212
BIOL PSYCHIATIIY
Correspondence
1992;32:207-213
A week after admission, her BP became increasingly labile, ranging between 160/90 and 190/130. She became pyrexial (38.5 axilla). Repeat blood cultures were negative and she was started on intramuscular Cephalospodn. Her white count rose to 16.0 and ESR to 40. A malarial parasite screen was neg,_.t!,te. She developed clouding of consciousness and had difficulty breathing due to stiffness of the neck and chest muscles. Pulse was 120/min and she was incontinent of urine. Neuroleptic malignant syndrome was diagnosed (creatinine phosphokinase was not measured), haloperidol was stopped, and efforts were made to control her excitement on large doses of diazepam, which proved to be most difficult (60 mg daily, intravenously). A lumbar puncture was attempted but not completed due to her agitation. Ten days after admission, right-sided rhythmic movements developed. Phenytoin was commenced to no effect. The patient became mute and did not respond to commands, At this point, she was transferred to an acute medical ward. Another EEG had to be abandoned due to movement. The lumbar puncture was repeated, this time successfully, showing possible cryptosporidium. Immediate transfer was arranged to a regional neurological center. Here, cryptosporidium was in fact ruled out. Tests for HIV 1 and 2 were negative. The white count had normalized, but the ESR had risen to 70. Three separate blood films showed neither malarial parasites nor trypanosomes. Protein electrophoresis and auto.antibody and immune complex screenings were unremarkable as were serum and cerebrospinal
fluid virology. Mantoux test was negative. An EEG, done successfully this time, showed three fits during the recording, each beginning from different foci in the left hemisphere. Three CT scans were normal. Herpes simplex encephalitis wu~ t,.~ ~nosr. ~ and IV acyclovir and chloramphenicol were commenced. The fits continued and proved extremely difficult to control despite combination treatment with five antiepileptic drugs--phenytoin, sodium valproate, clorazepam, phenobarbitone, and vigabatrinmall given intravenously. ESR remained high and touched i 10. Blood cultures remained negative througheut. After 2 weeks of little progress, high doses of steroids were commenced. This had a dramatic effect and over the next 3 weeks her level of consciousness improved to the point where she could walk with the physical support of the nursing staff. After 5 weeks she was transfered back to the initial referring teaching hospital. A gynecological examination showed that the abdominal mass was resolving and laparotomy was not done. The patient could now recognize her relatives. She could speak a meaningful sentence but only to her husband. She was able to walk slowly, unsupported. She remained afebrile. Two weeks after her return to the initial hospital she was discharged. She had asked to return to Ghana and her husband did in fact return there with her soon after her discharge, where she has remained, being cared for by her brother and sisters. Philip Steadman St George's Teaching Hospital London SWl7
Neurodevelopmental Model of Schizophrenia
prising because they cited and compared their imaging results with those of Jernigan et al (199 !), who cited our 1982 model in some d:~ail. i should like to remind those interested in our neurodevelopmental hypothesis that there were wree arguments advanced in 1982. The ~irst was that there is strong evidence that the braia undergoes profound changes in the second decade of life: this evidence includes a marked decline in cerebral metabolic rate as measured by the Kety-Schmidt method (evidence greatly strengthened and ex-
To the Editor: Dr. Swayze et al develop the view that schizophrenia might result from a developmental disorder of synaptic pruning during the second decade of life, but neglect to state that I put forward this notion in 1982 (Feinberg 1982/83). With my associates, we further extended our hypothesis to affective illness in 1990 (Feinberg et al 1990). This oversight is sur-
Lo~ fespondence
BIOL PSYCHIATRY 1992;32:207-213
panded by subsequent PET observations of Chugani et al (1987); profound reductions in the duration of deep (stage 4) sleep and in the amplitude and deasity of the delta EEG that characterizes this stage (evidence also strengthened by more extensive quantific: "3n (Feinberg et al 1990); and a diminished capacity to recover from brain lesions, notably those that cause aphasia. The second argument was that such extensive brain changes might sometimes be faulty and cause or predispose to those mental illnesses that have peripubertal or postpubertal onsets, ie., that the processes oi late brain development, at that time almost entirely ignored, be considered in the search for the etiology of schizophrenia. The third argument was that synaptic elimination, perhaps triggered t,,, endocrine events, could account for each of the brain cht.:,tges considered under the first argument. In our more recent article (Feinberg et al 1990), we extended our hypotheses regarding the neuronal events underlying late brain development. We proposed that change in synaptic organization (towards fewer but more effective synapses) was but one component of a transformation in which neurons lose plasticity and become "committed." Those interested in the biological and quantitative implications of this model should consult this article.
