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Mood Disorder With Manic Features in a Patient Treated With Granulocyte-Monocyte Colony Stimulating Factor
Letter Mood Disorder With Manic Features in a Patknl Treated With Granulocyte-Monocyte Colony Stimulating Factor SIR: We report the case of a 41-year-old female patient who developed symptoms of mania after a fortnight of treabTlent with GranulocyteMonocyte Colony Stimulating Factor (GMCSF)/(Leucomax).
Case Reporr The patient's history revealed that idiopathic neutropenia had been diagnosed at the age of 20. The patient had a blood count of 3,000 white cells (33% neutrophils). No cyclic variation was detected and bone marrow biopsy showed hypoplasia of the white cell line without abnonnal fonns. There was no particular hematological family history. In 1992, granulocyte colony stimulating factor (G-CSF)/ (Neupogen) treatment was commenced. In February 1994, the patient developed aseptic necrosis of the olecranon. Although G-eSF was suspected in this necrosis, no trace of medullary hyperplasia was found. Nevertheless, on December 16, 1994 the G-eSF was discontinued and replaced on December 21,1994 (Day 0) with granuloyete-monocyte colony stimulating factor (GM-eSF) at the dose of 51lg sclkg/day. The patient's laboratory results showed a leucocytosis of II,OOO/mm3 with 73% neutrophils. On 01.01.95 (Day II), the patient had an episode of acute dyspnea that resolved spontaneously. On 14.01.95 (Day 24), the patient developed
violent epigastric pain with a significant anxious overlay. Gastroscopy identified a foreign body (shellfish). All paraclinical tests were nonnal: routine blood tests, chest X ray, blood gases (hyperventilation: ~: 120,~: 26), ECG, chest computed tomography (CO scan. Symptoms resolved after diazepam infusion. On January 24,1995 (Day 34) she presented with flight of ideas, hyperthymia. garrulousness, psychomotor agitation, and insomnia. The neurological examination was nonnal. There was no significant psychiatric history, personal or familial. The patient received a combination of 16 mg
VOLUME 37. NUMBER 3. MAY - JUNE 1996
oral haloperidol (Haldol) daily and a 100 mg tablet of levomepramizine (Nozinan) nocte from January I to January 2,1995 (Day 34-Day 42). GM-eSF was stopped at the same time. On 01.02 her medication was reduced to 8 mg haloperidol daily. On 16.02 (Day 47) she presented with sinusitis, which was treated with IV antibiotics using an amoxicillinc1avulanic acid combination. One dose of G-eSF was administered. Another flare-up of the patient's psychiatric condition ensued, but the patient admitted that she had not taken her medication correctly. Treatment with neuroleptics was restarted, and the patient was fmally diseharged asymptomatic on March 13, 1995 (Day 62). A number of paraclinical tests were carried out: routine blood tests, thyroid function, electroencephalogram (EEG), lumbar puncture, cerebral CT sean with and without contrast, auditory- and visualevoked potentials, and EEG mapping. Cerebral nuclear magnetic resonance scans were all nonnaI. The cerebral seintography with [~c]d,l-hex amethylpropyleneamine oxime (HMPAO) showed a slight hypofixation in the cortex.
Discussion It would appear that administration of GM-CSF should be incriminated in the advent of this patient's psychiatric symptoms at least if we accept the chronology of events. There are three problems that hinder such a causal link. First, such a causal relation has never been described. I Second, there is the longtime interval between administration of GM-CSF and the onset of psychiatric symptoms. However, the acute dyspneic episode that occurred at Day 11 could be considered a feature of anxiety. Third, there is the problem of the length of the episode. Regarding the first point, it must be pointed out that this is not the case with other molecules of the cytokine group. This group includes2 G-CSF, erythropoietin, interleukins, and interferon. G-CSF (Filiarastim)1 has no known central effects. Erythropoietin (Epoetin Alpha) There have been reports· of acute tonicclonic episodes and visual hallucinations.
