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Brief Report   |    
Familial Leukoencephalopathy in Bipolar Disorder
Eileen P. Ahearn, M.D., Ph.D.; David C. Steffens, M.D.; Frederick Cassidy, M.D.; Susan A. Van Meter, M.D.; James M. Provenzale, M.D.; Michael F. Seldin, M.D., Ph.D.; Richard H. Weisler, M.D.; K. Ranga Rama Krishnan, M.D.
Am J Psychiatry 1998;155:1605-1607.
Abstract

Objective:Imaging studies of patients with bipolar disorder demonstrate changes in deep white matter and subcortical gray nuclei that are seen as focal hyperintensities on T2-weighted magnetic resonance imaging (MRI). The objective of this study was to examine MRIs in a family with a strong history of bipolar disorder to look for possible MRI abnormalities in members with and without affective illness.Method:The authors obtained MRIs of 21 members of a family with a strong history of bipolar disorder. Eight of the family members studied had bipolar illness, one had symptoms of bipolar disorder but did not meet full DSM-III-R criteria, two had unipolar disorder, and 10 did not have bipolar disorder. Results:Fifteen of the 21 family members had MRI findings, including six of 10 family members who had no affective disorder and all of those with bipolar disorder. Lesions of both white matter and subcortical gray nuclei were found.Conclusions:Although the clinical significance of these MRI findings is unknown, the high prevalence of MRI findings in both affected and unaffected family members suggests that MRI findings may potentially serve as a biological marker for bipolar disorder. Recent genetic studies have established a link between familial leukoencephalopathy and chromosome 19. If leukoencephalopathy appears to be related to bipolar disorder, it may allow clearer characterization of the genetics of the disorder. Am J Psychiatry 1998; 155: 1605-1607

Abstract Teaser
Figures in this Article

Considerable information is now available about the clinical features, treatment, and outcome of bipolar illness. However, despite advances in our understanding of the phenomenological aspects of manic depression, there are few biological markers. Magnetic resonance imaging (MRI) provides an opportunity to better understand the neuroanatomical substrates underlying this illness. The fact that patients with bipolar disorder who have MRI findings often have a family history of the disorder raises the possibility that such findings may correlate within families and could potentially allow clearer characterization of the genetics of the disorder.

Imaging studies in bipolar disorder allow one to observe deep white matter and subcortical changes, which are seen as focal signal hyperintensities on T2-weighted MRIs. Dupont et al. R2515511CHEBJBDE first observed white matter hyperintensities in up to 25% of young patients with bipolar disorder, findings that they reported to be stable over time. Others R2515511CHECJHJBR2515511CHECEHBJ have replicated these findings, and a study of never-treated patients with bipolar disorder found a similar trend that did not reach significance R2515511CHEBHHDB. The clinical significance of these MRI findings has yet to be determined.

White matter lesions are commonly found in elderly subjects. Bradley et al. R2515511CHEBBGBF found that 30% of patients over 60 years old had leukoencephalopathic changes according to MRI. Notably, white matter hyperintensities are not normally seen in younger subjects. George et al. R2515511CHECIIAF found no white matter lesions in subjects who were 45 years old or younger. In previous work R2515511CHEEBGAB, we found white matter hyperintensities in 40% of a group of control subjects but in only 1% of the control subjects who were 45 years old or younger. In the current study, we investigate whether the rate of deep white matter hyperintensities and subcortical hyperintensities is greater in families in which there is a strong genetic loading for bipolar illness.

A family with a substantial history of bipolar disorder was recruited from the Affective Disorders Program at Duke University Medical Center. Informed written consent was obtained from 23 of the family members. Participants were then interviewed by one of four psychiatrists (E.P.A., D.C.S., F.C., or S.A.V.M.) using the Structured Clinical Interview for DSM-III-R R2515511CHEDFDFA. A detailed database, adopted from the Duke Depression Evaluation Schedule R2515511CHEDGACD, was completed. Atherosclerotic risk factors were noted; these included smoking, hypertension, diabetes, hyperlipidemia, and a history of cardiac or cerebrovascular disease. Following the structured interview, a standardized diagnosis was determined by consensus for each subject during a diagnostic conference involving at least three psychiatrists, including the primary interviewer. Diagnostic information on family members not present or deceased was obtained from three reliable family informants, and the diagnostic category was assigned by consensus opinion of three clinicians (E.P.A., D.C.S., and S.A.V.M.).