for delta wave amplitude, cortical metabolic rate and synaptic density. J Theor Biol 142:149-161. Feinberg 1, March JD, Flach K, Maloney T, Chem W-J, Travis F (1990b): Maturational changes in amplitude, incidence and cyclic pattern of the 0-3 Hz (delta) electroencephalogramof human sleep. Brain Dysfunct 3: ! 83192. Jemigan TL, Zisook S, Heaton RK, Moranville JT, Hesselink JR, Braff DL (1991): Magnetic resonance imaging abnormalities in lent.iculta nuclei and cerebral cortex in schizophrenia(1991). Arch Gen Psychiatry 48:881890. Swayze VW II, Andreasen NC, Alliger RJ, Yuh WTC, Ehrhardt (1992): Subconical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging ~tudy. Biol Psychiatry 31:221-240.
Response To the Editor: We thank Dr. Feinberg for bringing to our atten•don his elegant and seminal neurodevelopmental model in which he postulated possible mechanisms of how and why schizophrenia often develops in adolescence (Feinberg 1982, 1983). In developing his comprehensive neurodevelopmental model, Dr. Feinberg was truly ahead of his time, and we regret the negligent omission in our recent paper of his important work. Victor W. Swayze 11I Nancy C. Andreasen I Randall J. Aliger ~ William T.C. Yuh 2 James C. Ehrhardt 2
Irwin Feinberg
Martinez VA Medical Center Martinez, CA
References Chugani HT, Phelps ME, Mazziotta JC (1987): Positron emission tomography of human brain functional development. Ann Neurol 22:487-497. Feinberg, I (1982/83): Schizophrenia: Due to a fault in programmed synaptic elimination during adolescence?J Psychiatry Res ! 7:319-334. Feinberg i, Thode HC Jr, Chugani }IT, March JD (1990a): Gamma distribution model describes maturational curves
213
JMentai Health Clinical Research Center and 2Departmem of Radiology The University of Iowa Hospitals and Clinics
References Feinberg I, (1982): Schizophreniaand late maturationalbrain changes in man. Psychopharmacol Bull 18:29-31. Feinberg 1, (1982/83): Schizophrenia: Due to a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17:319-334.
BIOL PSYCHIATIIY
Correspondence
1992;32:207-213
A week after admission, her BP became increasingly labile, ranging between 160/90 and 190/130. She became pyrexial (38.5 axilla). Repeat blood cultures were negative and she was started on intramuscular Cephalospodn. Her white count rose to 16.0 and ESR to 40. A malarial parasite screen was neg,_.t!,te. She developed clouding of consciousness and had difficulty breathing due to stiffness of the neck and chest muscles. Pulse was 120/min and she was incontinent of urine. Neuroleptic malignant syndrome was diagnosed (creatinine phosphokinase was not measured), haloperidol was stopped, and efforts were made to control her excitement on large doses of diazepam, which proved to be most difficult (60 mg daily, intravenously). A lumbar puncture was attempted but not completed due to her agitation. Ten days after admission, right-sided rhythmic movements developed. Phenytoin was commenced to no effect. The patient became mute and did not respond to commands, At this point, she was transferred to an acute medical ward. Another EEG had to be abandoned due to movement. The lumbar puncture was repeated, this time successfully, showing possible cryptosporidium. Immediate transfer was arranged to a regional neurological center. Here, cryptosporidium was in fact ruled out. Tests for HIV 1 and 2 were negative. The white count had normalized, but the ESR had risen to 70. Three separate blood films showed neither malarial parasites nor trypanosomes. Protein electrophoresis and auto.antibody and immune complex screenings were unremarkable as were serum and cerebrospinal
fluid virology. Mantoux test was negative. An EEG, done successfully this time, showed three fits during the recording, each beginning from different foci in the left hemisphere. Three CT scans were normal. Herpes simplex encephalitis wu~ t,.~ ~nosr. ~ and IV acyclovir and chloramphenicol were commenced. The fits continued and proved extremely difficult to control despite combination treatment with five antiepileptic drugs--phenytoin, sodium valproate, clorazepam, phenobarbitone, and vigabatrinmall given intravenously. ESR remained high and touched i 10. Blood cultures remained negative througheut. After 2 weeks of little progress, high doses of steroids were commenced. This had a dramatic effect and over the next 3 weeks her level of consciousness improved to the point where she could walk with the physical support of the nursing staff. After 5 weeks she was transfered back to the initial referring teaching hospital. A gynecological examination showed that the abdominal mass was resolving and laparotomy was not done. The patient could now recognize her relatives. She could speak a meaningful sentence but only to her husband. She was able to walk slowly, unsupported. She remained afebrile. Two weeks after her return to the initial hospital she was discharged. She had asked to return to Ghana and her husband did in fact return there with her soon after her discharge, where she has remained, being cared for by her brother and sisters. Philip Steadman St George's Teaching Hospital London SWl7
