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Diagnosis of dementia in cancer patients
BILL D. DAVIS· FRANCISCO FERNANDEZ, M.D.· FRANK ADAMS, M.D., F.R.C.P.C.· \ALERIE HOLMES, M.D. JOEL K. LEVY, Ph.D. • DOUGLAS LEWIS· JAMES NEIDHART
Diagnosis of dementia in cancer patients Cognitive impairment in these patients can go unrecognized ABSTRACT: Among 61 cancer patients referred for neuropsychiatric consultation, 43 (71%) had an organic mental disorder, and in 11 patients the disorder was consistent with dementia. Three of these cases are described in some detail to discuss the possible etiology of the organic mental disorder and to stress the importance of understanding the neurotoxic effects of chemotherapeutic agents.
Study based on psychiatric consuttations performed at the M. D. Anderson Hospitat and Tumor Institute. Houston. Reprint requests to Dr. Fernandez, St. Luke's Episcopal Hospital, 6120 Bertner Ave., Houston. TX 11030.
D
ementia is an organic mental disorder defined as "a loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. ", Clinically, demented patients manifest persistent impairment of memory, similar to that found in other disorders, and often confounding the diagnostic process. However, neuropsychiatric evaluation of a patient suspected of a dementia often reveals gross deficits in spatial orientation, calculating ability, recognition, and complex motor functions, in addition to the memory impairment. Once an accurate diagnosis of dementia has been made, an important distinction is made between the dementias associated with reversible organic illnesses (ie, secondary dementias) and those dementias for which an organic cause cannot be demonstrated but is inferred (ie, primary dementias).' Based on this classification, about 10% of Americans older than 65 years of age meet the criteria for dementia, 2 half of whom are considered to have Alzheimer's disease. '.' Recent reviews>" have indicated that 20% of patients evaluated for dementia have potentially reversible disease. A systematic evaluation of the contribution of chemotherapeutic agents for the subgroup of patients specifically with secondary drug-related dementias PSYCHOSOMATICS
would be of great value. The prevalence of organic mental disorders in cancer patients has been reported to be between 8%7 and 40%,· based on widely divergent diagnostic criteria and methods used in testing cognition. Adams' has stated that organic mental disorders are the most common neuropsychiatric complications of cancer and its treatment. Perhaps even more alarming is the fact that medically ill patients who are cognitively impaired have higher morbidity'O and mortality" than their cognitively intact counterparts. The detection of cognitive impairment is therefore very important in the treatment of cancer patients, alerting physicians to the possibility of potentially treatable and reversible neuropathology. We report here the results of our study of the prevalence of dementia in cancer patients seen by the neuropsychiatric consultation service of the University of Texas M. D. Anderson Hospital and Thmor Institute. In addition, we review three cases that significantly illustrate the importance of understanding the neurotoxic effects of current chemotherapeutic agents.
I Methods During an eight-week period, 107 consecutive cancer patients were referred to our service for a comprehensive diagnostic evaluation. Each pae---------------175
Dementia in cancer patients
tient provided an extensive personal and family history. and underwent a semistructured clinical interview to elicit the signs and symptoms of organic mental disorders. based on DSM-II1 criteria. We routinely assessed all patients with the Mini-Mental State (MMS) examination," Trail Making Tests Part A and B. 13 and a neurobehavioral examination (NBE) for critically ill cancer patients described elsewhere. "'." The NBE includes a modified Bender VisualMotor Gestalt Test," and assessment of general orientation, language functions, and sensory-motor functions, along with verbal, visual, and visualspatial memory. Both the MMS and the NBE are easy to administer and readily quantifiable. thus enhancing the clinician's ability to monitor conditions in which subtle loss of cognitive flexibility may occur, like changes that may accompany the treatment of many medical illnesses with neurotoxic agents. Dementia was diagnosed by a board-certified psychiatrist (FF) according to DSM-II1 criteria. All patients' records were then reviewed for demographic data and any other information relevant to the psychiatric diagnosis. Thirty-two patients with AIDS-related mental-status changes were excluded because of the high rate of cognitive dysfunction in this population. 17 In addition. 14 patients were excluded because of insufficient data for a definitive diagnosis at the time of consultation.
