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Extrapyramidal reactions
Extrapyramidal Reactions Neuropsychiatric Mimics in Patients with AIDS J. Robert Swenson, M.D., F.R.C.P.(C.), Milton Erman, M.D., James Labelle, M.D., and Joel E. Dimsdale, M.D.
Abstract: The use of neuroleptic medication as antiemetics, or in the treatment of neuropsychiatric disorders in patients with AIDS, may be associated with extrapyramidal side effects and lead to difficulty with diagnosis and management. Two cases are presented that describe severe extrapyramidal syndromes occurring in two patients with AIDS, one treated with prochlorperazine and the other with prochlorperazine and metoclopropramide. It is possible thaf the neuropathologic lesions found in pafienfs with fhe AlDS dementia complex may predispose to extrapyramidal side effects of neurolepfic medication. The differential diagnosis and treatment of delirium, dementia, depression, and extrapyramidal reactions in patients with AIDS is discussed.
Between 30% and 40% of patients with the acquired immune-deficiency syndrome (AIDS) develop neuropsychiatric complications during the course of their illness [1,2]. The initial presentation of central nervous (CNS) complications of AIDS may resemble psychiatric illness, and thus the management of organic mental disorders in patients with AIDS is often extremely complex. Patients with AIDS may well require neuroleptic medication for the treatment of delirium, psychosis, agitation, or overwhelming anxiety states, or for the treatment of nausea and vomiting associated with either the illness or as a side effect of some treatments [3]. From the Program in Consultation-Liaison Psychiatry and Behavioral Medicine, Department of Psychiatry, University of California, San Diego, La Jolla, California (J.R.S.; J.E.D.), the Department of Psychiatry, Scripps Clinic and Research Foundation, La Jolla, California (M.E.), and the Department of Medicine, University of California, San Diego, La Jolla, California 0-L.). Address reprint requests to: J. Dimsdale, M.D., University of California, San Diego Medical Center, T-004, 225 Dickinson Street, San Diego, CA 92103.
248 ISSN 0163~8343B983.50
Unfortunately, extrapyramidal side effects from neuroleptic medication may cause diagnostic uncertainty, exacerbate CNS dysfunction, and complicate management. We report two cases of severe extrapyramidal reactions occurring in patients with AIDS. These cases demonstrate the complexity of the differential diagnosis of neuropsychiatric signs and symptoms in patients with AIDS and the fact that extrapyramidal side effects of medication can be misattributed to depression: we speculate that certain patients with AIDS may be singularly vulnerable to extrapyramidal side effects when treated with neuroleptics.
Case Histories Patient 1 A 24-year-old homosexual male presented with cough, fever, and dyspnea on exertion and complained of feeling depressed, admitting that he had thought of killing himself by “turning on the gas in my apartment.” He had been diagnosed with AIDS approximately 1 year previously, and his neurologic examination at that time had been normal apart from the presence of a snout reflex. Eight months before the present admission he noted the onset of mild left lower extremity weakness, and 6 months prior to admission he noted impotence. At the time of admission he appeared chronically ill, with elevated temperature of 100.3”F, respiratory rate of 28 per minute, pulse of 116 bpm, and blood pressure of 1261% mm Hg. Throat examination revealed a scant whitish exudate, and cervical adenopathy was present. Pulmonary examination demGeneral Hospital Psychiatry 11,248-253,1989 0 1989Elsevier Science Publishing Co., Inc. 655AvenueoftheAmencas,NewYork,NY
10010
Extrapyramidal
onstrated decreased breath sounds in the left lung base. Mental status examination revealed a clear sensor-mm with intact orientation and memory, normal thought processes with content notable for suicidal ideation, and depressed mood. Neurologic examination demonstrated intact cranial nerves, normal cerebellar examination, and weakness and atrophy of the left lower extremity muscles, particularly of the tibialis anterior. Left knee and ankle deep tendon reflexes were hyperreflexic, and the left toe was upgoing. Pinprick sensation was decreased in the distribution of the left deep peroneal nerve. Snout and glabellar release reflexes were present. His gait was wide-based and asymmetric. Laboratory studies on admission demonstrated elevated liver function tests, a white blood count (WBC) of 2400 per microliter (normal 7800 4 3000) with lymphopenia, and a hemoglobin of 10.6 g/d1 (normal 16.0 +- 2) with macrocytosis on smear. Hepatitis B surface antibody was positive. Chest x-ray disclosed diffuse interstitial infiltrates compatible with pneumocystis . .