Twenty-one of 23 family members volunteered for MRI. Brain MRIs were performed with a General Electric 1.5 T Signa system. Five-mm thick T1-weighted (TR=500 msec, TE=20 msec) and T2-weighted (TR=2500 msec, TE=40/80 msec) 1H spin-echo pulse sequences were used to image the subject’s brain in the head coil of the MRI system. MRI scans were then assessed by using the modified Fazekas scale for the number, size, and location of white matter and subcortical gray nuclei lesions by two raters (J.M.P. and K.R.R.K.), who were blind to the patients’ diagnoses. Cohen’s kappa was calculated for the level of interrater agreement. Consensus opinion was then reached for all scans. An unpaired t test was used to compare the mean ages of the family members with positive and negative findings to assess whether there was an age-related effect.

The family pedigree (F1) demonstrates the rate of bipolar illness. Bipolar disorder was present in 14 (22%) of 65 family members. The rate of unipolar illness was 11% (seven family members). Of the 21 family members who had MRIs, eight had bipolar illness, one had symptoms of bipolar disorder but did not meet full DSM-III-R criteria, and two had unipolar illness. The mean age of the MRI participants was 41 years (range=12–66). The mean age at onset of bipolar illness was 18 years (range=8–40). Atherosclerotic risk factors were not striking (T1).

A summary of demographic data and MRI findings is found in T1. Interrater reliability for the interpretation of MRI scans was high (Cohen’s kappa=0.58). Points of disagreement were resolved by consensus opinion. Fifteen of the 21 family members had MRI findings, including six unaffected family members and all family members with bipolar disorder. Four of nine family members with bipolar disorder had deep white matter changes and eight had lesions of the subcortical gray nuclei. Neither of the two family members with unipolar illness had MRI findings. Of 10 family members with no affective illness, six had lesions in the subcortical gray nuclei. One of the six also had a white matter lesion. The size of lesions varied in this family from 1 mm to 5 mm. There was no significant correlation between lesion size or type (subcortical gray or white matter) and diagnosis. For lesions of white matter and subcortical gray nuclei, an unpaired t test comparing mean age of groups with and without MRI findings failed to demonstrate any age effect (white matter p=0.77, subcortical gray nuclei, p=0.90).

These preliminary data demonstrate a high prevalence of both white matter and subcortical findings in the family members who had bipolar disorder. White matter findings have been reported in young patients with bipolar disorder. The early data from this study seem to indicate a high prevalence of both white and subcortical findings in this "loaded" pedigree. Further, the prevalence of MRI findings in unaffected family members was high. The rate found is higher than that reported for control subjects in general R2515511CHEBBGBFR2515511CHEEBGAB. Of note, one unaffected family member is still a preadolescent and may yet manifest the disease. Age was not a significant factor when the family members with and without positive findings were compared. To our knowledge, this is the first report of a high prevalence of white matter and subcortical findings in family members of patients with bipolar disorder.

The clinical implications of MRI findings in patients with bipolar disorder and in their family members are not known. Only in late-onset bipolar disorder (onset after the age of 50) have organic factors been established as a frequent etiologic mechanism for the development of the illness R2515511CHEBBHICR2515511CHEDGBEF. Further research is needed to understand the MRI findings described herein and to establish the underlying pathophysiology. The high prevalence of white matter and subcortical findings in both affected and unaffected family members raises the possibility that these changes may serve as a biological marker for the illness. Further, recent genetic research has established a link between familial arteriopathy with subcortical leukoencephalopathy and chromosome 19 R2515511CHEBJJCJ. Notably, in one study of nine families with this disorder R2515511CHECCDGI, 22% had mood disorders. The MRI changes reported in bipolar illness may potentially correlate with genetic factors related to this disorder.

Received May 27, 1997; revisions received Dec. 1, 1997, and April 22, 1998; accepted May 15, 1998. From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, N.C.; and the Department of Medicine, Division of Molecular Medicine and Human Genetics, University of California, Davis. Address reprint requests to Dr. Ahearn, 900 Ridgefield Dr., Suite 320, Raleigh, NC 27609. This study was sponsored in part through a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression.

   
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FIGURE 1.

Pedigree of a Family With a High Rate of Affective Disorder

Dupont RM, Jernigan TL, Butters N: Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging. Arch Gen Psychiatry  1990; 47:55–59
[PubMed]
 
Swayze VW II, Andreasen NC, Alliger RJ, Ehrhardt JC, Yuh WT: Structural brain abnormalities in bipolar affective disorder: ventricular enlargement and focal signal hyperintensities. Arch Gen Psychiatry  1990; 47:1054–1059
[PubMed]
 
Figiel GS, Krishnan KRR, Rao VP, Doraiswamy M, Ellinwood EH, Nemeroff CB, Evans D, Boyko O: Subcortical hyperintensities on brain magnetic resonance imaging: a comparison of normal and bipolar subjects. J Neuropsychiatry Clin Neurosci  1991; 3:18–22
[PubMed]
 
Strakowski SM, Woods BT, Tohen M, Wilson DR, Douglass AW, Stoll AL: MRI subcortical hyperintensities in mania at first hospitalization. Biol Psychiatry  1993; 33:204–206
[PubMed]
[CrossRef]
 