I Results Of the 61 patients studied, 36 were men and 25 were women. The mean age was 52.2 years, ranging from 17 to 75 years. Education ranged from 0 to 20 years with a mean of 13 years. The psychiatric histories involved substance abuse ( II patients), anxiety disorders (2), manic-depressive iII-
176
Table-Psychiatric Diagnoses in 61 Cancer Patients Organic mental disorder Affective disorder Amnestic syndrome Anxiety disorder' Delirium Delusional syndrome Dementia Mixed features Personality disorder Adjustment disorder
8 1 1 6 1 11 11 4 6
Affective disorders Major depression Bipolar disorder
2
Anxiety disorder
2
Character disorder
3
No psychiatric diagnosis
4
Total
1
61
'In this context. anonDSM-llilerm.
ness (I), and dementia (I). Only 14 persons were inpatients and the rest were outpatients. The cancer diagnoses were representative of the consultation practices of the individual services. These included 15 patients with neoplastic disease of the lung, 13 with hematopoietic disease, and II with breast carcinoma. The remainder of the neoplasms involved head and neck cancer (8 patients), genitourinary neoplasm (7), gastrointestinal malignancies (5), endocrine-associated neoplasm (I), and an unknown primary (I). Clinically, 43 (71 %) of the 61 patients met criteria for an organic mental disorder, and of these 43, eleven (18% of all 61 patients) had a dementia (see the Table). All patients diagnosed as having dementia were able to complete the MMS; the average score was 20 (the normal score is 25 or more). Nine of these patients underwent EEG examinations, all of which showed abnormal function with mild to moderate slowing. Six patients received CT scans of the brain. Four had 'prominent cortical atrophy; two were normal. One of these patients (Case I) underwent a magnetic resonance imaging (MRI) scan of the brain, again with normal results.
easel A 17-year-old man with acute myelogenous leukemia was referred for consultation to evaluate a possible depression. He had no psychiatric history nor a history of substance abuse. He was being treated with six weeks on an amsacrine and cytosine arabinoside protocol after having previously received ,,-interferon. One week before his hospital admission. the patient had developed diplopia. A presumptive diagnosis of eNS leukemia was made. and he was treated with a single intrathecal dose of cytosine arabinoside. Findings from a subsequent lumbar puncture were normal. Over the course of the week this young man became withdrawn. apathetic, and anorexic; he developed a tremor and his speech deteriorated, prompting the neuropsychiatric consultation for depression. At the time of consultation the patient was alert, but disoriented to day and date. and his speech was slow and dysarthric. Neuropsychiatric examination revealed severe memory impairment. conceptual confusion, dyscalculia. and severe psychomotor retardation. The neurologic examination showed an intention tremor and saccadic eye movements. He could not complete information-processing tasks because of severe confusion. The results of a Bender-Gestalt exami-
PSYCHOSOMATICS
nation were grossly abnormal, and an EEG showed global slowing, but CT and MRI scans of the brain were normal. The patient was diagnosed as having an organic mental disorder consistent with dementia. No metabolic factor or infectious process was evident to account for this acute change. After follow-up at two months, his mental state improved slightly and he experienced a complete neurologic recovery.
Case 2 A 57-year-old woman who had undergone a left radical mastectomy for stage I breast cancer metastatic to the bone was referred for consultation because of a fluctuation in mental status. Two years previously she had been diagnosed as depressed and treated with various psychotropic agents, which failed to change her mood, affect, or behavior. Neurocognitive function had since declined steadily, resulting in disorientation, memory loss, decreased motivation, and gross apraxias and agnosias. The patient's recent history and clinical course were consistent with a degenerative process, although she had no psychiatric history prior to the treatment for depression nor a record of substance abuse. Neuropsychiatric evaluation revealed her to be alert, but oriented only to person and month. Her speech and language functions were impaired, disclosing a mild dysphasia and loss of grammatical structure. Her neurocognitive functioning was below the tenth percentile for her age. She displayed conceptual confusion and difficulty with constructions; her performance of verbal, visual, and visuospatial memory tasks was severely impaired, as was that of tasks requiring complex visuospatial orientation. Abnormal results of an EEG were consistent with a destructive disturbance of cerebral function. A CT scan of the brain showed no evidence of metastases but revealed cortical atrophy. The cause of the dementia was un-
APRIL 1987· VOL 28 • NO 4
known, but the clinical features and neurobehavioral test results were most consistent with senile dementia of the Alzheimer type. The patient was lost to follow-up.
Call 3 A 75-year-old woman with stage IV Hodgkin's disease was referred to our section for consultation because she complained of hallucinations. She had no history of psychiatric problems or substance abuse. Six years prior to the consultation, she had been treated for two years with nitrogen mustard, vincristine, prednisone, procarbazine, and bleomycin, and she attained full
Subtle impairments in arousal, attention, timing, and sequencing may be trivialized as depression. remission. Four years later, however, the patient experienced progressive disease and was treated with high dosages of cyclophosphamide, vinblastine, procarbazine, and prednisone. As the disease spread, she underwent two treatment cycles of cyclophosphamide, methotrexate, and high-dosage dexamethasone. At that time, the patient started complaining of nervousness, hallucinations, and agitation, treated periodically with haloperidol. At the time of our consultation, she had been episodically delirious for ten days. Her speech was incoherent and full of irrelevancies. Visual hallucinations and agitation were prominent. She was unable to complete a full neurobehavioral examination because of inattention, and her MMS score was 10 of 30. Results of lumbar puncture were normal, as was a CT scan of the brain. An EEG was diffusely abnormal with generalized slowing. The patient was diagnosed as having a prolonged confusional episode con-
sistent with delirium. She was discharged in the care of her family and. at follow-up one month later. was in a nursing home in the same condition. The agitation was treated effectively with low-dosage haloperidol. The delirium abated, and her mental status and condition were now consistent with a clinical dementia.
