disturbance (read next section).

NEUROPSYCHIATRIC TOXICITY

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
CNS adverse effects of IFN- include irritability, depression, personality changes, impaired concentration, fatigue, insomnia, and delirium. Ten of 58 patients with chronic HCV infection treated with recombinant human IFN- at the National Institutes of Health (NIH) clinical center¹⁹ developed psychiatric syndromes believed to be secondary to IFN- treatment. These symptoms increased in incidence with extended treatment. Feelings of irritability and anxiety superimposed on fatigue frequently occurred after the second or third month of treatment and presented as problems in the workplace, with relationships, or at home. Patients may describe overreactions to minor frustrations, such as uncontrollable tearfulness out of proportion to the circumstance.¹⁹ Additionally, there are two case reports of manic episodes occurring in middle-aged patients without psychiatric histories and who had been receiving IFN- therapy for several years.²³

The diagnosis of depression in patients treated with IFN- presents similar problems to other depressive syndromes associated with medical illnesses. In addition to the symptoms of sadness, anhedonia, guilt, and poor self-esteem, patients often experience fatigue, sleep disturbance, decreased appetite, weight loss, decreased libido, slowed thinking, and poor memory, which may reflect manifestations of hepatitis, direct physiological effects of IFN-, or a secondary depression. In our experience, depression associated with IFN- is more severe and occurs with greater frequency than what is typically experienced by medically ill patients with similar degrees of functional impairment.

Neuropsychological and personality profiles in patients with leukemia or ALS treated with IFN-^24,25 indicate delayed recall of verbal material, impaired speed and efficiency of cognitive processing, deficits in executive function, and personality and mood disturbances. Patients treated with IFN- demonstrate electroencephalographic changes consisting of frontal slowing (with return to baseline following discontinuation) and shortened latencies for visual-evoked potentials and brainstem auditory-evoked potentials.²⁶

Few predictive variables for psychiatric adverse effects of IFN- therapy exist. Results of the NIH¹⁹ study indicated that irritability and mood disturbances occurred, with the highest incidence in patients who had relatively minor hepatitis, received the highest dose (10 MIU) of IFN-, and who lost weight during treatment. Delirium tended to occur in patients with severe hepatitis, previous brain dysfunction, or drug and alcohol abuse. Data from this study suggest that a prior individual history or family history of psychiatric illness does not predict the development of depression, emotional lability, or anxiety with IFN- therapy. Additionally, a recent prospective study of 50 patients with chronic viral hepatitis found no evidence that patients with a pre-existing mood or anxiety disorders were more likely than patients without a psychiatric diagnosis to discontinue IFN- therapy.²⁷ One interesting caveat in this regard is that a prior history of alcohol or substance abuse may result in the development of an intense craving for alcohol and drugs, as well as symptoms of insomnia and anxiety late in the course of IFN- therapy.¹⁸ The neuropsychiatric toxicity associated with IFN- therapy appears to be a function of dose, duration, and route of administration. In patients with chronic myelogenous leukemia,²⁴ duration of treatment accounted for 55% of the variance in mood measures and neuropsychological test scores.

CLINICAL MANAGEMENT

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
As with IL-2 therapy, it is important to inform the patient and the family about the possible adverse effects, and to enlist their aid in early detection and management. It should be emphasized that while IFN- frequently causes psychiatric symptoms, they are usually of mild-to-moderate severity and will resolve after treatment stops. Irritability and depression are the most common mood problems caused by IFN- and often occur insidiously. In the case of HCV infection, the onset of these mood symptoms occurs just as the patient's hepatitis is beginning to respond to therapy. Consequently, the clinician should inquire about subtle changes in mood, behavior, and cognition that may be overlooked in the context of overall medical improvement. When the irritability is moderate-to-severe and affects social functioning or is associated with poor impulse control, the IFN- dose should be reduced if possible. Such reduction frequently leads to symptom alleviation within 48–72 hours, although careful monitoring is required, because the irritability or agitation can persist. Occasionally, the IFN- must be discontinued because of irritability. For irritability, anecdotal reports indicate that methylphenidate is effective in reducing the number of episodes and severity;²⁸ however, it is conceivable that the stimulant properties of methylphenidate could lead to increased irritability, as is sometimes observed when treating major depressive disorder.

