A Case of Subcortical Grey Matter Heterotopia Presenting as Bipolar Disorder James
A. Bourgeois,
Josef
Nisenbaum,
Karen G. Drexler,
A case of previously diagnosed bipolar disorder was found to be associated with unilateral subcortical grey matter heterotopia, cortical hemiatrophy, midline shift, and ventriculomegaly on magnetic resonance imaging (MRI). The patient responded to pharmacotherapy with lithium carbonate and carbamazepine. This case
P
SYCHIATRIC SYMPTOMS consistent with major affective illnesses (bipolar disorder and major depression) may be due to identifiable structural or systemic/metabolic (“organic”) causes. We recently managed a case of organic mood syndrome in a patient with strikingly abnormal congenital central nervous system (CNS) findings on magnetic resonance imaging (MRI). This patient had presented as a typical bipolar disorder patient. CASE REPORT A.A., a 34.year-old white man, active duty US Army E-4 cook, was evacuated from Operation Desert Storm in March 1991 following bizarre, inappropriate, and suicidal behavior. He had been in the Army Reserve until the summer of 1990, when he volunteered for active duty. He was subsequently deployed to Saudi Arabia in October 1990 and initially functioned well. He stated that in January 1991 “my job was eliminated” and that he subsequently had “nothing to do.” He became bored, took to writing 75 letters per week responding to those written “To Any Soldier,” and began to experience racing thoughts, elevated then depressed mood, feelings of hopelessness, decreased need for sleep, and suicidal ideation. He denied hallucinations and delusions. He was discovered in February 1991 with a loaded M-16 rifle pointed at his head. Urgent psychiatric referral was accomplished and the patient was evacuated to a military psychiatric hospital in Europe. While hospitalized, he was treated with lithium carbonate 600 mg orally twice daily and thiothixene 10 mg orally every night with eventual resolution of his acute psychiatric symptoms. He thereafter remained in stable condition and was sent to the United States for further psychiatric care and administrative disposition. The patient stated that he was first diagnosed with bipolar disorder 5 years previously. This diagnosis followed frequent episodes of depressed mood, suicidal ideation, a single suicide attempt by ingestion of an unknown medication. and four episodes of decreased need for sleep, elevated mood. staying awake for several nights, and financial and social indiscretions. He was psychiatrically hospitalized once and was treated with a regimen of lithium carbonate 600 mg orally twice daily with resolution of his psychiatric symptoms. He discontinued his lithium carbonate in August
Comprehensive
Psychiatry,
Vol.
33, No. 6 (November/December),
Ken M. Dobbins,
and Molly
J. Hall
dramatically illustrates the need for neuroimaging in psychiatric patients with apparently “functional” affective illness. This is a US government work. There are no restrictions on its use.
“my mood was fine so I didn’t need it 1990 because He denied current use of illicit drugs and anymore.” currently uses alcohol “rarely.” He had a distant history of polysubstance abuse (consisting of hallucinogen, amphetamine. barbiturate, and alcohol abuse beginning when he was a teenager and continuing until his 20s) and had been convicted for driving while intoxicated. He once briefly attended an outpatient alcohol treatment program. The patient was the first born of four children of deaf parents. There was no family history of psychiatric disorder. He was strongly left-handed and “can’t do anything with my right hand.” He was a below-average student and never completed high school. He was removed from his family’s home at age 12 and placed in a group home because of “incorrigible behavior” consisting of runaway behavior, physical fights, destruction of property, use of LSD, amphetamines, and barbiturates, and being “overactive.” He was treated during this period with an unknown psychiatric medication. He had been married four times, his first three marriages having ended in divorce, and he had