Case Study MRI Abnormalities in Adolescent Bipolar Affective Disorder KELLY N. BOTTERON, M.D., GARY S. FIGIEL, M.D., MARTIN W. WETZEL, M.D., JIM HUDZIAK, M.D., AND MICHELE VANEERDEWEGH, M.D.

Abstract. There is increasing evidence for structural differences in the brains of patients with affective disorders. Recent magnetic resonance imaging (MRI) studies have reported focal signal hyperintensities in the deep white matter of bipolar patients. These previous reports had focused on adult patients with prior episodes of illness. In this case report, the authors discuss a young adolescent patient during her first episode of mania and the finding of subcortical focal signal hyperintensities on brain MRI. The etiology, pathophysiology, and clinical correlates of these lesions will be reviewed. J. Am. Acad. Child Adolesc. Psychiatry, 1992,31, 2:258-261. Key Words: bipolar affective disorder, adolescent, magnetic resonance imaging. Over the past two decades there has been increasing evidence for structural brain abnormalities in psychiatric illness. Although the majority of the work has been focused on schizophrenia, there have also been reports of structural differences in affective disorders. Early studies in bipolar affective disorder using computed tomography (CT) reported differences including enlarged cerebral ventricles, sulcal widening, and cerebellar vermian atrophy in 10-30% of bipolar patients (Jeste et aI., 1988; Nasrallah, 1989). With the increased sensitivity of magnetic resonance imaging (MRI), additional anatomic differences are being detected in bipolar patients, specifically, reduced total cerebral volume (Nasrallah, 1991) and medial temporal lobe hypoplasia. In addition, bipolar patients are reported to have increased Tl relaxation times in temporal and frontal cortex (Rangel Guerra et aI., 1983) and red blood cells (Rosenthal et aI., 1986) in comparison with normal controls. Several recent controlled investigations have demonstrated an increased incidence of subcortical hyperintensities on T2-weighted MRI scans in the deep white matter of adult patients with bipolar affective disorder in comparison with normal controls (Dupont et aI., 1990; Figiel et aI., 1991; Swayze et aI., 1990). The studies to date have not investigated whether the hyperintensities could be detected at the onset of illness. All of these studies were done with adult bipolar subjects, most of whom had been ill for some time. To date, there have been no reports of MRI scans in adolescent or new onset bipolar patients. In this paper the authors describe a case of first onset bipolar disorder-manic phase-in a l5-year-old female who demonstrated subcortical signal hyperintensities. In addition, this patient demonstrated reversible neurological

Accepted September 4, 1991. From the Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri. Reprint requests to Dr. Figiel, Psychiatry Annex, Wesley Woods Hospital, 1821 Clifton Rd., N.E., Atlanta, GA 30329-5102. 0890-8567/92/3102-0258$03.00/0©1992 by the American Academy of Child and Adolescent Psychiatry.


signs, which resolved coincident with improvement in her mania.

Case Report The patient, a l4-year-old black girl, was born at full term with no known perinatal complications. Her mother used recreational drugs including cocaine during her pregnancy but had no known obstetrical complications. At the age of 9 months, she was placed in the home of her now adoptive parents. She had normal developmental milestones and no previous psychiatric or neurological illness. Raised in a very supportive and protective family, she had no knowledge of her adoption. She had no known history of drug or alcohol use. In the fall of her ninth grade year, she had the acute onset over several days of bizarre behavior with agitation, mood lability, restlessness, irritability, severe insomnia, hyperreligiousity, and delusional ideas. Usually not very religious, she was talking with classmates about the devil and judgment day and stated the devil was appearing and talking to her. She was disorganized in her behavior and speech. Within 4 days she was brought to the hospital for evaluation. She was afebrile and her physical exam was without abnormality. Her neurological exam was significant for unilateral four to six beat left ankle clonus and eight beat horizontal nystagmus bilaterally. On mental status exam, she was noted to be hypervigilant, paranoid, psychomotor agitated, .affectively labile, and at times displayed rapid perseverative speech with thought blocking. She complained of auditory and visual hallucinations of a religious nature. A CT scan with and without contrast on the night of admission was normal. The initial lumbar puncture was traumatic with 4,960 RBCs and 30 WBCs, with a normal protein and glucose. Her peripheral WBC count was not elevated. The remainder of her laboratory values were within normal limits except for a mildly elevated serum ammonia of 91 with otherwise normal liver function tests. A drug screen was negative. An EEG obtained after benzodiazepine sedation to treat agitation was reported as being consistent with benzodiazepine influence. The impression of the consulting psyJ. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992