Depression should be treated aggressively when it occurs. With severe depression, it is essential to reduce or stop the IFN-. In this clinical situation, reassurance and watchful waiting, while important, is not sufficient. Janssen et al.²⁹ reported two attempted suicides and one completed suicide in patients who became depressed during, or shortly after the initiation of, IFN- therapy for chronic viral hepatitis. While antidepressants are commonly used for IFN-–induced depression, no published studies demonstrate efficacy. Some case reports indicate success with using fluoxetine and nortriptyline in IFN-–treated patients with hepatitis C. Similarly, a few published cases suggest that selective serotonin reuptake inhibitors (SSRIs) may be beneficial in the IFN-–treated oncology population.¹⁷ In our experience, patients receiving IFN- are somewhat less likely to respond to antidepressants than patients with primary depression. Nonetheless, first-line treatment is with an SSRI, because these agents are safe and well tolerated by medical patients. Hospitalization and reducing or stopping the IFN- dose is mandatory for treatment of delirium. Neuroleptics should be used to treat the associated symptoms of agitation and attentional disturbances.²⁸ Consistent with laboratory findings, an open-label pilot study (see Valentine et al.¹⁷ for review) showed that the opiate antagonist naltrexone alleviated neurotoxic symptoms. Although one group¹⁷ reported using naltrexone most frequently for IFN-–induced cognitive impairment, there was no documented improvement in any particular form of symptomatology in the open-label study. In addition, opiate-antagonist use was reported to be problematic in patients requiring pain control with opioid agents.¹⁷

DISCUSSION AND CONCLUSION

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 
Cytokine therapy has become increasingly important in the treatment of a wide range of medical diseases. While such immunotherapy offers great therapeutic potential, CNS toxicity associated with this therapy can frequently limit treatment. Moreover, limited awareness of the clinical presentation of IL-2 and IFN- neurotoxicity can lead to misinterpretation and misdiagnosis of adverse events. The pathophysiology of cytokine-induced neuropsychiatric toxicity remains poorly understood. Furthermore, there is a clinical need to identify those persons most at risk for cytokine-induced CNS toxicity. Without reliable predictors of susceptibility to CNS toxicity to guide individual care, the high incidence of psychiatric morbidity associated with IL-2 and IFN- treatment calls for controlled trials of psychotropic premedication in patients receiving cytokine therapy. Consultation-liaison psychiatrists will be playing a larger role in the care of patients receiving cytokines in the future and should be aware of the special role of these medications in causing neuropsychiatric illnesses.

REFERENCES

TOP ABSTRACT INTRODUCTION IL-2 NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT IFN-{alpha} NEUROPATHOPHYSIOLOGICAL... FORMS OF TOXICITY NEUROPSYCHIATRIC TOXICITY CLINICAL MANAGEMENT DISCUSSION AND CONCLUSION REFERENCES

 