a 15-year-old daughter. He had been employed by a towing company and in fast-food restaurants in addition to his military service. He had had a tonsillectomy and an appendectomy. He denied any history of major medical illness. head injury, loss of consciousness, seizure, or medication allergy. Physical examination, including neurologic examination, was unremarkable. Mental status examination showed an appropriately dressed and groomed male in no distress, with no increased or decreased psychomotor movements. Speech was fluent without pressured speech. Relatedness was appropriate. Mood was “fine, level.” Atfect was essentially euthymic with occasional brief episodes of tearfulness and laughter. Thought content was without suicidal/homicidal ideation, hallucinations, delusions, or ideas of reference. Thought processes were logical without looseness of associ-
From the Departments of Psychiatr?/ and Radiology, USAF Medical Center Wright-Patterson. Wright-Patterson AFB. OH. The views expressed herein are solely those of the authors and do not necessarily represent the views of the Department of the Air Force or the Depatiment of Defense. Address reprint requests to James A. Bourgeois, M.D., SGhYElPsychiatry. USAF Medical Center, Wright-Patterson AFB. OH 45433. This is a US government work. There are no restrictions on its use. OOIO-440X/9213306-OOO9$O.OOlO
1992: pp 407-410
407
408
ations. He was oriented to person, place, and time. Memory was intact. Fund of knowledge was as expected for educational level. Chest x-ray, electrocardiogram, urinalysis, electroencephalography, serum chemistries, hemoglobin/hematocrit, platelets, thyroid panel, and rapid plasma reagin (RPR) were all normal or negative. Serum lithium level was 1.12 mEq/L (therapeutic range). White blood cell count was 12.4000 cells/pL with a normal differential. MRI of the head showed laminar heterotopic grey matter in the left fronto-parietal centrum semiovale with a small component of modular heterotopia along the subependymal surface of the body and lateral frontal horn of the left lateral ventricle. The heterotopia was surrounded by subcortical white matter. The corpus callosum and septum pellucidum were present. A single anterior cerebral artery was noted. There was nonuniform enlargement of the left lateral ventricle, atrophy of the left cerebral cortex, and midline shift of the contralateral right frontal lobe. These last three findings most likely represented compensatory changes (Fig LA-C).
BOURGEOIS ET AL
Neuropsychological testing showed intelligence in the low-average range, defects in visuospatial functioning, visual memory, complex right-handed motor skills, and higherorder reasoning abilities. All of these findings are consistent with longstanding and probably congenital impairment of the left cortical hemisphere, with a language-dominant right hemisphere. The patient remained in stable condition throughout his hospitalization, but was noted to have occasional irritability and difficulty with respect for other patients’ boundaries. After review of the MRI films, therapy with carbamazepine was considered for its “antikindling” effects.* This anticonvulsant is felt to dampen abnormal “subseizure” limbic electrical activity that may be associated with behavioral dyscontrol in various psychiatric settings; it is recommended for the patient with such psychiatric symptoms who has electroencephalographic or structural evidence of CNS abnormality, particularly in the temporal lobe(s).1-3 He was started on carbamazepine in addition to lithium carbonate; a carbamazepine dose of 200 mg orally twice daily gave a therapeutic level of 7.6 ug/mL. The patient was
Fig 1. (A-C) MRI transverse images of the brain showing left subcortical grey matter heterotopia, ventriculomegaly, midline shift, and (:ortical hemiatrophy.
GREY MATTER HETEROTOPIA
subsequently less irritable and intrusive, and tolerated the combination pharmacotherapy well. He was discharged in stable condition on lithium carbonate 600 mg orally twice daily and carbamazepine 200 mg orally twice daily with a recommendation for medical retirement.