I Discussion We have selected three patients whose problems are representative of those encountered by oncologists and that merit further attention. Case I is remarkable because it illustrates the disabling effects that may follow chemotherapy. Recent studies"· 20 have shown that treatment with high-dosage cytosine arabinoside may cause disabling CNS toxicity consisting of ataxia, nystagmus, and dysarthria, as well as marked intellectual impairment. The myth that certain chemotherapeutic agents, such as cisplatin, do not cross the blood-brain barrier and therefore have little effect on brain functions needs to be reexamined in light of new neuropsychological and neurophysiological methods of evaluating higher intellectual function and detecting specific neurologic dysfunctions. This patient's deterioration was dramatic, but we have encountered many patients in whom subtle impairments in such fundamental functions as arousal, attention, timing, and sequencing were trivialized as a depressive syndrome. These subtle changes in brain function may be consistent with a subcortical dementing process. 2' The issue of reversibility and recovery from the neurotoxicity of these agents has not yet been adequatelyaddressed. Case 2 highlights the increasing number of patients in whom cognitive impairment may go unrecognized. This is a significant problem for the 177
Dementia in cancer patients
oncologist because cancer is primarily a disease of older people,>' who concurrently are at increased risk of benign senescent changes as well as organic mental disorders. One of four general medical patients is believed to have a significant cognitive disturbance. 23 This fact is important for assessing patients' abilities to relate their histories, adjust to their illnesses, and comply with treatment. The problem is particularly important for oncologists engaged in experimental treatment because these patients may not be able to give informed consent. Case 3 is representative of the functionally adequate, older medical population who may have benign senescent changes but whose homeostasis may be disturbed by the stress of chemotherapy. There is evidence that the prognosis for recovery from delirium is inversely related to age," and that prolonged and treatment-resistant delirium might eventually progress to a dementia, or more remotely, to an amnestic syndrome or organic personality disorder. 2> In Cases 1 and 3, no infectious, metabolic, or CNS metastatic involvement could be found. Although these mental disorders could be ascribed to a paramalignant process, the close temporal association between drug administration and full-blown cognitive deterioration strongly implicates the chemotherapeutic agents as the most likely causal factors. The neuropsychiatric complications of these agents have been the subject of recent reviews, and descriptions of the mental status changes that occur can be found elsewhere. 1•.20.'"'' Although the prevalence of cognitive impairment in cancer patients is not known with exactitude, our experience is that the rate of organic mental disorders in patients referred for psychiatric consultation is between 60% and 70%. In a consecutive series of
head and neck cancer patients referred for depression, Adams and associates,. found that 60% of them had an organic mental disorder, reversible in half of the cases. In the 61 consultations reviewed here, 71 % of the patients were diagnosed as having an organic mental disorder, with II (18%) meeting criteria for dementia. This is higher than figures reported)O·12 for other medical inpatients, and probably reflects differences in diagnostic criteria, referral base population (ie, general medicine, neurology, or psychiatry), and screening methods to assess cognitive functions. The latter is perhaps the most important of these differences as physicians tend to rely on a brief mental status examination to grossly screen for brain function. Even when using a standardized and reliable examination, such as the MMS, the subtler cognitive impairments common in cancer patients may be missed.)) This is reflected in our data, where the mean MMS score was 20, indicating that its diagnostic accuracy for subtle forms of cognitive dysfunction may be poor. Folstein and associates)) recommended adding a visual analog scale to rate the level of consciousness and a tachistoscopic assessment to measure the capacity to attend and concentrate, in combination with the MMS specifically in cancer patients. There are significant problems with this suggestion: the difficulty of teaching the use of a tachistoscope to cognitively impaired patients, the difficulty of using this instrument at the bedside of medically ill patients, and the time involved in completing such a complicated evaluation. More research is urgently needed to develop a consistent mental status examination that is a sufficiently sensitive and reliable instrument for the detection ofdiffuse organic mental disorders in cancer patients. Until recently, little attention was
paid to the influence of age on response to treatment, survival, and toxicity of chemotherapy. Two current studies"'» suggest that older cancer patients, given the parameters examined in these studies, are not more likely than younger patients to experience serious toxic side effects from radiation and chemotherapy. However, changes in neuronal populations'· and neurotransmitter systems,""· among numerous other physiologic changes of aging,40.44 suggest that elderly patients are likely to require lower dosages of any medication necessary for treatment of a medical condition, including cancer. The approach to identifying cognitive impairments and their influence on the quality of life of cancer patients should include neuropsychiatric assessments to evaluate deficits, followed by specific neurodiagnostic studies.""" The use of new radioreceptor and neurotransmitter assays," as well as imaging techniques," will expand our understanding of the effects of cancer and its treatment on the brain, and will bring us closer to safer, more effective means of treating patients without causing disabling side effects. Further studies are urgently needed to evaluate the specific effects of antineoplastic agents on higher cortical functions and neurochemical events, and to assess their reversibility after dosage modification or drug discontinuation. 0 This work was supported in part by stipendsfrom the Dora Roberts Unrestricted Fund and the Harvey Wiess Chair for Research. University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute. Housron, Texas.