< which was confirmed by carmii pneumonia, bronchoscopy. The patient was treated with intravenous trimethoprim-sulfamethoxazole. During the initial hospital course the patient remained febrile and slightly tachypneic, with no major changes in his clinical status. Nerve conduction studies and electromyogram demonstrated diffuse denervation of all muscles sampled in the left lower extremity, consistent with a diffuse polyradiculopathy of the left leg. Computed tomographic (CT) scan of the brain done soon after admission revealed a large area of ringlike calcification (roughly 5 x 2 cm) in the region of the left anterior capsule, caudate head, and corona radiata. Several smaller foci of abnormal calcification were seen in the right corona radiata and some superior to the corpus callosum. There was no associated edema, mass effect, or contrast enhancement. It was felt that these findings represented old healed toxoplasmosis. In addition, the ventricular system was felt to be enlarged, as were the sylvian fissures, basilar cisterns, and cortical sulci, reflecting moderate volume loss. Because of nausea, he was started on prochlorperazine 10 mg three times daily. Five days later it was noted that he had become more depressed, withdrawn, and “passive” and seemed to have lost his will to live, and a psychiatric consultation was requested. During the initial psychiatric consultation, the patient reported that he had no past psychiatric history, and he stated that his major problem was “difficulty communicating.” He admitted feeling very depressed and having suicidal thoughts when initially diagnosed with his present episode of pneumonia; however, he said that he had decided he really wanted to live, and recover from this setback in order to move back home with his parents. His mother reported his
Side Effects in AIDS Patients
depression worsened rather suddenly over the previous 3 days and noted that he had lost his usual “angry fighting spirit.” His sleep was poor, with frequent awakenings, and his appetite appeared good; however, the nurses noted he had trouble swallowing and also commented that he was quite “rigid” when turned in bed. On mental status examination he appeared to be a young man with a remarkably immobile facial expression, staring gaze, and soft speech. He was alert and oriented to time and place. Thought association was unremarkable and he did not express suicidal ideation or plans, although he described his mood as depressed. Affect was withdrawn and lethargic. The initial impression was that this man was depressed: however, the differential diagnosis included extrapyramidal symptoms possibly due to the CNS lesion affecting the basal ganglia, and symptoms of the AIDS dementia complex (subacute encephalitis, AIDS encephalopathy). Examination and cultures of the cerebrospinal fluid did not reveal any evidence of infection, and repeat CT scan of the brain was unchanged. Prochlorperazine was discontinued because of possible extrapyramidal side effects. Over the following 2 days the patient’s status deteriorated, with development of bradykinesia and diffuse limb and truncal rigidity and inability to speak, although he seemed alert and tried to cooperate with examination. His temperature after admission had fluctuated from 98.3”F to 102.4”F with most readings below lOO.O”F;however, after the onset of rigidity, temperature was consistently over lOO.O”F, at times up to 103.7”F, and had to be managed with a cooling blanket. Blood pressure, which had been stable and in the normal range, became labile, fluctuating from 120/80 to 180/100 mm Hg. His pulse ranged from 96 to 144 bpm. He was profusely diaphoretic. Treatment with intravenous and then oral benztropine mesylate 2 mg three times daily produced dramatic improvement over the next few hours in his ability to speak and move his extremities. Muscular tone, however, remained quite rigid over the following 2 days, and he was started on levodopal carbidopa lO/lOOmg three times daily with improvement in rigidity. Vital signs stabilized over the next four days but he remained febrile and developed a marked leukopenia (WBC 700 per microliter), felt possibly to be secondary to levodopalcarbidopa; this was discontinued, and his WBC returned to pretreatment levels. After his speech returned, it was evident that he demonstrated cognitive impairment in orientation to time, ability to concentrate, and short-term memory, which fluctuated over the next few days but then cleared. Laboratory investigations during this acute episode revealed a markedly elevated creatine phosphokinase (CPK), which peaked at 2104 IUlL (normal O-175 IU/L), but had started to drop at the time of discharge. Liver function tests, which had been ele-
249
J. R. Swenson et al. vated at the time of admission, increased during the hospital course. At the time of discharge, he was alert and oriented, with no evidence of depression, and had regained his usual “grumpy mood” but hopeful attitude. He continued to have mild bradykinesia and was discharged on benztropine mesylate.
Patient 2 A 31-year-old homosexual male presented to the outpatient AIDS clinic requesting follow-up care after recently moving to the city. He had been diagnosed with AIDS 18 months previously and was currently undergoing treatment for pneumocystis pneumonia and cytomegalovirus retinitis. He also had two untreated lesions of Kaposi’s sarcoma. Medications he had been receiving included pentamidine isethinoate, ganciclovir, alprazolam, cefaclor, metoclopramide, prochlorperazine, and triazolam. He complained of anxiety, insomnia, decreased concentration, and difficulty moving his tongue. On physical examination he was a thin pale man with unanimated facies and flat effect. He was alert and oriented with intact recent and remote memory, and was able to repeat five numbers forward but only three backward. Snout and glabellar release signs were present. Muscular tone was increased; there was a cogwheeling type of rigidity, bilateral hand tremor, and decreased power in all limbs. Gait demonstrated slow small steps. It was felt that he demonstrated features of a parkinsonian syndrome as well as some features of the AIDS dementia complex. Prochlorperazine and metoclopramide were discontinued and the patient was started on benztropine mesylate 1.0 mg twice daily. When the patient was seen 1 week later, muscular rigidity and hand tremor had resolved and he was speaking more easily.