Neurodevelopmental Model of Schizophrenia
prising because they cited and compared their imaging results with those of Jernigan et al (199 !), who cited our 1982 model in some d:~ail. i should like to remind those interested in our neurodevelopmental hypothesis that there were wree arguments advanced in 1982. The ~irst was that there is strong evidence that the braia undergoes profound changes in the second decade of life: this evidence includes a marked decline in cerebral metabolic rate as measured by the Kety-Schmidt method (evidence greatly strengthened and ex-
To the Editor: Dr. Swayze et al develop the view that schizophrenia might result from a developmental disorder of synaptic pruning during the second decade of life, but neglect to state that I put forward this notion in 1982 (Feinberg 1982/83). With my associates, we further extended our hypothesis to affective illness in 1990 (Feinberg et al 1990). This oversight is sur-
Lo~ fespondence
BIOL PSYCHIATRY 1992;32:207-213
panded by subsequent PET observations of Chugani et al (1987); profound reductions in the duration of deep (stage 4) sleep and in the amplitude and deasity of the delta EEG that characterizes this stage (evidence also strengthened by more extensive quantific: "3n (Feinberg et al 1990); and a diminished capacity to recover from brain lesions, notably those that cause aphasia. The second argument was that such extensive brain changes might sometimes be faulty and cause or predispose to those mental illnesses that have peripubertal or postpubertal onsets, ie., that the processes oi late brain development, at that time almost entirely ignored, be considered in the search for the etiology of schizophrenia. The third argument was that synaptic elimination, perhaps triggered t,,, endocrine events, could account for each of the brain cht.:,tges considered under the first argument. In our more recent article (Feinberg et al 1990), we extended our hypotheses regarding the neuronal events underlying late brain development. We proposed that change in synaptic organization (towards fewer but more effective synapses) was but one component of a transformation in which neurons lose plasticity and become "committed." Those interested in the biological and quantitative implications of this model should consult this article.
for delta wave amplitude, cortical metabolic rate and synaptic density. J Theor Biol 142:149-161. Feinberg 1, March JD, Flach K, Maloney T, Chem W-J, Travis F (1990b): Maturational changes in amplitude, incidence and cyclic pattern of the 0-3 Hz (delta) electroencephalogramof human sleep. Brain Dysfunct 3: ! 83192. Jemigan TL, Zisook S, Heaton RK, Moranville JT, Hesselink JR, Braff DL (1991): Magnetic resonance imaging abnormalities in lent.iculta nuclei and cerebral cortex in schizophrenia(1991). Arch Gen Psychiatry 48:881890. Swayze VW II, Andreasen NC, Alliger RJ, Yuh WTC, Ehrhardt (1992): Subconical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging ~tudy. Biol Psychiatry 31:221-240.
Response To the Editor: We thank Dr. Feinberg for bringing to our atten•don his elegant and seminal neurodevelopmental model in which he postulated possible mechanisms of how and why schizophrenia often develops in adolescence (Feinberg 1982, 1983). In developing his comprehensive neurodevelopmental model, Dr. Feinberg was truly ahead of his time, and we regret the negligent omission in our recent paper of his important work. Victor W. Swayze 11I Nancy C. Andreasen I Randall J. Aliger ~ William T.C. Yuh 2 James C. Ehrhardt 2
Irwin Feinberg
Martinez VA Medical Center Martinez, CA
References Chugani HT, Phelps ME, Mazziotta JC (1987): Positron emission tomography of human brain functional development. Ann Neurol 22:487-497. Feinberg, I (1982/83): Schizophrenia: Due to a fault in programmed synaptic elimination during adolescence?J Psychiatry Res ! 7:319-334. Feinberg i, Thode HC Jr, Chugani }IT, March JD (1990a): Gamma distribution model describes maturational curves
213
JMentai Health Clinical Research Center and 2Departmem of Radiology The University of Iowa Hospitals and Clinics
References Feinberg I, (1982): Schizophreniaand late maturationalbrain changes in man. Psychopharmacol Bull 18:29-31. Feinberg 1, (1982/83): Schizophrenia: Due to a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17:319-334.