REFERENCES 1 Diagnostic and Statistical Manual of Mental Disorders. ed 3. Washington. DC. American Psychiatric Association. 1960 2. National Institutes of Health Task Force: Senil-
PSYCHOSOMATICS
178
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ity reconsidered: Treatment possibilities lor mental impairment in the elderly. JAMA 244:259-263.1980. 3. Plum F: Dementia: An approaching epidemic. Nature 279:372-373, 1979. 4. Wells CE: Chronic brain disease: An overview. Am J Psychiatry 135:1-12.1978. 5. Smith JS. Kiloh LG: The investigation 01 dementia: Results in 200 consecutive admissions. Lancet 1:824-827,1981. 6. Cummings JL: Treatable dementias. Adv NeurO/38:165-183,1983. 7. Derogatis LR, Morrow GR, Fetting J. et al: The prevalence 01 psychiatric disorders among cancer patients. JAMA 249: 751- 757. 1983. 8. Levine PM. Silberfarb PM. Lipowski ZJ: Mental disorders in cancer patients. Cancer 42:1385-1391.1978. 9. Adams F: Neuropsychiatric evaluation and treatment of delirium in the critically ill cancer patient. CancerBul/36:156-160, 1984. 10. Lipsky BA. Bayko EJ. Inui TS. et al: Risk factors for acquiring pneumococcal infections. Arch Intern Med 146:2179-2185, 1986. 11. Rabins PV. Folstein MF: Delirium and dementia: Diagnostic criteria and latality rates. Br J Psychiatry 140:149-153.1982. 12. Folstein MF. Folstein SE. McHugh PR: 'Minimental state': A practical method for grading the cognitive state of patients for the clinician. JPsychialrRes 12:189-198, 1984. 13. Lezak MD: Neuropsychological Assessment, ed 2. New York, Oxford University Press. 1983. 14. Adams F, Larson DL. Goepfert H: Does the diagnosis of depression in head and neck cancer mask organic brain disease? Otolaryngol HeadNeckSurg92:618-624,l984. 15. Adams F, Levy JKL: Neurobehavioral examination of the critically ill patient. Symposium presented at the Scientilic Program of the Canadian Psychiatric Association. 36th Annual Meeting, Vancouver. BC. sept 25. 1986. 16. Lacks P: Bender-Gestalt Screening for Brain Dysfunction. New York, Wiley-Interscience. 1984. 17. Price RW. Navia BA, Cho E-S: AIDSencephalopathy. Neurol Clin 4:285-301.1986. 18. Barnett MJ. Richards MA. Ganesan TS, et al: Central nervous system toxicity 01 high-dose
APRIL 1987' V0L28 • NO 4
cytosine arabinoside. Semin Onco/12(suppl 3):227-232.1985 19. Herzig RH, Lazarus HM, Herzig GP, et al: Central nervous system toxicity of high-dose cytosine arabinoside. Semin Onco/12(suppl 3):233-236.1985. 20. Hwang TL, Yung WKA. Estey EH. et al: Central nervous system toxicity with high-dose Ara-C. Neurology 35: 1475-1479, 1985. 21. Albert ML. Feldman RG. Willis AL: The 'subcortical dementia' 01 progressive supranuclear palsy. J NeuroJ Neurosurg Psychiatry 37:121-130.1974. 22. Peterson BA. Kennedy BJ: Aging and cancer management. Part I: Clinical observations. Cancer 29:322-332. 1979. 23. Knights EB. Folstein MF: Unsuspected emotional and cognitive disturbance in medical patients. Ann Intern Med87:723-724. 1977. 24. Morse RM. Litin EM: The anatomy 01 a delirium. Am J Psychiatry 128: 111-116. 1971. 25. Lipowski ZJ: Delirium: Acute Brain Failure in Man. Springfield. III. Charles C Thomas,
1980. 26. Weiss HD. Walker MD. Wiernik PH: Neurotox27.