Discussion When patient 1 was admitted to the hospital, his
depressed mood and suicidal ideation, and the rapid development of withdrawn affect, passive behavior, and finally catatonic symptoms initially seemed to imply a major depression. It is recognized that functional catatonia is associated with affective disorders [4,5], and thus a diagnosis of “lethal catatonia” was considered in the differential diagnosis of this patient‘s clinical presentation. However, the findings of the mental status examination prior to his rapid deterioration, the absence of suicidal ideation or psychosis, and the presence of neurologic signs and symptoms raised the suspicion that his clinical deterioration represented an acute organic process rather than a major affective disorder. The presence of impaired cog250
nition, depression, leg weakness, and snout and
glabellar release signs and CT findings of cortical atrophy and ventricular enlargement are all consistent with symptoms and signs of the AIDS dementia complex [6,7]. Navia and associates describe patients with the severe form of this dementia as becoming “bedridden and mute, with a wide-eyed stare and little or no response to their surroundings,” which would certainly describe this patient’s condition after his sudden deterioration. In addition, they note that the course of the dementia may include sudden acceleration of symptoms, especially in the setting of systemic illness [6]. The presence of the acute onset of rigidity in association with mental status changes, both of which coincided with a course of prochlorperazine administration, raised the possibility that this patient’s acute symptoms represented a severe extrapyramidal syndrome with many of the features of the neuroleptic malignant syndrome (NMS). In addition to his mental status changes and muscular rigidity, this patient’s acute course was marked by instability of blood pressure and pulse, tachypnea, profuse diaphoresis, and elevated CPK, all of which are found in NMS [8,9]. The diagnosis of NMS in this patient is complicated by preexisting fever and elevated liver enzymes (although both of these parameters worsened when the patient deteriorated) and leukopenia secondary to AIDS. In support of this diagnosis is the dramatic improvement this patient experienced when treated with anticholinergic and dopamine agonist medication. In patient 1, extrapyramidal side effects of prochlorperazine were initially thought to represent signs and symptoms of depression requiring psychiatric consultation. Patient 2 demonstrated extrapyramidal symptoms and signs that improved rapidly after procholorperazine and metoclopramide were discontinued and treatment with anticholine@ medication was instituted. Review of the literature revealed two other reports of extrapyramidal symptoms occurring in AIDS patients treated for nausea with low-dose metoclopramide or chlorpromazine [lo] and prochlorperazine [ 111. Also of note is a case of neuroleptic malignant syndrome in a patient with AIDS who was treated with prochlorperazine and droperidol [12]. Patients suffering from the AIDS dementia complex may be unusually susceptible to extrapyramidal side effects from neuroleptic medication. It has been demonstrated in schizophrenic patients that increased severity of neuroleptic drug-induced parkinsonism is associated with larger ven-
Extrapyramidal Side Effects in AIDS Patients
tricular-brain ratios, suggesting that brain atrophy may increase the risk of this side effect [13]. In addition to brain atrophy, neuropathologic lesions found in brains of patients with the-AIDS dementia complex are found predominantly in white matter and subcortical structures, with the basal ganglia often showing severe involvement [6,14]. Elderly patients with drug-induced parkinsonism have been found to be at increased risk of later developing idiopathic Parkinson’s disease, indicating that drug-induced parkinsonism may, in some patients, reflect a reduced supply of dopaminergic neurons in the substantia nigra [15]. Whether brain atrophy or clinically inapparent basal ganglia dysfunction in patients with the AIDS dementia complex would predispose them to extrapyramidal side effects from neuroleptic medication, or to the neuroleptic malignant syndrome, which may be the most extreme type of extrapyramidal toxicity [16], is a question that requires further investigation. These cases also demonstrate the difficulty of differentiating the various neuropsychiatric syndromes that can occur in patients with AIDS. Each syndrome may present with slowness in speech and gait, unanimated facies, and dysphoric mood (Tables 1 and 2). Thus any psychiatric symptoms must first be considered to have underlying organic etiology. Reversible organic illness causing delirium, such as CNS infection, hypoxemia, and electrolyte imbalance, must be ruled out. In addition to neuroleptics, medications used in treating patients with AIDS, such as antibiotics and antiviral agents, antineoplastic drugs, and azidothymidine, may have neuropsychiatric side effects, which can include depression, visual hallucinations, mania, insomnia, and agitation [17]. Neurologic examination may be helpful in differentiating early dementia from functional psychiatric illness. The presence of snout and glabellar release signs, slowed saccadic eye movements, and difficulty repeating five numbers backward has been found by one clinician to occur commonly prior to the development of early dementia [18]. Neuropsychiatric testing should include both selfreport measures of cognitive function and objective measures of performance; the most sensitive tests to detect early organic brain dysfunction in patients with AIDS include tests of spatial motor coordination [17]. An electroencephalogram may demonstrate nonfocal diffuse slowing in delirium or dementia: however, normal results may occur in early stages of either process [19]. Examination of the cerebrospinal fluid is essential to rule out CNS
Table 1. Affective disorders that can occur in patients with AIDS Symptoms and Disorder Major depression
signs
Treatment”
Dysphoric mood, insomnia, poor concentration,
Consider antidepressants with low anticholinergic activity.
apathy, psychomotor retardation, forgetfulness (all may occur in dementia). Adjustment disorder with depressed or anxious mood
Sadness, guilt, worthlessness, disbelief, numbness, denial; anger, fearfulness, panic attacks, insomnia, anorexia.
Psychotherapy, family therapy, group therapy, AIDS self-help groups, benzodiazepines.
“O&row D, Grant I, Atkinson H: Assessment and management of the AIDS patient with neuropsychiatric disturbances. J Clin Psychiatry 49(5, Suppl): 14-22, 1988
infection. CT scanning may demonstrate abnormalities such as those found in CNS toxoplasmosis or lymphoma, or atrophy and white matter abnormalities found in the AIDS dementia complex [6]. Finally, although it may not be possible to differentiate between depression and the early stages of AIDS dementia, clinical observation and repeated neuropsychiatric testing over time will usually provide a definitive diagnosis. Treatment of the various functional and organic mental disorders that can occur in patients with AIDS is shown in Tables 1 and 2. There are, as yet, few reports of clinical trials of psychotropic medications in patients with AIDS, although many experienced clinicians recommend low doses of high-potency neuroleptics such as haloperidol for treatment of psychosis [2,17]. Preliminary data suggest azidothymidine [17,20] or psychostimulants [17,21] may be helpful in treatment of AIDS dementia. Treatment of nausea might best be initiated by nonneuroleptic antihistaminic medications such as dimenhydrinate. Unfortunately, these drugs have anticholinergic properties that could precipitate or exacerbate delirium [22], and they may not be as effective as the antiemetics with dopamineantagonist activity, such as prochlorperazine, me251
J. R. Swenson et al.
Table
2. Organic
mental
disorders
that may occur
in patients
Symptoms
Disorder
with AIDS Treatment
and signs
Dementia
Early: forgetfulness, poor concentration; apathy; psychomotor retardation (may be indistinguishable from major depression), loss of balance, leg weakness, tremor. Later: disorientation, psychosis, severe memory impairment, mutism, seizures, death.
