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Bipolar affective disorder heralding cerebral demyelination in adreno-myelo-leukodystrophy
Brain & Development 22 (2000) 184±187
Case report
www.elsevier.com/locate/braindev
Bipolar affective disorder heralding cerebral demyelination in adreno-myelo-leukodystrophy Doron Gothelf a, Ronen Levite b,c, Natan Gadoth b,c,* a
b
Geha Psychiatric Hospital, Petah-Tiqwa, Tel Aviv, Israel Department of Neurology, Sapir Medical Center, Meir General Hospital, Kfar Saba, 44281Tel Aviv, Israel c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Received 5 February 1999; received in revised form 25 October 1999; accepted 2 December 1999
Abstract A young male with adrenomyeloleukodystrophy (AMLD), diagnosed at the age of 25 years, presented with signs of bipolar affective disorder (BPD) concomitant with radiological ®ndings of central demyelination. There was a marked deterioration of the earlier relatively benign neurological dysfunction, leading to fatal bulbar syndrome. The association of BPD with central demyelination in AMLD is in agreement with previously reported cases of this and other types of multifocal central demyelination diseases. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Leukodystrophy; Adrenal; Myelin; Affective disorder; Mania; Depression
1. Introduction The neuropsychiatric research in general, and studies of bipolar affective disorder (BPD) in particular, have focused mainly on cortical and subcortical gray matter abnormalities, while abnormalities of the white matter were relatively neglected. The precise pathophysiology of BPD is still unknown. Modem neuroimaging techniques have disclosed hyperintense areas on T2-weighted magnetic resonance images in some patients [1,2] though, demyelination was not found in patients with unipolar affective disorder or schizophrenia [2]. Thus, it seems that the association between demyelination and BPD is not merely a product of chronic intractable disease. Furthermore, the high rate of BPD among patients with demyelinating diseases of the central nervous system (CNS) [3±7] may serve as additional evidence of the role played by central demyelination in affective disorders. Table 1 summarizes conditions in which central demyelination has been associated with psychiatric symptoms. 2. Case report A 32-year-old Jewish Ashkenazi male presented to our * Corresponding author. Tel.: 1972-9-747-2513; fax: 1972-9-7461460. E-mail address: [email protected] (N. Gadoth)
liaison psychiatric services with an acute onset of markedly disorganized and irritable behavior. The patient was diagnosed as having Addison's disease at the age of 11 years. Prednisone 7.5 mg and aldosterone 0.1 mg per day were initiated and carefully maintained. His school achievement was considered average and he was described as a hyperactive adolescent. At the age of 12 years he scored an IQ of 111 on the Wechsler Intelligence Scale for Children (WISC), with the performance scale being higher than the verbal. The psychological report mentioned that he was anxious about his body image and showed weakness of ego; otherwise, no psychiatric symptoms were present. At age 18 years, the patient was drafted for three years' military service (compulsory in Israel) in a non-combat unit. Seven years later he began to complain of progressive dif®culty in gait, frequent falls and urinary urgency. Neurological examination revealed spastic paraparesis, with laboratory ®ndings of high level of plasma very-long-chain fatty acid in both the patient and his mother. The diagnosis was AMLD was con®rmed. Findings in brain computed tomography (CT) and magnetic resonance imaging (MRI), cerebrospinal ¯uid composition, pattern reversal visual evoked potential, brainstem auditory evoked potential, and nerve conduction velocities were all normal. Electroencephalography showed the presence of non-speci®c diffuse slowing, similar to a number of recordings obtained since the age of 12 years. Thereafter, a continuous slow deterioration in motor ability
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0012 9-1
D. Gothelf et al. / Brain & Development 22 (2000) 184±187
185
Table 1 Reported psychiatric manifestations in central demyelination diseases. BPD, bipolar affective disorder Clinical entity Multiple sclerosis Metachromatic leukodystrophy Onset at age 10 to 30 years Onset before age 10 years Adrenoleukodystrophy
No. of patients 702 55 74 109 a
1b 2b a b
Rates of psychiatric manifestations
Reference
1.4% BPD
[7]
53% Schizophrenic and manic psychosis 0% 12.8% Dementia 11.0% learning dif®culties 7.3% Behavioral changes 2.7% Schizophrenia 22.2% Other BPD BPD
[3] [3] [4]
[5] [6]
Most of the patients with onset before age 21 years. Onset after age 21 years.