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icity 01 commonly used antineoplastic agents. N EnglJ Med291:75-127, 1974. Adams F. Quesada JR. Gutterman JU: Neuropsychiatric manifestations 01 human leukocyte interferon therapy in patients with cancer. JAMA 252:938-941 , 1984. Kaplan RS. Wiernik PH: Neurotoxicity 01 antitumor agents. in Perry MC. Yarbro JW (eds): Toxicity of Chemotherapy. New York. Grune & Stratton. 1984. Silberfarb PM: Chemotherapy and cognitive defects in cancer patients. Annu Rev Med 34:35-46.1983. Anthony JC. LeResche L, Niaz V. et al: Limits of the 'Mini-Mental State' as a screening test for dementia and delirium among hospital patients. Psychol Med 12:397-408, 1982. Roca RP, Klein LE, Kirby SM, et al: Recognition of dementia among medical inpatients. Arch Intern Med 144:73-75. 1984. Erkinjuntti T. Wikstrom J. Palo J, et al: Dementia among medical inpatients: Evaluation 01 2000 consecutive admissions. Arch Intern Med 146:1923-1926.1986. Folstein MF, Fetting JH. Lobo A, et al: Cognitive assessment of cancer patients. Cancer 53:2443-2449,1984.
34. Mor V. Masterson-Allen S. Goldberg RJ. et al: Relationship between age at diagnosis and treatments received by cancer patients. JAm Geriatr Soc 33:585-589.1985. 35. Cohen HJ. Bartolucci A: Age and treatment 01 multiple myeloma: Southeastern Cancer Study Group experience. Am J Med 79:316324.1985. 36. While P. Hiley CR. Goodhart MJ, et al: Neocortical cholinergic neurons in elderly people. Lancet 1:668-671.1977. 37. McGreer E. McGreer PL: Neurotransmitter metabolism in the aging brain, in Terry RD. Gershon S (eds): Aging. New York. Raven Press, 1976, vOl 3. pp 389-403. 38. Robinson OS: Changes in monoamine oxidase and monoamines with human developmentand aging. FedProc34:103-107. 1975. 39. Berry EK. Berry RH: Cholinergic and GABA systems in dementia and old age. Br J PSychiatry131:139.1977. 40. Finch CE, Hay/lick L: Handbook ofthe Biology of Aging. New York. Van Nostrand Reinhold. 1977. 41 . Ouslander JG: Drug therapy in the elderly. AnnlnternMed95:711-722.1981. 42. Greenblatt OJ. Sellers EM. Shader RI: Drug therapy: Drug disposition in old age. N Engl J Med306:1081-1088.1982. 43. Bernstein JG: Handbook of Drug Therapy in Psychialry. Boston. John Wright PSG. 1983. 44. Triggs EJ. Nation RL, Ashley JJ: Pharmacokinetics in the elderly. Eur J Clin Pharmacol 8:55-62,1975. 45. Adams F. Adams T: Quality of life: A cerebral affair, in Mastromarino AJ (ed): The Biology and Treatmenl of Colorectal Cancer Metastasis. Hingham. Mass, Martinus Nijhoff. 1986. 46. Larson EB. Reifler BV. Sumi SM. et al: Diagnostic tests in the evaluation of dementia: A prospective study of 200 elderly outpatients. Arch Intern Med 146:1917-1922,1986. 47. AdamsF, KavanaghJ. RaberM, et al: Neuropsychiatric manilestations of caracemide toxicity in a phase I trial, abstract. Proceedings 01 the Annual Meeting of the American Society of Clinical Oncology. May 1985. Houston, Texas. 48. Duffy FH: Topographic display of evoked p0tentials: Clinical applications of brain electrical activity mapping (BEAM). Ann NY Acad Sci 388: 183-196, 1982.
179
Diagnosis of dementia in cancer patients Cognitive impairment in these patients can go unrecognized ABSTRACT: Among 61 cancer patients referred for neuropsychiatric consultation, 43 (71%) had an organic mental disorder, and in 11 patients the disorder was consistent with dementia. Three of these cases are described in some detail to discuss the possible etiology of the organic mental disorder and to stress the importance of understanding the neurotoxic effects of chemotherapeutic agents.
Study based on psychiatric consuttations performed at the M. D. Anderson Hospitat and Tumor Institute. Houston. Reprint requests to Dr. Fernandez, St. Luke's Episcopal Hospital, 6120 Bertner Ave., Houston. TX 11030.