No definite treatment known; psychostimulants or azidothymidine may help.”
Delirium
Acute onset, fluctuating course: disorientation, impaired attention, memory impairment, decreased level of consciousness, psychosis, hallucinations, disorganized thinking.
Investigate and correct cause (CNS infection, medications, electrolyte imbalance, hypoxemia); low-dose neuroleptics for agitation (watch for EPS).”
Unanimated facies, akinesia, tremor, rigidity; coinciding with administration of neuroleptic medication.
Withdraw neuroleptic if possible; anticholinergic medication, benzodiazepines.
Fever, rigidity, decreased level consciousness, autonomic nervous system instability.
Withdraw neuroleptic; therapy; dantrolene, bromocriptine.h
Extrapyramidal
Neuroleptic
reactions
malignant
syndrome
“Ostrow D, Grant I, Atkinson H: Assessment and management of the AIDS patient with neuropsychiatric Psychiatry 49(5, Suppl): 14-22, 1988 “Guze BH, Baxter LR: Neuroleptic malignant syndrome. Am J Psychiatry 142: 1137-1135,
toclopramide, or domperidone. If it is necessary to use neuroleptics as antiemetics, or for the treatment of neuropsychiatric complications, in patients with AIDS, they should be used in low doses, and clinicians must remain alert to the possibility of extrapyramidal side effects in these patients.
References 1. Faulstich ME: Psychiatric aspects of AIDS. Am J Psychiatry 144:551-556, 1987 2. Wolcott DL, Fawzy FI, Pasnau RO: Acquired immune deficiency syndrome (AIDS) and consultation-liaison psychiatry. Gen Hosp Psychiatry 7:280292, 1985 3. Gordin FM, Simon GL, Wofsy CB, Milks J: Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 100:495-499, 1984 4. Abrams R, Taylor MA: Catatonia: A prospective clinical study. Arch Gen Psychiatry 33:579-581, 1976 5. Mann SC, Caroff SN, Bleier HR, Welz WKR, Kling MA, Hayashida M: Lethal catatonia. Am J Psychiatry 143:1374-1381, 1986
252
supportive
disturbances.
J Clin
1985
6. Navia BA, Jordan BD, Price RW: The AIDS dementia complex: I. Clinical features. Ann Neurol19:517-524, 1986 7. Gabuzda DH, Hirsch MS: Neurologic manifestations of infection with human immunodeficiency virus: clinical features and pathogenesis. Ann Intern Med 107:383-391, 1987 8. Guze BH, Baxter LR: Neuroleptic malignant syndrome. N Engl J Med 313:163-166, 1985 9. Levenson JL: Neuroleptic malignant syndrome. Am J Psychiatry 142:1137-1145, 1985 10. Hollander H, Golden J, Mendelson T, Cortland D: Extrapyramidal symptoms in AIDS patients given low-dose metoclopramide or chlorpromazine. (Letter.) Lancet ii:1186, 1985 11. Edelstein H, Knight R: Severe parkinsonism in two AIDS patients taking prochlorperazine. (Letter.) Lancet ii:341-342, 1987 12. Bernstein WB, Scherokman 8: Neuroleptic malignant syndrome in a patient with acquired immunodeficiency syndrome. Acta Neurol Stand 73:636637, 1986 13. Hoffman WF, Labs SM, Casey DE: Neurolepticinduced parkinsonism in older schizophrenics. Biol Psychiatry 22~427-439, 1987 14. Navia BA, Cho ES, Petit0 CK, Price RW: The AIDS
Extrapyramidal Side Effects in AIDS Patients
15. 16. 17.
18.
dementia complex: II. Neuropathology. Ann Nemo1 19:525-535, 1986 Wilson JA, Smith RG: Relation between elderly and AIDS patients with drug-induced Parkinson’s disease. (Letter.) Lancet ii:686, 1987 Sternberg DE: Neuroleptic malignant syndrome: The pendulum swings. (Editorial.) Am J Psychiatry 143:1273-1275, 1986 Ostrow D, Grant I, Atkinson H: Assessment and management of the AIDS patient with neuropsychiatric disturbances. J Clin Psychiatry 49(5, Suppl):lP22, 1988 Teschke RS: A tetrad of neurologic signs sensitive to early human immunodeficiency virus brain disease. (Letter.) Arch Neurol 44:693, 1987
19. Fenton TW: AIDS-related psychiatric disorder. Br J Psychiatry 151:579-588, 1987 20. Yarchoan R, Thomas RV, Grafman J, et al: Longterm administration of 3’-azido-2’,3’-dideoxythymidine to patients with AIDS-related neurological disease. Ann Neural 23(Suppl):S82-S87, 1988 21. Femandez F, Adams F, Levy JK, et al: Cognitive impairment due to AIDS-related complex and its response to psychostimulants. Psychosomatics 29:3846, 1988 22. Douglas WW: Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In Gilman AG, Goodman LS, Rall TW, et al (eds), The Pharmacologic Basis of Therapeutics. New York, Macmillan, 1985, pp 622-624
253
Abstract: The use of neuroleptic medication as antiemetics, or in the treatment of neuropsychiatric disorders in patients with AIDS, may be associated with extrapyramidal side effects and lead to difficulty with diagnosis and management. Two cases are presented that describe severe extrapyramidal syndromes occurring in two patients with AIDS, one treated with prochlorperazine and the other with prochlorperazine and metoclopropramide. It is possible thaf the neuropathologic lesions found in pafienfs with fhe AlDS dementia complex may predispose to extrapyramidal side effects of neurolepfic medication. The differential diagnosis and treatment of delirium, dementia, depression, and extrapyramidal reactions in patients with AIDS is discussed.