1. Hanisch UW, Quirion R: Interleukin-2 as a neuroregulatory cytokine. Brain Research Reviews 1996; 21:246–284
2. Rosenberg SA, Yang JC, Topalian SL, et al: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994; 271:907–913[Abstract/Free Full Text]
3. Saris SC PN, Rosenberg SA: The effect of intravenous interleukin-2 on brain water content. J Neurosurg 1989; 71:169–174[Medline]
4. Denicoff KD, Durkin TM, Lotze MT, et al: The neuroendocrine effects of interleukin 2 treament. J Clin Endocrinol Metab 1989; 69:402–410[Abstract/Free Full Text]
5. Vial T, Descotes J: Clinical toxicity of interleukin-2. Drug Saf 1992; 7:417–433[Medline]
6. Kammula US, White DE, Rosenberg SA: Trends in the safety of high-dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer 1998; 83:797–805[Medline]
7. Palmer PA, Atzpodien J, Philip T, et al: Comparison of two modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma. Cancer Biotherapy 1993; 8:123–135[Medline]
8. Denicoff KD, Rubinow DR, Papa MZ, et al: The neuropsychiatric effects of treatment with interleukin 2 and lymphokine-activated killer cells. Ann Intern Med 1987; 107:293–300
9. Karp BI, Yang JC, Khorsand M, et al: Multiple cerebral lesions complicating therapy with interleukin 2. Neurology 1996; 47:417–424[Abstract/Free Full Text]
10. Pace A, Pietrangeli A, Bove L, et al: Neurotoxicity of antitumoral IL-2 therapy: evoked cognitive potentials and brain mapping. Italian Journal of Neuroscience 1994; 15:341–346
11. Meyers CA, Valentine AD: Neurological and psychiatric adverse effects of immunological therapy. CNS Drugs 1995; 3:56–68
12. Sipahimalani A, Masand PS: Use of respiridone in delirium. Ann Clin Psychiatry 1997; 9:105–106[Medline]
13. Sipahimalani A, Masand PS: Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422–430[Abstract/Free Full Text]
14. Triozzi PL, Kinney P, Rinehart JJ: Central nervous system toxicity of biological response modifiers. Ann N Y Acad Sci 1990; 594:347–354[Medline]
15. Licinio J, Kling MA, Hauser P: Cytokines and brain function: relevance to interferon alpha-induced mood and cognitive changes. Semin Oncol 1998; 25:30–38[Medline]
16. Blalock JE, Smith EM: Human leukocyte interferon: structural and biological relatedness to adrenocorticotrophic hormone and endorphins. Proc Nat Acad Sci USA 1980; 77:5972–5974[Abstract/Free Full Text]
17. Valentine AD, Meyers CA, Kling MA, et al: Mood and cognitive side effects of interferon alpha therapy. Semin Oncol 1998; 25:39–47[Medline]
18. Adams ML, Cicero TJ: Alcohol intoxication and withdrawal: the role of nitric oxide. Alcohol 1998; 16:153–158[Medline]
19. Renault PF, Hoofnagle JH, Park Y, et al: Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987; 147:1577–1580
20. Vial T, Descotes J: Clinical toxicity of the interferons. Drug Saf 1994; 10:115–150[Medline]
21. Pardo M, Marriott E, Moliner MC, et al: Risks and benefits of interferon-alfa in the treatment of hepatitis. Drug Saf 1995; 13:304–316[Medline]
22. Lindsay KL, Davis GL, Schiff ER, et al: Group HIT: response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatology 1996; 24:1034–1040
23. Strite D, Valentine AD, Meyers CA: Manic episodes in two patients treated with interferon alpha. J Neuropsychiatry Clin Neurosci 1997; 9:273–276[Abstract/Free Full Text]
24. Pavol MA, Meyers CA, Rexer JL, et al: Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia. Neurology 1995; 45:947–950[Abstract]
25. Poutianien E, Hokkanen M-LN, Farkkila M: Reversible cognitive decline during high-alfa interferon treatment. Pharmacol Biochem Behav 1994; 47:901–905[Medline]
26. Forman AD: Neurologic complications of cytokine therapy. Oncology 1994; 8:105–110[Medline]
27. Pariante CM, Orrú MG, Baita A, Farci MG, Carpiniello B: Treatment with interferon- in patients with chronic hepatitis and mood or anxiety disorders. The Lancet 1999; 354:131–132[Medline]
28. Renault PF, Hoofnagle JH: Side effects of alpha interferon. Semin Liver Dis 1989; 9:273–277[Medline]
29. Janssen HLA, Brouwer JT, van der Mast RC, et al: Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994; 21:241–243[Medline]

This article has been cited by other articles:

				J. R. Fann, C. M. Alfano, S. Roth-Roemer, W. J. Katon, and K. L. Syrjala Impact of Delirium on Cognition, Distress, and Health-Related Quality of Life After Hematopoietic Stem-Cell Transplantation J. Clin. Oncol., April 1, 2007; 25(10): 1223 - 1231. [Abstract] [Full Text] [PDF]

				O. A. Kalyoncu, D. Tan, H. Mirsal, O. Pektas, and M. Beyazyurek Major depressive disorder with psychotic features induced by interferon-{alpha} treatment for hepatitis C in a polydrug abuser J Psychopharmacol, January 1, 2005; 19(1): 102 - 105. [Abstract] [PDF]

				S. C. Matthews, M. P. Paulus, and J. E. Dimsdale Contribution of Functional Neuroimaging to Understanding Neuropsychiatric Side Effects of Interferon in Hepatitis C Psychosomatics, August 1, 2004; 45(4): 281 - 286. [Abstract] [Full Text] [PDF]

				C. U. Onyike, J. O. Bonner, C. G. Lyketsos, and G. J. Treisman Mania During Treatment of Chronic Hepatitis C With Pegylated Interferon and Ribavirin Am J Psychiatry, March 1, 2004; 161(3): 429 - 435. [Full Text] [PDF]

				L. Tamam, D. Yerdelen, and N. Ozpoyraz Psychosis Associated with Interferon Alfa Therapy for Chronic Hepatitis B Ann. Pharmacother., March 1, 2003; 37(3): 384 - 387. [Abstract] [Full Text] [PDF]

				K. Ademmer, M. Beutel, R. Bretzel, J. Clemens, and C. Reimer Suicidal Ideation With IFN-{alpha} and Ribavirin in a Patient With Hepatitis C Psychosomatics, August 1, 2001; 42(4): 365 - 367. [Full Text] [PDF]

Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Lerner, D. M. Articles by Rosenstein, D. L. Search for Related Content PubMed Citation Articles by Lerner, D. M. Articles by Rosenstein, D. L. Other Treatment Other Neuroscience

Get information about faster international access.

Privacy Policy

Copyright © 1999 Academy of Psychosomatic Medicine. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us