D
ementia is an organic mental disorder defined as "a loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. ", Clinically, demented patients manifest persistent impairment of memory, similar to that found in other disorders, and often confounding the diagnostic process. However, neuropsychiatric evaluation of a patient suspected of a dementia often reveals gross deficits in spatial orientation, calculating ability, recognition, and complex motor functions, in addition to the memory impairment. Once an accurate diagnosis of dementia has been made, an important distinction is made between the dementias associated with reversible organic illnesses (ie, secondary dementias) and those dementias for which an organic cause cannot be demonstrated but is inferred (ie, primary dementias).' Based on this classification, about 10% of Americans older than 65 years of age meet the criteria for dementia, 2 half of whom are considered to have Alzheimer's disease. '.' Recent reviews>" have indicated that 20% of patients evaluated for dementia have potentially reversible disease. A systematic evaluation of the contribution of chemotherapeutic agents for the subgroup of patients specifically with secondary drug-related dementias PSYCHOSOMATICS
would be of great value. The prevalence of organic mental disorders in cancer patients has been reported to be between 8%7 and 40%,· based on widely divergent diagnostic criteria and methods used in testing cognition. Adams' has stated that organic mental disorders are the most common neuropsychiatric complications of cancer and its treatment. Perhaps even more alarming is the fact that medically ill patients who are cognitively impaired have higher morbidity'O and mortality" than their cognitively intact counterparts. The detection of cognitive impairment is therefore very important in the treatment of cancer patients, alerting physicians to the possibility of potentially treatable and reversible neuropathology. We report here the results of our study of the prevalence of dementia in cancer patients seen by the neuropsychiatric consultation service of the University of Texas M. D. Anderson Hospital and Thmor Institute. In addition, we review three cases that significantly illustrate the importance of understanding the neurotoxic effects of current chemotherapeutic agents.
I Methods During an eight-week period, 107 consecutive cancer patients were referred to our service for a comprehensive diagnostic evaluation. Each pae---------------175
Dementia in cancer patients
tient provided an extensive personal and family history. and underwent a semistructured clinical interview to elicit the signs and symptoms of organic mental disorders. based on DSM-II1 criteria. We routinely assessed all patients with the Mini-Mental State (MMS) examination," Trail Making Tests Part A and B. 13 and a neurobehavioral examination (NBE) for critically ill cancer patients described elsewhere. "'." The NBE includes a modified Bender VisualMotor Gestalt Test," and assessment of general orientation, language functions, and sensory-motor functions, along with verbal, visual, and visualspatial memory. Both the MMS and the NBE are easy to administer and readily quantifiable. thus enhancing the clinician's ability to monitor conditions in which subtle loss of cognitive flexibility may occur, like changes that may accompany the treatment of many medical illnesses with neurotoxic agents. Dementia was diagnosed by a board-certified psychiatrist (FF) according to DSM-II1 criteria. All patients' records were then reviewed for demographic data and any other information relevant to the psychiatric diagnosis. Thirty-two patients with AIDS-related mental-status changes were excluded because of the high rate of cognitive dysfunction in this population. 17 In addition. 14 patients were excluded because of insufficient data for a definitive diagnosis at the time of consultation.
I Results Of the 61 patients studied, 36 were men and 25 were women. The mean age was 52.2 years, ranging from 17 to 75 years. Education ranged from 0 to 20 years with a mean of 13 years. The psychiatric histories involved substance abuse ( II patients), anxiety disorders (2), manic-depressive iII-
176
Table-Psychiatric Diagnoses in 61 Cancer Patients Organic mental disorder Affective disorder Amnestic syndrome Anxiety disorder' Delirium Delusional syndrome Dementia Mixed features Personality disorder Adjustment disorder
8 1 1 6 1 11 11 4 6
Affective disorders Major depression Bipolar disorder
2
Anxiety disorder
2
Character disorder
3
No psychiatric diagnosis
4
Total
1
61
'In this context. anonDSM-llilerm.
ness (I), and dementia (I). Only 14 persons were inpatients and the rest were outpatients. The cancer diagnoses were representative of the consultation practices of the individual services. These included 15 patients with neoplastic disease of the lung, 13 with hematopoietic disease, and II with breast carcinoma. The remainder of the neoplasms involved head and neck cancer (8 patients), genitourinary neoplasm (7), gastrointestinal malignancies (5), endocrine-associated neoplasm (I), and an unknown primary (I). Clinically, 43 (71 %) of the 61 patients met criteria for an organic mental disorder, and of these 43, eleven (18% of all 61 patients) had a dementia (see the Table). All patients diagnosed as having dementia were able to complete the MMS; the average score was 20 (the normal score is 25 or more). Nine of these patients underwent EEG examinations, all of which showed abnormal function with mild to moderate slowing. Six patients received CT scans of the brain. Four had 'prominent cortical atrophy; two were normal. One of these patients (Case I) underwent a magnetic resonance imaging (MRI) scan of the brain, again with normal results.