DISCUSSION
Grey matter heterotopias are collections of grey matter in abnormal locations in the brain and represent one of a group of congenital CNS malformations known as the migrational disorders.4 During early fetal development, the neuroblasts migrate radially from their proliferative zones along the ventricular surfaces to their final anatomical positions.5 In the case of grey matter heterotopias, there is an arrest of neuronal migration between the third and fifth fetal months.4-8 This arrest generally indicates severe structural abnormalities of the brain.‘The heterotopias are round masses of grey matter between 0.5 cm and 3.0 cm in size, may be single or multiple, and may be found anywhere from the subependymal surface to the cortex.4J The areas of heterotopia are noncalcifying, which distinguishes them from the lesions of tuberous sclerosis, which may be of similar size and shape and in similar locations.‘J The abnormal cortex may be thickened and disorganized, while the adjacent white matter may be thinned.5 It has been proposed that grey matter heterotopias may be due to intrauterine insult (vascular, infectious, or teratogenic) to the developing fetal brain, although there have been suggestions that a genetic vulnerability may be present.a.5x7 Grey matter heterotopias may be associated with other congenital abnormalities (Table 1).“-8 When the areas of heterotopia are near the ependymal surface, a characteristic “nodular” Table 1. Other Congenital Abnormalities Associated With Grey Matter Heterotopias Agenesis of the corpus callosum Ventricular dilatation Schizencephaly Polymicrogyria Pachygyria Arrhinencephaly Cerebellar anomalies Chiari II malformation Stenosis of the aqueduct of Sylvius Anomalies of other organ systems
409
appearance has been reported with the older technique of cerebral pneumography.h.7 A series of 10 cases of subependymal heterotopias reported by Bergeron’ were all associated with psychomotor retardation and impairment in intellectual development. Most patients had died before 1 year of age, and only one had survived to age 8.’ Seizures are also commonly seen in patients with subcortical heterotopias.“J Radiologic imaging of grey matter heterotopias was originally done with cerebral pneumography, with later development of the computed tomography (CT) scan, but MRI is now preferred because of its superior ability to discriminate white matter from grey matter.lJ Barkovich et a1.5 reported on MRI imaging of three cases with heterotopic grey matter, ages 2 through 7, all of whom suffered from seizures. Byrd et al.” reported on six cases of grey matter heterotopia out of a group of 24 children with migrational disorders. They noted that isolated heterotopias may be clinically asymptomatic; when symptomatic, patients most often exhibit seizures in infancy and/or early childhood.4 Isolated grey matter heterotopias are said to have the best prognosis of the migrational dis0rders.j Regarding our case, the fact that the patient’s CNS abnormalities were unilateral and included a single anterior cerebral artery suggests an intrauterine vascular event as causative, as any toxic or infectious process would most likely have damaged both sides of the brain. Cerebral angiography might have provided more information in this regard, but because of the patient’s normal neurologic status, it was not performed. While it is impossible to definitively state that this patient’s psychiatric condition is referable to his abnormal CNS development, the relatively early onset of “incorrigible behavior” and a lack of family history of psychiatric disorder make a link between his grey matter heterotopia and current psychiatric condition plausible and attractive. His neuropsychological testing results support this connection. His behavioral response to the combination of lithium carbonate and carbamazepine make life-long pharmacotherapy likely. This case rather dramatically supports the practice of obtaining MRI of the brain on cases
410
BOURGEOIS ET AL
of apparent “functional” psychiatric illness as part of a full “rule out organic causes” evaluation. Patients with such CNS abnormalities can be helped to understand that their “abnormal brain” may be responsible for their psychiatric
symptoms. Fully informing such patients of their “organic” findings may assist in management issues such as medication and follow-up compliance.
REFERENCES 1. Kessler AJ, Barklage NE, Jefferson JW. Mood disorders in the psychoneurologic borderland: three cases of responsiveness to carbamazepine. Am J Psychiatry 1989;146: 81-83. 2. Israel M, Beaudry review. Can J Psychiatry
P. Carbamazepine 1988;33:577-584.
in psychiatry:
a
3. Yatham LN, McHale PA. Carbamazepine in the treatment of aggression: a case report and a review of the literature. Acta Psychiatr Stand 1988;78:188-190. 4. Byrd SE, Osborn RE, Bohan and MR evaluation of migrational
TP, Nadich TP. The CT disorders of the brain.
Part II. Schizencephaly, heterotopia, and polymicrogyria. Pediatr Radio1 1989;19:219-222. 5. Barkovich AJ, Chuang SH, Norman D. MR of neuronal migration anomalies. Am J Radio1 1988;150:179-187. 6. Mueller CF. Heterotopic grey matter. Radiology 1970; 94:357-358. 7. Bergeron RT. Radiographic demonstration of cortical heterotopia. Acta Radio1 1969;9:135-139. 8. Larroche J-C. Malformations of the nervous system. In: Adams JH, Corsellis JAN, Duchen LW (eds): Greenfield’s Neuropathology. ed. 4. New York, NY: Wiley, 1984: 411-412.