was documented. Intellectual function was preserved, and there was no psychiatric symptomatology. At age 30 years a second brain MRI scan was again normal (Fig. 1A±C). On presentation to our clinic two years later, the patient appeared euphoric and irritable with delusions of grandeur, pressured speech, ¯ight of ideas and decreased need for sleep, indicating a manic-psychotic episode. Daily treatment with a combination of oral haloperidol 2 mg and carbamazepine 600 mg alleviated the psychotic and manic symptoms. However, he soon suffered a major depressive episode marked by sadness, depressive affect, loss of appetite, early morning awakening, anhedonia, anergia, and suicidal ideation. Fluvoxamine 150 mg per day was added, and the haloperidol tapered down. There was no change in the symptoms of depression, however, until three months later. Subsequently, a gradual impairment in short-term memory was noted, followed by poor social judgment and inappropriate behavior. At the same time, the depressive symptoms improved, the suicidal thoughts disappeared, the patient's appetite improved, and he reported not being sad. A marked decline in motor function, urinary retention (requiring constant catheterization) and progressive dysphagia and dysarthria appeared soon after. At this point contrast-enhanced brain MRI was performed, disclosing (in contrast to that performed just two years earlier) asymmetrical periventricular demyelination involving the tapetum adjacent to the occipital horns, the internal capsule, and pons (see Fig. 1D±F). The patient died nine months after the onset of the psychiatric affective symptomatology from bulbar palsy. 3. Discussion In a 1986 survey 700,000 residents of Monroe County, N.Y., Schiffer et al. [7] found 10 patients with both de®nite multiple sclerosis (MS) and BPD. This is about double the expected rate of 5.4, for this size population. The MS symp-
toms had appeared ®rst, at a mean of 7.8 years earlier than the ®rst affective episode mean ages 23.5 and 31.3 years, respectively. The other researchers have reported that the rate of psychosis is not increased in MS [8]. No speci®c location of the plaques has been clearly linked to the psychiatric symptoms. Additional disorders of myelinat ion that have been associated with BPD and psychotic symptoms are MDS dementia complex, Binswanger's disease, primary degeneration of the corpus callosum (Marchiafave-Bignami disease), toluene intoxication, and the group of leukodystrophies [9]. The various clinical forms of metachromatic leukodystrophy (MLD) represent disorders of central and peripheral myelin associated with a number of mutations in the gene locus for the lysosomal enzyme aryl sulfatase-A. Among the 55 published cases of MLD, 53% were associated with psychotic symptoms, both schizophrenic and manic-like in all of them, onset of MLD was at 10 to 30 years of age. None of the 74 patients with an earlier onset suffered from psychosis [3]. Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by a defect in the degradation of VLCFA, which leads to central and peripheral demyelination with concomitant adrenal insuf®ciency [10]. The phenotypic spectrum ranges from mild adolescent- or adult-onset adrenomyeloleukodystrophy (AMLD) to the fulminant childhood cerebral form. All clinical forms of ALD eventually progress to involve the brain, and all are fatal [10]. Kitchin et al. [4] reviewed 109 cases of ALD, most of them with onset before 21 years, and found that in 17%, the presenting symptom was exclusively psychiatric while in 56%, psychiatric symptoms appeared during the course of the disease. Interestingly, the patients with the milder form, AMLD, did not have psychiatric symptoms. The most common psychiatric manifestations were dementia followed by learning dif®culties, `behavioral changes', and schizophrenia-like symptoms. There are only three cases of BPD with adult onset ALD [5,6].
186
D. Gothelf et al. / Brain & Development 22 (2000) 184±187
Fig. 1. (A±C) Normal brain MRI performed two years before eruption of the affective bipolar symptoms. (D±F) Demyelination lesions on MRI performed a few months after onset of bipolar affective symptoms. (D) Axial T2 weighted MR' images showing areas of increased signal density in the periventricular areas surrounding the atria and occipital horns of the lateral ventricles, especially on the left ( " ). Similar changes are present in the posterior limbs of the internal capsule bilaterally ( " " ). (E) Axial T2 weighted images showing bilateral areas of increased signal intensity in the pons. (F) Gadolinium-DTPA enhanced T1 weighted images showing minimal enhancement at the margins of the lesions surrounding the left occipital horn.