easel A 17-year-old man with acute myelogenous leukemia was referred for consultation to evaluate a possible depression. He had no psychiatric history nor a history of substance abuse. He was being treated with six weeks on an amsacrine and cytosine arabinoside protocol after having previously received ,,-interferon. One week before his hospital admission. the patient had developed diplopia. A presumptive diagnosis of eNS leukemia was made. and he was treated with a single intrathecal dose of cytosine arabinoside. Findings from a subsequent lumbar puncture were normal. Over the course of the week this young man became withdrawn. apathetic, and anorexic; he developed a tremor and his speech deteriorated, prompting the neuropsychiatric consultation for depression. At the time of consultation the patient was alert, but disoriented to day and date. and his speech was slow and dysarthric. Neuropsychiatric examination revealed severe memory impairment. conceptual confusion, dyscalculia. and severe psychomotor retardation. The neurologic examination showed an intention tremor and saccadic eye movements. He could not complete information-processing tasks because of severe confusion. The results of a Bender-Gestalt exami-
PSYCHOSOMATICS
nation were grossly abnormal, and an EEG showed global slowing, but CT and MRI scans of the brain were normal. The patient was diagnosed as having an organic mental disorder consistent with dementia. No metabolic factor or infectious process was evident to account for this acute change. After follow-up at two months, his mental state improved slightly and he experienced a complete neurologic recovery.
Case 2 A 57-year-old woman who had undergone a left radical mastectomy for stage I breast cancer metastatic to the bone was referred for consultation because of a fluctuation in mental status. Two years previously she had been diagnosed as depressed and treated with various psychotropic agents, which failed to change her mood, affect, or behavior. Neurocognitive function had since declined steadily, resulting in disorientation, memory loss, decreased motivation, and gross apraxias and agnosias. The patient's recent history and clinical course were consistent with a degenerative process, although she had no psychiatric history prior to the treatment for depression nor a record of substance abuse. Neuropsychiatric evaluation revealed her to be alert, but oriented only to person and month. Her speech and language functions were impaired, disclosing a mild dysphasia and loss of grammatical structure. Her neurocognitive functioning was below the tenth percentile for her age. She displayed conceptual confusion and difficulty with constructions; her performance of verbal, visual, and visuospatial memory tasks was severely impaired, as was that of tasks requiring complex visuospatial orientation. Abnormal results of an EEG were consistent with a destructive disturbance of cerebral function. A CT scan of the brain showed no evidence of metastases but revealed cortical atrophy. The cause of the dementia was un-
APRIL 1987· VOL 28 • NO 4
known, but the clinical features and neurobehavioral test results were most consistent with senile dementia of the Alzheimer type. The patient was lost to follow-up.
Call 3 A 75-year-old woman with stage IV Hodgkin's disease was referred to our section for consultation because she complained of hallucinations. She had no history of psychiatric problems or substance abuse. Six years prior to the consultation, she had been treated for two years with nitrogen mustard, vincristine, prednisone, procarbazine, and bleomycin, and she attained full
Subtle impairments in arousal, attention, timing, and sequencing may be trivialized as depression. remission. Four years later, however, the patient experienced progressive disease and was treated with high dosages of cyclophosphamide, vinblastine, procarbazine, and prednisone. As the disease spread, she underwent two treatment cycles of cyclophosphamide, methotrexate, and high-dosage dexamethasone. At that time, the patient started complaining of nervousness, hallucinations, and agitation, treated periodically with haloperidol. At the time of our consultation, she had been episodically delirious for ten days. Her speech was incoherent and full of irrelevancies. Visual hallucinations and agitation were prominent. She was unable to complete a full neurobehavioral examination because of inattention, and her MMS score was 10 of 30. Results of lumbar puncture were normal, as was a CT scan of the brain. An EEG was diffusely abnormal with generalized slowing. The patient was diagnosed as having a prolonged confusional episode con-
sistent with delirium. She was discharged in the care of her family and. at follow-up one month later. was in a nursing home in the same condition. The agitation was treated effectively with low-dosage haloperidol. The delirium abated, and her mental status and condition were now consistent with a clinical dementia.