A. Bourgeois,
Josef
Nisenbaum,
Karen G. Drexler,
A case of previously diagnosed bipolar disorder was found to be associated with unilateral subcortical grey matter heterotopia, cortical hemiatrophy, midline shift, and ventriculomegaly on magnetic resonance imaging (MRI). The patient responded to pharmacotherapy with lithium carbonate and carbamazepine. This case
P
SYCHIATRIC SYMPTOMS consistent with major affective illnesses (bipolar disorder and major depression) may be due to identifiable structural or systemic/metabolic (“organic”) causes. We recently managed a case of organic mood syndrome in a patient with strikingly abnormal congenital central nervous system (CNS) findings on magnetic resonance imaging (MRI). This patient had presented as a typical bipolar disorder patient. CASE REPORT A.A., a 34.year-old white man, active duty US Army E-4 cook, was evacuated from Operation Desert Storm in March 1991 following bizarre, inappropriate, and suicidal behavior. He had been in the Army Reserve until the summer of 1990, when he volunteered for active duty. He was subsequently deployed to Saudi Arabia in October 1990 and initially functioned well. He stated that in January 1991 “my job was eliminated” and that he subsequently had “nothing to do.” He became bored, took to writing 75 letters per week responding to those written “To Any Soldier,” and began to experience racing thoughts, elevated then depressed mood, feelings of hopelessness, decreased need for sleep, and suicidal ideation. He denied hallucinations and delusions. He was discovered in February 1991 with a loaded M-16 rifle pointed at his head. Urgent psychiatric referral was accomplished and the patient was evacuated to a military psychiatric hospital in Europe. While hospitalized, he was treated with lithium carbonate 600 mg orally twice daily and thiothixene 10 mg orally every night with eventual resolution of his acute psychiatric symptoms. He thereafter remained in stable condition and was sent to the United States for further psychiatric care and administrative disposition. The patient stated that he was first diagnosed with bipolar disorder 5 years previously. This diagnosis followed frequent episodes of depressed mood, suicidal ideation, a single suicide attempt by ingestion of an unknown medication. and four episodes of decreased need for sleep, elevated mood. staying awake for several nights, and financial and social indiscretions. He was psychiatrically hospitalized once and was treated with a regimen of lithium carbonate 600 mg orally twice daily with resolution of his psychiatric symptoms. He discontinued his lithium carbonate in August
Comprehensive
Psychiatry,
Vol.
33, No. 6 (November/December),
Ken M. Dobbins,
and Molly
J. Hall
dramatically illustrates the need for neuroimaging in psychiatric patients with apparently “functional” affective illness. This is a US government work. There are no restrictions on its use.
“my mood was fine so I didn’t need it 1990 because He denied current use of illicit drugs and anymore.” currently uses alcohol “rarely.” He had a distant history of polysubstance abuse (consisting of hallucinogen, amphetamine. barbiturate, and alcohol abuse beginning when he was a teenager and continuing until his 20s) and had been convicted for driving while intoxicated. He once briefly attended an outpatient alcohol treatment program. The patient was the first born of four children of deaf parents. There was no family history of psychiatric disorder. He was strongly left-handed and “can’t do anything with my right hand.” He was a below-average student and never completed high school. He was removed from his family’s home at age 12 and placed in a group home because of “incorrigible behavior” consisting of runaway behavior, physical fights, destruction of property, use of LSD, amphetamines, and barbiturates, and being “overactive.” He was treated during this period with an unknown psychiatric medication. He had been married four times, his first three marriages having ended in divorce, and he had a 15-year-old daughter. He had been