chiatrist in the emergency room was that the patient was acutely manic, and she was admitted. During her admission, she was also seen in consultation by pediatric neurology and internal medicine. A repeat lumbar puncture within 2 days of admission was completely normal with no cells present, normal protein and glucose, and a negative herpes titer and immunoglobulin profile. Her unilateral ankle clonus and nystagmus resolved within the first several days of admission. Her agitation and psychoses had mildly improved by this point. The psychiatrists and consultants concluded she had no infectious or other organic disease. She was initially treated with benzodiazepines; neuroleptics were added on the 2nd hospital day. A brain MRI with gadolinium enhancement was performed on the third day of hospitalization. The scan was done on a 1.0 Tesla Siemensunit at the Mallinckrodt Institute of Radiology with Tl-, TI-, and proton density-weighted axial images obtained. The MRI was significant for hyperintensities on the T2- and proton density-weighted scans. The hyperintensities were bilaterally present posterior to the occipital horns of the lateral ventricles in the deep white matter of the occipital lobes (Fig. 1). Each lesion measured approximately 7.5 mm in diameter.

1. Proton density T2-weighted axial scan. Closed arrows point to bilateral subcortical hyperintensities in the occipital lobes.


J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992

The patient showed moderate improvement in her auditory and visual hallucinations rating on neuroleptics but continued to have religious and grandiose delusions and was inappropriately affectionate with staff. For further control of her symptoms and maintenance medication, lithium was added on the 7th day of admission. She continued to improve markedly after the addition of lithium and was free of hallucinations, delusions, hyperreligiousity, psychomotor agitation, and thought disorder by the 17th day of hospitalization. Her sleep and appetite normalized and her parents reported she was back to her baseline functioning. She was discharged on haloperidol and lithium carbonate. On followup over 5 months she was tapered off haloperidol without return of psychotic symptoms and has been maintained on lithium (with therapeutic blood levels) with no evidence for relapse of affective or psychotic symptoms. Discussion Two observations drawn from this case report will be discussed. First, this patient demonstrates that the deep white matter hyperintensities on T2- and proton density-weighted MRI scans may be present upon initial presentation in some bipolar patients as early as adolescence. These hyperintensities have thus far been reported only in adult bipolar patients who have had multiple episodes of illness. Second, this case provides another example of reversible neurological signs during an episode of mania. Three recent studies from three different institutions have reported that patients with bipolar affective disorder have an increased incidence of T2- weighted hyperintensities in deep white matter on MRI scans in comparison with normal controls. Dupont et al. (1990) reported that nine of 19 bipolar patients and none of the 10 age-matched controls demonstrated subcortical hyperintensities. On blind evaluations they recorded a hyperintensity as present if there were regions of high signal on both the T2- weighted and proton density-balanced images. The patients' mean age was 37. Seven of the nine patients who had subcortical hyperintensities were rescanned I year later and the hyperintensities were judged to be unchanged. In addition, they reported that patients with hyperintensities scored significantly lower on several specific neuropsychological tests involving fluency and recall. Figiel et al. (1991) reported eight of 18 bipolar patients versus one of 18 age-matched controls demonstrated deep white matter hyperintensities. Images were blindly evaluated and the lesions were only judged to be significant if they were present on both the T2- weighted and proton density images. Lateral ventricular enlargement was also found to be present in eight of 18 bipolar patients and no controls, but was not significantly related to the presence of subcortical hyperintensities. The patients' mean age was 35. Swayze et al. (1990) compared 48 patients with bipolar affective disorder with 54 schizophrenic patients and 47 normal controls. They reported that 19% of the bipolar patients had subcortical hyperintensities compared with 9.3% of the schizophrenics and 4.3% of the controls. There was a statistically significant difference between bipolar patients and controls. Lesions were blindly judged to be present if 259