Between 30% and 40% of patients with the acquired immune-deficiency syndrome (AIDS) develop neuropsychiatric complications during the course of their illness [1,2]. The initial presentation of central nervous (CNS) complications of AIDS may resemble psychiatric illness, and thus the management of organic mental disorders in patients with AIDS is often extremely complex. Patients with AIDS may well require neuroleptic medication for the treatment of delirium, psychosis, agitation, or overwhelming anxiety states, or for the treatment of nausea and vomiting associated with either the illness or as a side effect of some treatments [3]. From the Program in Consultation-Liaison Psychiatry and Behavioral Medicine, Department of Psychiatry, University of California, San Diego, La Jolla, California (J.R.S.; J.E.D.), the Department of Psychiatry, Scripps Clinic and Research Foundation, La Jolla, California (M.E.), and the Department of Medicine, University of California, San Diego, La Jolla, California 0-L.). Address reprint requests to: J. Dimsdale, M.D., University of California, San Diego Medical Center, T-004, 225 Dickinson Street, San Diego, CA 92103.
248 ISSN 0163~8343B983.50
Unfortunately, extrapyramidal side effects from neuroleptic medication may cause diagnostic uncertainty, exacerbate CNS dysfunction, and complicate management. We report two cases of severe extrapyramidal reactions occurring in patients with AIDS. These cases demonstrate the complexity of the differential diagnosis of neuropsychiatric signs and symptoms in patients with AIDS and the fact that extrapyramidal side effects of medication can be misattributed to depression: we speculate that certain patients with AIDS may be singularly vulnerable to extrapyramidal side effects when treated with neuroleptics.
Case Histories Patient 1 A 24-year-old homosexual male presented with cough, fever, and dyspnea on exertion and complained of feeling depressed, admitting that he had thought of killing himself by “turning on the gas in my apartment.” He had been diagnosed with AIDS approximately 1 year previously, and his neurologic examination at that time had been normal apart from the presence of a snout reflex. Eight months before the present admission he noted the onset of mild left lower extremity weakness, and 6 months prior to admission he noted impotence. At the time of admission he appeared chronically ill, with elevated temperature of 100.3”F, respiratory rate of 28 per minute, pulse of 116 bpm, and blood pressure of 1261% mm Hg. Throat examination revealed a scant whitish exudate, and cervical adenopathy was present. Pulmonary examination demGeneral Hospital Psychiatry 11,248-253,1989 0 1989Elsevier Science Publishing Co., Inc. 655AvenueoftheAmencas,NewYork,NY
10010
Extrapyramidal
onstrated decreased breath sounds in the left lung base. Mental status examination revealed a clear sensor-mm with intact orientation and memory, normal thought processes with content notable for suicidal ideation, and depressed mood. Neurologic examination demonstrated intact cranial nerves, normal cerebellar examination, and weakness and atrophy of the left lower extremity muscles, particularly of the tibialis anterior. Left knee and ankle deep tendon reflexes were hyperreflexic, and the left toe was upgoing. Pinprick sensation was decreased in the distribution of the left deep peroneal nerve. Snout and glabellar release reflexes were present. His gait was wide-based and asymmetric. Laboratory studies on admission demonstrated elevated liver function tests, a white blood count (WBC) of 2400 per microliter (normal 7800 4 3000) with lymphopenia, and a hemoglobin of 10.6 g/d1 (normal 16.0 +- 2) with macrocytosis on smear. Hepatitis B surface antibody was positive. Chest x-ray disclosed diffuse interstitial infiltrates compatible with pneumocystis . .< which was confirmed by carmii pneumonia, bronchoscopy. The patient was treated with intravenous trimethoprim-sulfamethoxazole. During the initial hospital course the patient remained febrile and slightly tachypneic, with no major changes in his clinical status. Nerve conduction studies and electromyogram demonstrated diffuse denervation of all muscles sampled in the left lower extremity, consistent with a diffuse polyradiculopathy of the left leg. Computed tomographic (CT) scan of the brain done soon after admission revealed a large area of ringlike calcification (roughly 5 x 2 cm) in the region of the left anterior capsule, caudate head, and corona radiata. Several smaller foci of abnormal calcification were seen in the right corona radiata and some superior to the corpus callosum. There was no associated edema, mass effect, or contrast enhancement. It was felt that these findings represented old healed toxoplasmosis. In addition, the ventricular system was felt to be enlarged, as were the sylvian fissures, basilar cisterns, and cortical sulci, reflecting moderate volume loss. Because of nausea, he was started on prochlorperazine 10 mg three times daily. Five days later it was noted that he had become more depressed, withdrawn, and “passive” and seemed to have lost his will to live, and a psychiatric consultation was requested. During the initial psychiatric consultation, the patient reported that he had no past psychiatric history, and he stated that his major problem was “difficulty communicating.” He admitted feeling very depressed and having suicidal thoughts when initially diagnosed with his present episode of pneumonia; however, he said that he had decided he really wanted to live, and recover from this setback in order to move back home with his parents. His mother reported his