Findings of progressive spastic paraparesis in a young male with intact intellectual skills, no radiological or electrophysio logical evidence of cerebral demyelination, adrenal insuf®ciency and accumulation of VLCFA are compatible with a diagnosis of AMLD. Similar to three previously reported cases [5,6], late cerebral involvement was heralded by symptoms identical to BPD which were followed by intellectual decline and bulbar signs concomitant with resolution of the affective symptoms. Filley and
Gross [9] and Hyde et al. [3] who extensively reviewed psychosis in CNS white matter disorders, described a similar sequence. The time elapsed from onset of the affective disorder to the neurological deterioration ranged from 12 months [5] similar to our patient, to 7 years [6]. In the two cases reported by Menza et al. [6], this interval was 7 years. To the best of our knowledge this is the ®rst report documenting the onset of bipolar affective symptoms concomi-
D. Gothelf et al. / Brain & Development 22 (2000) 184±187
tant with the onset of central demyelination. Brain MRI scans, performed twice while the patient had only spinal symptoms, were normal. Based on these ®ndings and the previous clinical reports, we speculate that BPD symptoms may herald central demyelination in AMLD. As the demyelinating process progresses, cognitive deterioration appears while the affective symptoms disappear. The relatively early appearance of the BPD symptoms in the course of demyelination is in agreement with reports of deep white matter focal lesions observed in BPD patients [1]. References [1] Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R. T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry 1995;152:1139±1144. [2] Dupont RM, Jernigan TL, Heindel W, et al. Magnetic resonance imaging and mood disorders. Loacalization of white matter and other subcortical abnormalities. Arch Gen Psychiatry 1995;52:747±755.
187
[3] Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992;49:401±406. [4] Kitchin W, Cohen-Cole SA, Mickel SF. Adrenoleukodystrophy: frequency of presentation as a psychotic disorder. Biol Psychiatry 1987;22:1375±1387. [5] Leo RJ. Behavioral changes and affective instability associated with adult-onset adrenoleukodystrophy. Psycho Somatics 1998;39:176± 177. [6] Menza MA, Blake J, Goldberg L. Affective symptoms and adrenleukodystrophy: A report of two cases. Psycho Somatics 1988;29:442± 445. [7] Schiffer RB, Wineman M, Weitkamp LR. Association between bipolar affective disorder and multiple sclerosis. Am J Psychiatry 1986;143:94±95. [8] Trimble MR, Grant I. Psychiatric aspects of multiple sclerosis. In: Benson DF, Blumer D, editors. Psychiatric aspects of neurological disease, Vol. 2. New York: Grune & Stratton, 1982. pp. 279± 298. [9] Filley CM, Gross KF. Psychosis with cerebral white matter disease. Neuropsychiatry, Neurobiol and Behav Neurol 1992;5:119±125. [10] Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997;120:1485±1508.
Case report
www.elsevier.com/locate/braindev
Bipolar affective disorder heralding cerebral demyelination in adreno-myelo-leukodystrophy Doron Gothelf a, Ronen Levite b,c, Natan Gadoth b,c,* a
b
Geha Psychiatric Hospital, Petah-Tiqwa, Tel Aviv, Israel Department of Neurology, Sapir Medical Center, Meir General Hospital, Kfar Saba, 44281Tel Aviv, Israel c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Received 5 February 1999; received in revised form 25 October 1999; accepted 2 December 1999
Abstract A young male with adrenomyeloleukodystrophy (AMLD), diagnosed at the age of 25 years, presented with signs of bipolar affective disorder (BPD) concomitant with radiological ®ndings of central demyelination. There was a marked deterioration of the earlier relatively benign neurological dysfunction, leading to fatal bulbar syndrome. The association of BPD with central demyelination in AMLD is in agreement with previously reported cases of this and other types of multifocal central demyelination diseases. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Leukodystrophy; Adrenal; Myelin; Affective disorder; Mania; Depression
1. Introduction The neuropsychiatric research in general, and studies of bipolar affective disorder (BPD) in particular, have focused mainly on cortical and subcortical gray matter abnormalities, while abnormalities of the white matter were relatively neglected. The precise pathophysiology of BPD is still unknown. Modem neuroimaging techniques have disclosed hyperintense areas on T2-weighted magnetic resonance images in some patients [1,2] though, demyelination was not found in patients with unipolar affective disorder or schizophrenia [2]. Thus, it seems that the association between demyelination and BPD is not merely a product of chronic intractable disease. Furthermore, the high rate of BPD among patients with demyelinating diseases of the central nervous system (CNS) [3±7] may serve as additional evidence of the role played by central demyelination in affective disorders. Table 1 summarizes conditions in which central demyelination has been associated with psychiatric symptoms. 2. Case report A 32-year-old Jewish Ashkenazi male presented to our * Corresponding author. Tel.: 1972-9-747-2513; fax: 1972-9-7461460. E-mail address: [email protected] (N. Gadoth)