30S
Letter
Interleukin 2 (Aldesleukin) Agitation, anxiety, confusion, drowsiness, syncope, depression, hallucinations, paralysis, speech disorders, and convulsions have been described. 3 Interferon Alpha (Interferon Alfa) Since interferon is the oldest available cytokine, its central nervous system (CNS) effects are the best known,' including anxiety, irritability, delirium, depression and manic episodes, obsessional and phobic disorders, agitation, paranoia, amnesia, confusion, stupor, and coma. These effects have even been described with small doses. Usually, these effects occur early and are reversible once the medication is ceased; however, in severe cases they may appear late and persist for up to 6 weeks. No neurophysiological mechanism has been advanced to explain these disturbances. It should be stated that, although this type of adverse reaction has not been described with either GM-CSF or G-CSF, severely disturbed CNS function has been observed with other cytokines. The second and third points presuppose either an accumulation phenomenon, which is unlikely in light of bioavailability studies, or
306
formation of an active metabolite or even of an immune complex. Nevertheless, this type of rmding exists and is known with interferon. The hypothesis of a potentializing interaction with G-CSF when the patient relapsed during hospitalization, although not entirely excluded, is highly unlikely, however, since the patient has recommenced this medication without the advent of psychiatric symptoms. N. H. Zdanowicz, M.D. C. M. Reynaert, M.D. P. P. Janoe, Ph.D. Ph. J-M Wulleman, M.D. C. J. Chatelain, M.D. Department of Psychosomatic Medicine Hematologic Unit The Universite Catholique de Louvain Cliniques de Mont-Godinne Yvoir, Belgium References I. Dewey DR, Fopny PA, Ford ME, et al: Orog Infonnation, edited by McEvoy OK. Bethesda, MD, American Hospital Fonnulary Service, 1994, pp. 615-620, 903-909, 924932 2. Wilson JO, Braunwald E, Isselbacher 10, et al: Harrison's: Principles of Internal Medicine, 12th Edition. New York, McGraw-Hill, 1991, pp. 63 3. Eurocetus: Proleukin prescribing infonnation. New York, Eurocetus,1993
PSYCHOSOMATICS
Case Reporr The patient's history revealed that idiopathic neutropenia had been diagnosed at the age of 20. The patient had a blood count of 3,000 white cells (33% neutrophils). No cyclic variation was detected and bone marrow biopsy showed hypoplasia of the white cell line without abnonnal fonns. There was no particular hematological family history. In 1992, granulocyte colony stimulating factor (G-CSF)/ (Neupogen) treatment was commenced. In February 1994, the patient developed aseptic necrosis of the olecranon. Although G-eSF was suspected in this necrosis, no trace of medullary hyperplasia was found. Nevertheless, on December 16, 1994 the G-eSF was discontinued and replaced on December 21,1994 (Day 0) with granuloyete-monocyte colony stimulating factor (GM-eSF) at the dose of 51lg sclkg/day. The patient's laboratory results showed a leucocytosis of II,OOO/mm3 with 73% neutrophils. On 01.01.95 (Day II), the patient had an episode of acute dyspnea that resolved spontaneously. On 14.01.95 (Day 24), the patient developed
violent epigastric pain with a significant anxious overlay. Gastroscopy identified a foreign body (shellfish). All paraclinical tests were nonnal: routine blood tests, chest X ray, blood gases (hyperventilation: ~: 120,~: 26), ECG, chest computed tomography (CO scan. Symptoms resolved after diazepam infusion. On January 24,1995 (Day 34) she presented with flight of ideas, hyperthymia. garrulousness, psychomotor agitation, and insomnia. The neurological examination was nonnal. There was no significant psychiatric history, personal or familial. The patient received a combination of 16 mg
VOLUME 37. NUMBER 3. MAY - JUNE 1996
oral haloperidol (Haldol) daily and a 100 mg tablet of levomepramizine (Nozinan) nocte from January I to January 2,1995 (Day 34-Day 42). GM-eSF was stopped at the same time. On 01.02 her medication was reduced to 8 mg haloperidol daily. On 16.02 (Day 47) she presented with sinusitis, which was treated with IV antibiotics using an amoxicillinc1avulanic acid combination. One dose of G-eSF was administered. Another flare-up of the patient's psychiatric condition ensued, but the patient admitted that she had not taken her medication correctly. Treatment with neuroleptics was restarted, and the patient was fmally diseharged asymptomatic on March 13, 1995 (Day 62). A number of paraclinical tests were carried out: routine blood tests, thyroid function, electroencephalogram (EEG), lumbar puncture, cerebral CT sean with and without contrast, auditory- and visualevoked potentials, and EEG mapping. Cerebral nuclear magnetic resonance scans were all nonnaI. The cerebral seintography with [~c]d,l-hex amethylpropyleneamine oxime (HMPAO) showed a slight hypofixation in the cortex.