Side Effects in AIDS Patients
depression worsened rather suddenly over the previous 3 days and noted that he had lost his usual “angry fighting spirit.” His sleep was poor, with frequent awakenings, and his appetite appeared good; however, the nurses noted he had trouble swallowing and also commented that he was quite “rigid” when turned in bed. On mental status examination he appeared to be a young man with a remarkably immobile facial expression, staring gaze, and soft speech. He was alert and oriented to time and place. Thought association was unremarkable and he did not express suicidal ideation or plans, although he described his mood as depressed. Affect was withdrawn and lethargic. The initial impression was that this man was depressed: however, the differential diagnosis included extrapyramidal symptoms possibly due to the CNS lesion affecting the basal ganglia, and symptoms of the AIDS dementia complex (subacute encephalitis, AIDS encephalopathy). Examination and cultures of the cerebrospinal fluid did not reveal any evidence of infection, and repeat CT scan of the brain was unchanged. Prochlorperazine was discontinued because of possible extrapyramidal side effects. Over the following 2 days the patient’s status deteriorated, with development of bradykinesia and diffuse limb and truncal rigidity and inability to speak, although he seemed alert and tried to cooperate with examination. His temperature after admission had fluctuated from 98.3”F to 102.4”F with most readings below lOO.O”F;however, after the onset of rigidity, temperature was consistently over lOO.O”F, at times up to 103.7”F, and had to be managed with a cooling blanket. Blood pressure, which had been stable and in the normal range, became labile, fluctuating from 120/80 to 180/100 mm Hg. His pulse ranged from 96 to 144 bpm. He was profusely diaphoretic. Treatment with intravenous and then oral benztropine mesylate 2 mg three times daily produced dramatic improvement over the next few hours in his ability to speak and move his extremities. Muscular tone, however, remained quite rigid over the following 2 days, and he was started on levodopal carbidopa lO/lOOmg three times daily with improvement in rigidity. Vital signs stabilized over the next four days but he remained febrile and developed a marked leukopenia (WBC 700 per microliter), felt possibly to be secondary to levodopalcarbidopa; this was discontinued, and his WBC returned to pretreatment levels. After his speech returned, it was evident that he demonstrated cognitive impairment in orientation to time, ability to concentrate, and short-term memory, which fluctuated over the next few days but then cleared. Laboratory investigations during this acute episode revealed a markedly elevated creatine phosphokinase (CPK), which peaked at 2104 IUlL (normal O-175 IU/L), but had started to drop at the time of discharge. Liver function tests, which had been ele-
249
J. R. Swenson et al. vated at the time of admission, increased during the hospital course. At the time of discharge, he was alert and oriented, with no evidence of depression, and had regained his usual “grumpy mood” but hopeful attitude. He continued to have mild bradykinesia and was discharged on benztropine mesylate.
Patient 2 A 31-year-old homosexual male presented to the outpatient AIDS clinic requesting follow-up care after recently moving to the city. He had been diagnosed with AIDS 18 months previously and was currently undergoing treatment for pneumocystis pneumonia and cytomegalovirus retinitis. He also had two untreated lesions of Kaposi’s sarcoma. Medications he had been receiving included pentamidine isethinoate, ganciclovir, alprazolam, cefaclor, metoclopramide, prochlorperazine, and triazolam. He complained of anxiety, insomnia, decreased concentration, and difficulty moving his tongue. On physical examination he was a thin pale man with unanimated facies and flat effect. He was alert and oriented with intact recent and remote memory, and was able to repeat five numbers forward but only three backward. Snout and glabellar release signs were present. Muscular tone was increased; there was a cogwheeling type of rigidity, bilateral hand tremor, and decreased power in all limbs. Gait demonstrated slow small steps. It was felt that he demonstrated features of a parkinsonian syndrome as well as some features of the AIDS dementia complex. Prochlorperazine and metoclopramide were discontinued and the patient was started on benztropine mesylate 1.0 mg twice daily. When the patient was seen 1 week later, muscular rigidity and hand tremor had resolved and he was speaking more easily.