liaison psychiatric services with an acute onset of markedly disorganized and irritable behavior. The patient was diagnosed as having Addison's disease at the age of 11 years. Prednisone 7.5 mg and aldosterone 0.1 mg per day were initiated and carefully maintained. His school achievement was considered average and he was described as a hyperactive adolescent. At the age of 12 years he scored an IQ of 111 on the Wechsler Intelligence Scale for Children (WISC), with the performance scale being higher than the verbal. The psychological report mentioned that he was anxious about his body image and showed weakness of ego; otherwise, no psychiatric symptoms were present. At age 18 years, the patient was drafted for three years' military service (compulsory in Israel) in a non-combat unit. Seven years later he began to complain of progressive dif®culty in gait, frequent falls and urinary urgency. Neurological examination revealed spastic paraparesis, with laboratory ®ndings of high level of plasma very-long-chain fatty acid in both the patient and his mother. The diagnosis was AMLD was con®rmed. Findings in brain computed tomography (CT) and magnetic resonance imaging (MRI), cerebrospinal ¯uid composition, pattern reversal visual evoked potential, brainstem auditory evoked potential, and nerve conduction velocities were all normal. Electroencephalography showed the presence of non-speci®c diffuse slowing, similar to a number of recordings obtained since the age of 12 years. Thereafter, a continuous slow deterioration in motor ability
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0012 9-1
D. Gothelf et al. / Brain & Development 22 (2000) 184±187
185
Table 1 Reported psychiatric manifestations in central demyelination diseases. BPD, bipolar affective disorder Clinical entity Multiple sclerosis Metachromatic leukodystrophy Onset at age 10 to 30 years Onset before age 10 years Adrenoleukodystrophy
No. of patients 702 55 74 109 a
1b 2b a b
Rates of psychiatric manifestations
Reference
1.4% BPD
[7]
53% Schizophrenic and manic psychosis 0% 12.8% Dementia 11.0% learning dif®culties 7.3% Behavioral changes 2.7% Schizophrenia 22.2% Other BPD BPD
[3] [3] [4]
[5] [6]
Most of the patients with onset before age 21 years. Onset after age 21 years.
was documented. Intellectual function was preserved, and there was no psychiatric symptomatology. At age 30 years a second brain MRI scan was again normal (Fig. 1A±C). On presentation to our clinic two years later, the patient appeared euphoric and irritable with delusions of grandeur, pressured speech, ¯ight of ideas and decreased need for sleep, indicating a manic-psychotic episode. Daily treatment with a combination of oral haloperidol 2 mg and carbamazepine 600 mg alleviated the psychotic and manic symptoms. However, he soon suffered a major depressive episode marked by sadness, depressive affect, loss of appetite, early morning awakening, anhedonia, anergia, and suicidal ideation. Fluvoxamine 150 mg per day was added, and the haloperidol tapered down. There was no change in the symptoms of depression, however, until three months later. Subsequently, a gradual impairment in short-term memory was noted, followed by poor social judgment and inappropriate behavior. At the same time, the depressive symptoms improved, the suicidal thoughts disappeared, the patient's appetite improved, and he reported not being sad. A marked decline in motor function, urinary retention (requiring constant catheterization) and progressive dysphagia and dysarthria appeared soon after. At this point contrast-enhanced brain MRI was performed, disclosing (in contrast to that performed just two years earlier) asymmetrical periventricular demyelination involving the tapetum adjacent to the occipital horns, the internal capsule, and pons (see Fig. 1D±F). The patient died nine months after the onset of the psychiatric affective symptomatology from bulbar palsy. 3. Discussion In a 1986 survey 700,000 residents of Monroe County, N.Y., Schiffer et al. [7] found 10 patients with both de®nite multiple sclerosis (MS) and BPD. This is about double the expected rate of 5.4, for this size population. The MS symp-
toms had appeared ®rst, at a mean of 7.8 years earlier than the ®rst affective episode mean ages 23.5 and 31.3 years, respectively. The other researchers have reported that the rate of psychosis is not increased in MS [8]. No speci®c location of the plaques has been clearly linked to the psychiatric symptoms. Additional disorders of myelinat ion that have been associated with BPD and psychotic symptoms are MDS dementia complex, Binswanger's disease, primary degeneration of the corpus callosum (Marchiafave-Bignami disease), toluene intoxication, and the group of leukodystrophies [9]. The various clinical forms of metachromatic leukodystrophy (MLD) represent disorders of central and peripheral myelin associated with a number of mutations in the gene locus for the lysosomal enzyme aryl sulfatase-A. Among the 55 published cases of MLD, 53% were associated with psychotic symptoms, both schizophrenic and manic-like in all of them, onset of MLD was at 10 to 30 years of age. None of the 74 patients with an earlier onset suffered from psychosis [3]. Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by a defect in the degradation of VLCFA, which leads to central and peripheral demyelination with concomitant adrenal insuf®ciency [10]. The phenotypic spectrum ranges from mild adolescent- or adult-onset adrenomyeloleukodystrophy (AMLD) to the fulminant childhood cerebral form. All clinical forms of ALD eventually progress to involve the brain, and all are fatal [10]. Kitchin et al. [4] reviewed 109 cases of ALD, most of them with onset before 21 years, and found that in 17%, the presenting symptom was exclusively psychiatric while in 56%, psychiatric symptoms appeared during the course of the disease. Interestingly, the patients with the milder form, AMLD, did not have psychiatric symptoms. The most common psychiatric manifestations were dementia followed by learning dif®culties, `behavioral changes', and schizophrenia-like symptoms. There are only three cases of BPD with adult onset ALD [5,6].