Bradley WG, Waluch V, Brant-Zawadzki M, Yadley RA, Wyckoff RR: Patchy, periventricular white matter lesions in the elderly: a common observation during NMR imaging. Noninvasive Med Imaging  1984; 1:35–41
 
George AE, de Leon MJ, Kalnin A, Rosner L, Goodgold A, Chase N: Leukoencephalopathy in normal and pathologic aging: MRI of brain lucencies. Am J Neuroradiol  1986; 7:567–570
[PubMed]
 
Krishnan KRR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB: Magnetic resonance imaging of the caudate nuclei in depression. Arch Gen Psychiatry  1992; 49:553–557
[PubMed]
 
Spitzer RL, Williams JBW, Gibbon M, First MB: User’s Guide for the Structured Clinical Interview for DSM-III-R (SCID). Washington, DC, American Psychiatric Press, 1990
 
Krishnan KRR, Hays JC, Tupler LA, George LK, Blazer DG: Clinical and phenomenologic comparisons of late-onset and early-onset depression. Am J Psychiatry  1995; 152:785–788
[PubMed]
 
Shulman K, Post F: Bipolar affective disorder in old age. Br J Psychiatry  1980; 136:26–32
[PubMed]
[CrossRef]
 
Snowdon J: A retrospective case-note study of bipolar disorder in old age. Br J Psychiatry  1991; 158:485–490
[PubMed]
[CrossRef]
 
Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas J, Cabanis E, Baudrimont M, Maciazek J, Bach M, Bousser M: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet  1993; 3:256–259
[PubMed]
[CrossRef]
 
Bousser MG, Tournier-Lasserve E: Summary of the proceedings of the First International Workshop on CADASIL. Stroke  1994; 25:704–707
[PubMed]
[CrossRef]
 

FIGURE 1.

Pedigree of a Family With a High Rate of Affective Disorder

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References

Dupont RM, Jernigan TL, Butters N: Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging. Arch Gen Psychiatry  1990; 47:55–59
[PubMed]
 
Swayze VW II, Andreasen NC, Alliger RJ, Ehrhardt JC, Yuh WT: Structural brain abnormalities in bipolar affective disorder: ventricular enlargement and focal signal hyperintensities. Arch Gen Psychiatry  1990; 47:1054–1059
[PubMed]
 
Figiel GS, Krishnan KRR, Rao VP, Doraiswamy M, Ellinwood EH, Nemeroff CB, Evans D, Boyko O: Subcortical hyperintensities on brain magnetic resonance imaging: a comparison of normal and bipolar subjects. J Neuropsychiatry Clin Neurosci  1991; 3:18–22
[PubMed]
 
Strakowski SM, Woods BT, Tohen M, Wilson DR, Douglass AW, Stoll AL: MRI subcortical hyperintensities in mania at first hospitalization. Biol Psychiatry  1993; 33:204–206
[PubMed]
[CrossRef]
 
Bradley WG, Waluch V, Brant-Zawadzki M, Yadley RA, Wyckoff RR: Patchy, periventricular white matter lesions in the elderly: a common observation during NMR imaging. Noninvasive Med Imaging  1984; 1:35–41
 
George AE, de Leon MJ, Kalnin A, Rosner L, Goodgold A, Chase N: Leukoencephalopathy in normal and pathologic aging: MRI of brain lucencies. Am J Neuroradiol  1986; 7:567–570
[PubMed]
 
Krishnan KRR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB: Magnetic resonance imaging of the caudate nuclei in depression. Arch Gen Psychiatry  1992; 49:553–557
[PubMed]
 
Spitzer RL, Williams JBW, Gibbon M, First MB: User’s Guide for the Structured Clinical Interview for DSM-III-R (SCID). Washington, DC, American Psychiatric Press, 1990
 
Krishnan KRR, Hays JC, Tupler LA, George LK, Blazer DG: Clinical and phenomenologic comparisons of late-onset and early-onset depression. Am J Psychiatry  1995; 152:785–788
[PubMed]
 
Shulman K, Post F: Bipolar affective disorder in old age. Br J Psychiatry  1980; 136:26–32
[PubMed]
[CrossRef]
 
Snowdon J: A retrospective case-note study of bipolar disorder in old age. Br J Psychiatry  1991; 158:485–490
[PubMed]
[CrossRef]
 
Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas J, Cabanis E, Baudrimont M, Maciazek J, Bach M, Bousser M: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet  1993; 3:256–259
[PubMed]
[CrossRef]
 
Bousser MG, Tournier-Lasserve E: Summary of the proceedings of the First International Workshop on CADASIL. Stroke  1994; 25:704–707
[PubMed]
[CrossRef]
 
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