I Discussion We have selected three patients whose problems are representative of those encountered by oncologists and that merit further attention. Case I is remarkable because it illustrates the disabling effects that may follow chemotherapy. Recent studies"· 20 have shown that treatment with high-dosage cytosine arabinoside may cause disabling CNS toxicity consisting of ataxia, nystagmus, and dysarthria, as well as marked intellectual impairment. The myth that certain chemotherapeutic agents, such as cisplatin, do not cross the blood-brain barrier and therefore have little effect on brain functions needs to be reexamined in light of new neuropsychological and neurophysiological methods of evaluating higher intellectual function and detecting specific neurologic dysfunctions. This patient's deterioration was dramatic, but we have encountered many patients in whom subtle impairments in such fundamental functions as arousal, attention, timing, and sequencing were trivialized as a depressive syndrome. These subtle changes in brain function may be consistent with a subcortical dementing process. 2' The issue of reversibility and recovery from the neurotoxicity of these agents has not yet been adequatelyaddressed. Case 2 highlights the increasing number of patients in whom cognitive impairment may go unrecognized. This is a significant problem for the 177
Dementia in cancer patients
oncologist because cancer is primarily a disease of older people,>' who concurrently are at increased risk of benign senescent changes as well as organic mental disorders. One of four general medical patients is believed to have a significant cognitive disturbance. 23 This fact is important for assessing patients' abilities to relate their histories, adjust to their illnesses, and comply with treatment. The problem is particularly important for oncologists engaged in experimental treatment because these patients may not be able to give informed consent. Case 3 is representative of the functionally adequate, older medical population who may have benign senescent changes but whose homeostasis may be disturbed by the stress of chemotherapy. There is evidence that the prognosis for recovery from delirium is inversely related to age," and that prolonged and treatment-resistant delirium might eventually progress to a dementia, or more remotely, to an amnestic syndrome or organic personality disorder. 2> In Cases 1 and 3, no infectious, metabolic, or CNS metastatic involvement could be found. Although these mental disorders could be ascribed to a paramalignant process, the close temporal association between drug administration and full-blown cognitive deterioration strongly implicates the chemotherapeutic agents as the most likely causal factors. The neuropsychiatric complications of these agents have been the subject of recent reviews, and descriptions of the mental status changes that occur can be found elsewhere. 1•.20.'"'' Although the prevalence of cognitive impairment in cancer patients is not known with exactitude, our experience is that the rate of organic mental disorders in patients referred for psychiatric consultation is between 60% and 70%. In a consecutive series of
head and neck cancer patients referred for depression, Adams and associates,. found that 60% of them had an organic mental disorder, reversible in half of the cases. In the 61 consultations reviewed here, 71 % of the patients were diagnosed as having an organic mental disorder, with II (18%) meeting criteria for dementia. This is higher than figures reported)O·12 for other medical inpatients, and probably reflects differences in diagnostic criteria, referral base population (ie, general medicine, neurology, or psychiatry), and screening methods to assess cognitive functions. The latter is perhaps the most important of these differences as physicians tend to rely on a brief mental status examination to grossly screen for brain function. Even when using a standardized and reliable examination, such as the MMS, the subtler cognitive impairments common in cancer patients may be missed.)) This is reflected in our data, where the mean MMS score was 20, indicating that its diagnostic accuracy for subtle forms of cognitive dysfunction may be poor. Folstein and associates)) recommended adding a visual analog scale to rate the level of consciousness and a tachistoscopic assessment to measure the capacity to attend and concentrate, in combination with the MMS specifically in cancer patients. There are significant problems with this suggestion: the difficulty of teaching the use of a tachistoscope to cognitively impaired patients, the difficulty of using this instrument at the bedside of medically ill patients, and the time involved in completing such a complicated evaluation. More research is urgently needed to develop a consistent mental status examination that is a sufficiently sensitive and reliable instrument for the detection ofdiffuse organic mental disorders in cancer patients. Until recently, little attention was
paid to the influence of age on response to treatment, survival, and toxicity of chemotherapy. Two current studies"'» suggest that older cancer patients, given the parameters examined in these studies, are not more likely than younger patients to experience serious toxic side effects from radiation and chemotherapy. However, changes in neuronal populations'· and neurotransmitter systems,""· among numerous other physiologic changes of aging,40.44 suggest that elderly patients are likely to require lower dosages of any medication necessary for treatment of a medical condition, including cancer. The approach to identifying cognitive impairments and their influence on the quality of life of cancer patients should include neuropsychiatric assessments to evaluate deficits, followed by specific neurodiagnostic studies.""" The use of new radioreceptor and neurotransmitter assays," as well as imaging techniques," will expand our understanding of the effects of cancer and its treatment on the brain, and will bring us closer to safer, more effective means of treating patients without causing disabling side effects. Further studies are urgently needed to evaluate the specific effects of antineoplastic agents on higher cortical functions and neurochemical events, and to assess their reversibility after dosage modification or drug discontinuation. 0 This work was supported in part by stipendsfrom the Dora Roberts Unrestricted Fund and the Harvey Wiess Chair for Research. University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute. Housron, Texas.
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