186
D. Gothelf et al. / Brain & Development 22 (2000) 184±187
Fig. 1. (A±C) Normal brain MRI performed two years before eruption of the affective bipolar symptoms. (D±F) Demyelination lesions on MRI performed a few months after onset of bipolar affective symptoms. (D) Axial T2 weighted MR' images showing areas of increased signal density in the periventricular areas surrounding the atria and occipital horns of the lateral ventricles, especially on the left ( " ). Similar changes are present in the posterior limbs of the internal capsule bilaterally ( " " ). (E) Axial T2 weighted images showing bilateral areas of increased signal intensity in the pons. (F) Gadolinium-DTPA enhanced T1 weighted images showing minimal enhancement at the margins of the lesions surrounding the left occipital horn.
Findings of progressive spastic paraparesis in a young male with intact intellectual skills, no radiological or electrophysio logical evidence of cerebral demyelination, adrenal insuf®ciency and accumulation of VLCFA are compatible with a diagnosis of AMLD. Similar to three previously reported cases [5,6], late cerebral involvement was heralded by symptoms identical to BPD which were followed by intellectual decline and bulbar signs concomitant with resolution of the affective symptoms. Filley and
Gross [9] and Hyde et al. [3] who extensively reviewed psychosis in CNS white matter disorders, described a similar sequence. The time elapsed from onset of the affective disorder to the neurological deterioration ranged from 12 months [5] similar to our patient, to 7 years [6]. In the two cases reported by Menza et al. [6], this interval was 7 years. To the best of our knowledge this is the ®rst report documenting the onset of bipolar affective symptoms concomi-
D. Gothelf et al. / Brain & Development 22 (2000) 184±187
tant with the onset of central demyelination. Brain MRI scans, performed twice while the patient had only spinal symptoms, were normal. Based on these ®ndings and the previous clinical reports, we speculate that BPD symptoms may herald central demyelination in AMLD. As the demyelinating process progresses, cognitive deterioration appears while the affective symptoms disappear. The relatively early appearance of the BPD symptoms in the course of demyelination is in agreement with reports of deep white matter focal lesions observed in BPD patients [1]. References [1] Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R. T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry 1995;152:1139±1144. [2] Dupont RM, Jernigan TL, Heindel W, et al. Magnetic resonance imaging and mood disorders. Loacalization of white matter and other subcortical abnormalities. Arch Gen Psychiatry 1995;52:747±755.
187
[3] Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992;49:401±406. [4] Kitchin W, Cohen-Cole SA, Mickel SF. Adrenoleukodystrophy: frequency of presentation as a psychotic disorder. Biol Psychiatry 1987;22:1375±1387. [5] Leo RJ. Behavioral changes and affective instability associated with adult-onset adrenoleukodystrophy. Psycho Somatics 1998;39:176± 177. [6] Menza MA, Blake J, Goldberg L. Affective symptoms and adrenleukodystrophy: A report of two cases. Psycho Somatics 1988;29:442± 445. [7] Schiffer RB, Wineman M, Weitkamp LR. Association between bipolar affective disorder and multiple sclerosis. Am J Psychiatry 1986;143:94±95. [8] Trimble MR, Grant I. Psychiatric aspects of multiple sclerosis. In: Benson DF, Blumer D, editors. Psychiatric aspects of neurological disease, Vol. 2. New York: Grune & Stratton, 1982. pp. 279± 298. [9] Filley CM, Gross KF. Psychosis with cerebral white matter disease. Neuropsychiatry, Neurobiol and Behav Neurol 1992;5:119±125. [10] Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997;120:1485±1508.