they were visualized on T2-weighted scans. Male bipolar patients were found to have a trend toward lateral ventricular enlargement in comparison with controls. They found a weak trend relating subcortical hyperintensities to ventricular enlargement. The bipolar patients' mean age was 34. These reports do not indicate whether any of the subjects were studied during the first episode of their illness. In fact, the reports characterize the patients as generally older with several previous episodes. Their mean age was in the mid30s, and the mean number of previous hospitalizations when reported ranged from 2.2 to 5.89. Very little, if any, is currently known about the etiology of these hyperintensities in bipolar patients (Dupont et aI., Figiel et aI., 1991; Swayze et al.). There are no neuropathological data in the literature with which to correlate these abnormalities. These subcortical hyperintensities have signal characteristics similar to lesions seen in association with a variety of etiological mechanisms including perinatal complications, ischemic, post-traumatic, anoxic, infectious, and demyelinating diseases (Figie1 et aI., 1991). Subcortical hyperintensities have been reported in several psychiatric disorders and some elderly normal controls. Elderly depressed patients have been shown to have an increased severity of white matter hyperintensities in comparison with agematched controls. In both the healthy and the depressed elderly, these abnormalities are age-dependent, associated with atherosclerotic risk factors and are felt to reflect pathological changes resulting from ischemia to the subcortical brain regions (Figiel et aI., 1991). However, the subcortical hyperintensities observed in bipolar patients show no such correlation, suggesting different underlying pathophysiologies. In the three series reporting subcortical hyperintensities in bipolar patients, the only statistically significant association found was a positive correlation with the number of previous psychiatric hospitalizations by Dupont et aI. (1990). The other two groups did not report testing for this relationship. The hyperintensities were not significantly correlated with atherosclerotic risk factors (Figiel et aI., 1991), neuroleptic treatment (DuPont et aI., 1990), lithium treatment (Dupont et aI., 1990; Figiel et aI., 1991; Swayze et aI., 1990), history of electroconvulsive therapy, age of onset, current age, family history of affective disorders, or history of psychosis (Dupont et aI., 1990; Figiel et al., 1991). However, the sample sizes were relatively small, thus reducing the statistical power to find significantly correlated factors. This case is consistent with these reports that did not find an etiological role involving treatment or repeated episodes of illness. In addition, this young patient was a nonsmoker and had no prior drug or alcohol use, thus not supporting their hypothesized correlation (Epstein 1990; Swayze et aI., 1990). The regional distribution of these deep white matter hyperintensities was reported to be almost exclusively in the frontal and frontal-parietal deep white matter. However, this case demonstrated a different distribution. The deep white matter hyperintensities were present in the occipital lobes. The clinical correlates of the hyperintensities anatomic distribution is currently unknown. Interestingly, the patient presented clinically with visual hallucinations. Before any re260

ports of MRI abnormalities in the white matter of psychiatric patients, it was known that various disease processes which affect the occipital lobes may result in visual hallucinations (Cummings, 1985). Additionally, it has been previously noted that patients with late onset psychoses who present with prominent visual hallucinations frequently have large deep white matter hyperintensities in close proximity to the visual pathways and association areas in the occipital lobes (Botteron et aI., 1991; Breitner et aI., 1990). Clearly, further studies are needed to help clarify the significance of the lesion's location both to clinical characteristics and diagnostic categories. This case also presents the interesting feature of reversible neurological findings present during an episode of affective illness that resolved with treatment. Here, the patient presented with unilateral clonus and nystygmus, which resolved over the first several days of treatment for mania. Her manic symptoms also improved over this time but were still present after the resolution of the neurological signs. Reversible neurological findings have been previously reported in patients with affective disorder. There have been several case reports in patients with depression (Freeman et aI., 1985; Staton et aI., 1981), including bipolar depressed patients (Cutler and Post, 1982; Keshavan and Goswamy, 1983). To the authors' knowledge there is only one previous case report of reversible focal neurological findings during a manic episode. In that case, a significant improvement was reported in a preexisting hemiparesis during mania (Robinson, 1976). The pathophysiology of reversible neurological changes is unknown. Previous speculations of possible etiological mechanisms have suggested that alteration in biogenic amine metabolism (hypothesized to underlie affective illness) may interact with the normal biochemical asymmetry in the distribution of these biogenic amines in the central nervous system and result in lateralized motor and cognitive deficits (Freeman et aI., 1985). In conclusion, this case suggests that subcortical hyperintensities may be present in some patients with adolescent onset bipolar disorder. Although the pathophysiology and etiology of the lesions is unclear, they have an appearance similar to lesions seen in perinatal trauma, anoxia, or postinfarction processes. Swayze et aI. (1990) postulated a priori that the lesions may be related to perinatal insults, and Nasrallah (1991) has hypothesized that a neurodevelopmenta1 etiological process may be important not only in schizophrenia but in bipolar affective disorder as well. He based his hypothesis on structural brain changes and bipolar disorder that are similar to those reported in schizophrenia: ventricular enlargement, sulcal widening, cerebellar atrophy, decreased cerebral volume, and medial temporal lobe hypoplasia. He did not discuss the possible significance of the recently reported signal hyperintensities. However, there are potential neurodevelopmental etiologies for the subcortiCal white matter hyperintensities, and further investigation is needed to clarify this possibility. Further work regarding the etiology, pathogenesis, and natural history of T2-weighted hyperintensities in bipolar affective disorder is necessary, including controlled studies J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992


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MRI abnormalities in adolescent bipolar affective disorder.

There is increasing evidence for structural differences in the brains of patients with affective disorders. Recent magnetic resonance imaging (MRI) st...
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