Discussion It would appear that administration of GM-CSF should be incriminated in the advent of this patient's psychiatric symptoms at least if we accept the chronology of events. There are three problems that hinder such a causal link. First, such a causal relation has never been described. I Second, there is the longtime interval between administration of GM-CSF and the onset of psychiatric symptoms. However, the acute dyspneic episode that occurred at Day 11 could be considered a feature of anxiety. Third, there is the problem of the length of the episode. Regarding the first point, it must be pointed out that this is not the case with other molecules of the cytokine group. This group includes2 G-CSF, erythropoietin, interleukins, and interferon. G-CSF (Filiarastim)1 has no known central effects. Erythropoietin (Epoetin Alpha) There have been reports· of acute tonicclonic episodes and visual hallucinations.
30S
Letter
Interleukin 2 (Aldesleukin) Agitation, anxiety, confusion, drowsiness, syncope, depression, hallucinations, paralysis, speech disorders, and convulsions have been described. 3 Interferon Alpha (Interferon Alfa) Since interferon is the oldest available cytokine, its central nervous system (CNS) effects are the best known,' including anxiety, irritability, delirium, depression and manic episodes, obsessional and phobic disorders, agitation, paranoia, amnesia, confusion, stupor, and coma. These effects have even been described with small doses. Usually, these effects occur early and are reversible once the medication is ceased; however, in severe cases they may appear late and persist for up to 6 weeks. No neurophysiological mechanism has been advanced to explain these disturbances. It should be stated that, although this type of adverse reaction has not been described with either GM-CSF or G-CSF, severely disturbed CNS function has been observed with other cytokines. The second and third points presuppose either an accumulation phenomenon, which is unlikely in light of bioavailability studies, or
306
formation of an active metabolite or even of an immune complex. Nevertheless, this type of rmding exists and is known with interferon. The hypothesis of a potentializing interaction with G-CSF when the patient relapsed during hospitalization, although not entirely excluded, is highly unlikely, however, since the patient has recommenced this medication without the advent of psychiatric symptoms. N. H. Zdanowicz, M.D. C. M. Reynaert, M.D. P. P. Janoe, Ph.D. Ph. J-M Wulleman, M.D. C. J. Chatelain, M.D. Department of Psychosomatic Medicine Hematologic Unit The Universite Catholique de Louvain Cliniques de Mont-Godinne Yvoir, Belgium References I. Dewey DR, Fopny PA, Ford ME, et al: Orog Infonnation, edited by McEvoy OK. Bethesda, MD, American Hospital Fonnulary Service, 1994, pp. 615-620, 903-909, 924932 2. Wilson JO, Braunwald E, Isselbacher 10, et al: Harrison's: Principles of Internal Medicine, 12th Edition. New York, McGraw-Hill, 1991, pp. 63 3. Eurocetus: Proleukin prescribing infonnation. New York, Eurocetus,1993
PSYCHOSOMATICS