Discussion When patient 1 was admitted to the hospital, his
depressed mood and suicidal ideation, and the rapid development of withdrawn affect, passive behavior, and finally catatonic symptoms initially seemed to imply a major depression. It is recognized that functional catatonia is associated with affective disorders [4,5], and thus a diagnosis of “lethal catatonia” was considered in the differential diagnosis of this patient‘s clinical presentation. However, the findings of the mental status examination prior to his rapid deterioration, the absence of suicidal ideation or psychosis, and the presence of neurologic signs and symptoms raised the suspicion that his clinical deterioration represented an acute organic process rather than a major affective disorder. The presence of impaired cog250
nition, depression, leg weakness, and snout and
glabellar release signs and CT findings of cortical atrophy and ventricular enlargement are all consistent with symptoms and signs of the AIDS dementia complex [6,7]. Navia and associates describe patients with the severe form of this dementia as becoming “bedridden and mute, with a wide-eyed stare and little or no response to their surroundings,” which would certainly describe this patient’s condition after his sudden deterioration. In addition, they note that the course of the dementia may include sudden acceleration of symptoms, especially in the setting of systemic illness [6]. The presence of the acute onset of rigidity in association with mental status changes, both of which coincided with a course of prochlorperazine administration, raised the possibility that this patient’s acute symptoms represented a severe extrapyramidal syndrome with many of the features of the neuroleptic malignant syndrome (NMS). In addition to his mental status changes and muscular rigidity, this patient’s acute course was marked by instability of blood pressure and pulse, tachypnea, profuse diaphoresis, and elevated CPK, all of which are found in NMS [8,9]. The diagnosis of NMS in this patient is complicated by preexisting fever and elevated liver enzymes (although both of these parameters worsened when the patient deteriorated) and leukopenia secondary to AIDS. In support of this diagnosis is the dramatic improvement this patient experienced when treated with anticholinergic and dopamine agonist medication. In patient 1, extrapyramidal side effects of prochlorperazine were initially thought to represent signs and symptoms of depression requiring psychiatric consultation. Patient 2 demonstrated extrapyramidal symptoms and signs that improved rapidly after procholorperazine and metoclopramide were discontinued and treatment with anticholine@ medication was instituted. Review of the literature revealed two other reports of extrapyramidal symptoms occurring in AIDS patients treated for nausea with low-dose metoclopramide or chlorpromazine [lo] and prochlorperazine [ 111. Also of note is a case of neuroleptic malignant syndrome in a patient with AIDS who was treated with prochlorperazine and droperidol [12]. Patients suffering from the AIDS dementia complex may be unusually susceptible to extrapyramidal side effects from neuroleptic medication. It has been demonstrated in schizophrenic patients that increased severity of neuroleptic drug-induced parkinsonism is associated with larger ven-
Extrapyramidal Side Effects in AIDS Patients
tricular-brain ratios, suggesting that brain atrophy may increase the risk of this side effect [13]. In addition to brain atrophy, neuropathologic lesions found in brains of patients with the-AIDS dementia complex are found predominantly in white matter and subcortical structures, with the basal ganglia often showing severe involvement [6,14]. Elderly patients with drug-induced parkinsonism have been found to be at increased risk of later developing idiopathic Parkinson’s disease, indicating that drug-induced parkinsonism may, in some patients, reflect a reduced supply of dopaminergic neurons in the substantia nigra [15]. Whether brain atrophy or clinically inapparent basal ganglia dysfunction in patients with the AIDS dementia complex would predispose them to extrapyramidal side effects from neuroleptic medication, or to the neuroleptic malignant syndrome, which may be the most extreme type of extrapyramidal toxicity [16], is a question that requires further investigation. These cases also demonstrate the difficulty of differentiating the various neuropsychiatric syndromes that can occur in patients with AIDS. Each syndrome may present with slowness in speech and gait, unanimated facies, and dysphoric mood (Tables 1 and 2). Thus any psychiatric symptoms must first be considered to have underlying organic etiology. Reversible organic illness causing delirium, such as CNS infection, hypoxemia, and electrolyte imbalance, must be ruled out. In addition to neuroleptics, medications used in treating patients with AIDS, such as antibiotics and antiviral agents, antineoplastic drugs, and azidothymidine, may have neuropsychiatric side effects, which can include depression, visual hallucinations, mania, insomnia, and agitation [17]. Neurologic examination may be helpful in differentiating early dementia from functional psychiatric illness. The presence of snout and glabellar release signs, slowed saccadic eye movements, and difficulty repeating five numbers backward has been found by one clinician to occur commonly prior to the development of early dementia [18]. Neuropsychiatric testing should include both selfreport measures of cognitive function and objective measures of performance; the most sensitive tests to detect early organic brain dysfunction in patients with AIDS include tests of spatial motor coordination [17]. An electroencephalogram may demonstrate nonfocal diffuse slowing in delirium or dementia: however, normal results may occur in early stages of either process [19]. Examination of the cerebrospinal fluid is essential to rule out CNS
Table 1. Affective disorders that can occur in patients with AIDS Symptoms and Disorder Major depression
signs
Treatment”
Dysphoric mood, insomnia, poor concentration,
Consider antidepressants with low anticholinergic activity.
apathy, psychomotor retardation, forgetfulness (all may occur in dementia). Adjustment disorder with depressed or anxious mood
Sadness, guilt, worthlessness, disbelief, numbness, denial; anger, fearfulness, panic attacks, insomnia, anorexia.
Psychotherapy, family therapy, group therapy, AIDS self-help groups, benzodiazepines.
“O&row D, Grant I, Atkinson H: Assessment and management of the AIDS patient with neuropsychiatric disturbances. J Clin Psychiatry 49(5, Suppl): 14-22, 1988
infection. CT scanning may demonstrate abnormalities such as those found in CNS toxoplasmosis or lymphoma, or atrophy and white matter abnormalities found in the AIDS dementia complex [6]. Finally, although it may not be possible to differentiate between depression and the early stages of AIDS dementia, clinical observation and repeated neuropsychiatric testing over time will usually provide a definitive diagnosis. Treatment of the various functional and organic mental disorders that can occur in patients with AIDS is shown in Tables 1 and 2. There are, as yet, few reports of clinical trials of psychotropic medications in patients with AIDS, although many experienced clinicians recommend low doses of high-potency neuroleptics such as haloperidol for treatment of psychosis [2,17]. Preliminary data suggest azidothymidine [17,20] or psychostimulants [17,21] may be helpful in treatment of AIDS dementia. Treatment of nausea might best be initiated by nonneuroleptic antihistaminic medications such as dimenhydrinate. Unfortunately, these drugs have anticholinergic properties that could precipitate or exacerbate delirium [22], and they may not be as effective as the antiemetics with dopamineantagonist activity, such as prochlorperazine, me251
J. R. Swenson et al.
Table
2. Organic
mental
disorders
that may occur
in patients
Symptoms
Disorder
with AIDS Treatment
and signs
Dementia
Early: forgetfulness, poor concentration; apathy; psychomotor retardation (may be indistinguishable from major depression), loss of balance, leg weakness, tremor. Later: disorientation, psychosis, severe memory impairment, mutism, seizures, death.