employed by a towing company and in fast-food restaurants in addition to his military service. He had had a tonsillectomy and an appendectomy. He denied any history of major medical illness. head injury, loss of consciousness, seizure, or medication allergy. Physical examination, including neurologic examination, was unremarkable. Mental status examination showed an appropriately dressed and groomed male in no distress, with no increased or decreased psychomotor movements. Speech was fluent without pressured speech. Relatedness was appropriate. Mood was “fine, level.” Atfect was essentially euthymic with occasional brief episodes of tearfulness and laughter. Thought content was without suicidal/homicidal ideation, hallucinations, delusions, or ideas of reference. Thought processes were logical without looseness of associ-
From the Departments of Psychiatr?/ and Radiology, USAF Medical Center Wright-Patterson. Wright-Patterson AFB. OH. The views expressed herein are solely those of the authors and do not necessarily represent the views of the Department of the Air Force or the Depatiment of Defense. Address reprint requests to James A. Bourgeois, M.D., SGhYElPsychiatry. USAF Medical Center, Wright-Patterson AFB. OH 45433. This is a US government work. There are no restrictions on its use. OOIO-440X/9213306-OOO9$O.OOlO
1992: pp 407-410
407
408
ations. He was oriented to person, place, and time. Memory was intact. Fund of knowledge was as expected for educational level. Chest x-ray, electrocardiogram, urinalysis, electroencephalography, serum chemistries, hemoglobin/hematocrit, platelets, thyroid panel, and rapid plasma reagin (RPR) were all normal or negative. Serum lithium level was 1.12 mEq/L (therapeutic range). White blood cell count was 12.4000 cells/pL with a normal differential. MRI of the head showed laminar heterotopic grey matter in the left fronto-parietal centrum semiovale with a small component of modular heterotopia along the subependymal surface of the body and lateral frontal horn of the left lateral ventricle. The heterotopia was surrounded by subcortical white matter. The corpus callosum and septum pellucidum were present. A single anterior cerebral artery was noted. There was nonuniform enlargement of the left lateral ventricle, atrophy of the left cerebral cortex, and midline shift of the contralateral right frontal lobe. These last three findings most likely represented compensatory changes (Fig LA-C).
BOURGEOIS ET AL
Neuropsychological testing showed intelligence in the low-average range, defects in visuospatial functioning, visual memory, complex right-handed motor skills, and higherorder reasoning abilities. All of these findings are consistent with longstanding and probably congenital impairment of the left cortical hemisphere, with a language-dominant right hemisphere. The patient remained in stable condition throughout his hospitalization, but was noted to have occasional irritability and difficulty with respect for other patients’ boundaries. After review of the MRI films, therapy with carbamazepine was considered for its “antikindling” effects.* This anticonvulsant is felt to dampen abnormal “subseizure” limbic electrical activity that may be associated with behavioral dyscontrol in various psychiatric settings; it is recommended for the patient with such psychiatric symptoms who has electroencephalographic or structural evidence of CNS abnormality, particularly in the temporal lobe(s).1-3 He was started on carbamazepine in addition to lithium carbonate; a carbamazepine dose of 200 mg orally twice daily gave a therapeutic level of 7.6 ug/mL. The patient was
Fig 1. (A-C) MRI transverse images of the brain showing left subcortical grey matter heterotopia, ventriculomegaly, midline shift, and (:ortical hemiatrophy.
GREY MATTER HETEROTOPIA
subsequently less irritable and intrusive, and tolerated the combination pharmacotherapy well. He was discharged in stable condition on lithium carbonate 600 mg orally twice daily and carbamazepine 200 mg orally twice daily with a recommendation for medical retirement.
DISCUSSION
Grey matter heterotopias are collections of grey matter in abnormal locations in the brain and represent one of a group of congenital CNS malformations known as the migrational disorders.4 During early fetal development, the neuroblasts migrate radially from their proliferative zones along the ventricular surfaces to their final anatomical positions.5 In the case of grey matter heterotopias, there is an arrest of neuronal migration between the third and fifth fetal months.4-8 This arrest generally indicates severe structural abnormalities of the brain.‘The heterotopias are round masses of grey matter between 0.5 cm and 3.0 cm in size, may be single or multiple, and may be found anywhere from the subependymal surface to the cortex.4J The areas of heterotopia are noncalcifying, which distinguishes them from the lesions of tuberous sclerosis, which may be of similar size and shape and in similar locations.‘J The abnormal cortex may be thickened and disorganized, while the adjacent white matter may be thinned.5 It has been proposed that grey matter heterotopias may be due to intrauterine insult (vascular, infectious, or teratogenic) to the developing fetal brain, although there have been suggestions that a genetic vulnerability may be present.a.5x7 Grey matter heterotopias may be associated with other congenital abnormalities (Table 1).“-8 When the areas of heterotopia are near the ependymal surface, a characteristic “nodular” Table 1. Other Congenital Abnormalities Associated With Grey Matter Heterotopias Agenesis of the corpus callosum Ventricular dilatation Schizencephaly Polymicrogyria Pachygyria Arrhinencephaly Cerebellar anomalies Chiari II malformation Stenosis of the aqueduct of Sylvius Anomalies of other organ systems
409
appearance has been reported with the older technique of cerebral pneumography.h.7 A series of 10 cases of subependymal heterotopias reported by Bergeron’ were all associated with psychomotor retardation and impairment in intellectual development. Most patients had died before 1 year of age, and only one had survived to age 8.’ Seizures are also commonly seen in patients with subcortical heterotopias.“J Radiologic imaging of grey matter heterotopias was originally done with cerebral pneumography, with later development of the computed tomography (CT) scan, but MRI is now preferred because of its superior ability to discriminate white matter from grey matter.lJ Barkovich et a1.5 reported on MRI imaging of three cases with heterotopic grey matter, ages 2 through 7, all of whom suffered from seizures. Byrd et al.” reported on six cases of grey matter heterotopia out of a group of 24 children with migrational disorders. They noted that isolated heterotopias may be clinically asymptomatic; when symptomatic, patients most often exhibit seizures in infancy and/or early childhood.4 Isolated grey matter heterotopias are said to have the best prognosis of the migrational dis0rders.j Regarding our case, the fact that the patient’s CNS abnormalities were unilateral and included a single anterior cerebral artery suggests an intrauterine vascular event as causative, as any toxic or infectious process would most likely have damaged both sides of the brain. Cerebral angiography might have provided more information in this regard, but because of the patient’s normal neurologic status, it was not performed. While it is impossible to definitively state that this patient’s psychiatric condition is referable to his abnormal CNS development, the relatively early onset of “incorrigible behavior” and a lack of family history of psychiatric disorder make a link between his grey matter heterotopia and current psychiatric condition plausible and attractive. His neuropsychological testing results support this connection. His behavioral response to the combination of lithium carbonate and carbamazepine make life-long pharmacotherapy likely. This case rather dramatically supports the practice of obtaining MRI of the brain on cases
410
BOURGEOIS ET AL
of apparent “functional” psychiatric illness as part of a full “rule out organic causes” evaluation. Patients with such CNS abnormalities can be helped to understand that their “abnormal brain” may be responsible for their psychiatric
symptoms. Fully informing such patients of their “organic” findings may assist in management issues such as medication and follow-up compliance.
REFERENCES 1. Kessler AJ, Barklage NE, Jefferson JW. Mood disorders in the psychoneurologic borderland: three cases of responsiveness to carbamazepine. Am J Psychiatry 1989;146: 81-83. 2. Israel M, Beaudry review. Can J Psychiatry
P. Carbamazepine 1988;33:577-584.
in psychiatry:
a
3. Yatham LN, McHale PA. Carbamazepine in the treatment of aggression: a case report and a review of the literature. Acta Psychiatr Stand 1988;78:188-190. 4. Byrd SE, Osborn RE, Bohan and MR evaluation of migrational
TP, Nadich TP. The CT disorders of the brain.
Part II. Schizencephaly, heterotopia, and polymicrogyria. Pediatr Radio1 1989;19:219-222. 5. Barkovich AJ, Chuang SH, Norman D. MR of neuronal migration anomalies. Am J Radio1 1988;150:179-187. 6. Mueller CF. Heterotopic grey matter. Radiology 1970; 94:357-358. 7. Bergeron RT. Radiographic demonstration of cortical heterotopia. Acta Radio1 1969;9:135-139. 8. Larroche J-C. Malformations of the nervous system. In: Adams JH, Corsellis JAN, Duchen LW (eds): Greenfield’s Neuropathology. ed. 4. New York, NY: Wiley, 1984: 411-412.