No definite treatment known; psychostimulants or azidothymidine may help.”
Delirium
Acute onset, fluctuating course: disorientation, impaired attention, memory impairment, decreased level of consciousness, psychosis, hallucinations, disorganized thinking.
Investigate and correct cause (CNS infection, medications, electrolyte imbalance, hypoxemia); low-dose neuroleptics for agitation (watch for EPS).”
Unanimated facies, akinesia, tremor, rigidity; coinciding with administration of neuroleptic medication.
Withdraw neuroleptic if possible; anticholinergic medication, benzodiazepines.
Fever, rigidity, decreased level consciousness, autonomic nervous system instability.
Withdraw neuroleptic; therapy; dantrolene, bromocriptine.h
Extrapyramidal
Neuroleptic
reactions
malignant
syndrome
“Ostrow D, Grant I, Atkinson H: Assessment and management of the AIDS patient with neuropsychiatric Psychiatry 49(5, Suppl): 14-22, 1988 “Guze BH, Baxter LR: Neuroleptic malignant syndrome. Am J Psychiatry 142: 1137-1135,
toclopramide, or domperidone. If it is necessary to use neuroleptics as antiemetics, or for the treatment of neuropsychiatric complications, in patients with AIDS, they should be used in low doses, and clinicians must remain alert to the possibility of extrapyramidal side effects in these patients.
References 1. Faulstich ME: Psychiatric aspects of AIDS. Am J Psychiatry 144:551-556, 1987 2. Wolcott DL, Fawzy FI, Pasnau RO: Acquired immune deficiency syndrome (AIDS) and consultation-liaison psychiatry. Gen Hosp Psychiatry 7:280292, 1985 3. Gordin FM, Simon GL, Wofsy CB, Milks J: Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 100:495-499, 1984 4. Abrams R, Taylor MA: Catatonia: A prospective clinical study. Arch Gen Psychiatry 33:579-581, 1976 5. Mann SC, Caroff SN, Bleier HR, Welz WKR, Kling MA, Hayashida M: Lethal catatonia. Am J Psychiatry 143:1374-1381, 1986
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supportive
disturbances.
J Clin
1985
6. Navia BA, Jordan BD, Price RW: The AIDS dementia complex: I. Clinical features. Ann Neurol19:517-524, 1986 7. Gabuzda DH, Hirsch MS: Neurologic manifestations of infection with human immunodeficiency virus: clinical features and pathogenesis. Ann Intern Med 107:383-391, 1987 8. Guze BH, Baxter LR: Neuroleptic malignant syndrome. N Engl J Med 313:163-166, 1985 9. Levenson JL: Neuroleptic malignant syndrome. Am J Psychiatry 142:1137-1145, 1985 10. Hollander H, Golden J, Mendelson T, Cortland D: Extrapyramidal symptoms in AIDS patients given low-dose metoclopramide or chlorpromazine. (Letter.) Lancet ii:1186, 1985 11. Edelstein H, Knight R: Severe parkinsonism in two AIDS patients taking prochlorperazine. (Letter.) Lancet ii:341-342, 1987 12. Bernstein WB, Scherokman 8: Neuroleptic malignant syndrome in a patient with acquired immunodeficiency syndrome. Acta Neurol Stand 73:636637, 1986 13. Hoffman WF, Labs SM, Casey DE: Neurolepticinduced parkinsonism in older schizophrenics. Biol Psychiatry 22~427-439, 1987 14. Navia BA, Cho ES, Petit0 CK, Price RW: The AIDS
Extrapyramidal Side Effects in AIDS Patients
15. 16. 17.
18.
dementia complex: II. Neuropathology. Ann Nemo1 19:525-535, 1986 Wilson JA, Smith RG: Relation between elderly and AIDS patients with drug-induced Parkinson’s disease. (Letter.) Lancet ii:686, 1987 Sternberg DE: Neuroleptic malignant syndrome: The pendulum swings. (Editorial.) Am J Psychiatry 143:1273-1275, 1986 Ostrow D, Grant I, Atkinson H: Assessment and management of the AIDS patient with neuropsychiatric disturbances. J Clin Psychiatry 49(5, Suppl):lP22, 1988 Teschke RS: A tetrad of neurologic signs sensitive to early human immunodeficiency virus brain disease. (Letter.) Arch Neurol 44:693, 1987
19. Fenton TW: AIDS-related psychiatric disorder. Br J Psychiatry 151:579-588, 1987 20. Yarchoan R, Thomas RV, Grafman J, et al: Longterm administration of 3’-azido-2’,3’-dideoxythymidine to patients with AIDS-related neurological disease. Ann Neural 23(Suppl):S82-S87, 1988 21. Femandez F, Adams F, Levy JK, et al: Cognitive impairment due to AIDS-related complex and its response to psychostimulants. Psychosomatics 29:3846, 1988 22. Douglas WW: Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In Gilman AG, Goodman LS, Rall TW, et al (eds), The Pharmacologic Basis of Therapeutics. New York, Macmillan, 1985, pp 622-624
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