Psychiatry Research: Neuroimaging 139 (2005) 263 – 267 www.elsevier.com/locate/psychresns Case report Left frontotemporal hyperperfusion in a patient with post-stroke mania Masaru Mimura a,*, Kazuyuki Nakagome a, Natsuko Hirashima a, Hiroshi Ishiwata a, Kunitoshi Kamijima a, Akira Shinozuka b, Hiroshi Matsuda c a Department of Neuropsychiatry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan b Department of Radiology, Showa University School of Medicine, Tokyo, Japan c Department of Nuclear Medicine, Saitama Medical School Hospital, Saitama, Japan Received 28 September 2004; received in revised form 13 April 2005; accepted 8 May 2005 Abstract A 78-year-old housewife with major depression developed a right-sided infarction in the territory of the middle cerebral arteries, followed by acute post-stroke mania. Comparison between pre- and post-stroke SPECT scans demonstrated a unique pattern of left orbitofrontal hyperperfusion with extensive right frontal hypoperfusion. A functional imbalance between right and left orbitofrontal cortices may be important in mania. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Orbitofrontal cortex; Single photon emission tomography; Mood disorder 1. Introduction Although post-stroke depression is well recognized, the occurrence of mania following stroke has been infrequently reported (Starkstein et al., 1990). Most reported patients with post-stroke mania have shown abnormalities of the frontal cortex, even when the structural lesion was located outside of the frontal lobes (Benke et al., 2002). Recent neuroimaging stud- ies suggest that the frontal lobes, including the medial orbitofrontal cortex, temporal lobe, and basal ganglia, are involved in mania (Blumberg et al., 2000). We describe a patient with recurrent depression who had a cerebral infarction followed by post-stroke mania. Comparison between pre- and post-stroke cerebral blood flow demonstrated a unique pattern of circulatory disturbance in organic mania. 2. Case report * Corresponding author. Tel.: +81 3 3784 8569; fax: +81 3 3784 8354. E-mail address: mimura@med.showa-u.ac.jp (M. Mimura). A 78-year-old, right-handed housewife first manifested depressed mood at age 42. She was diagnosed 0925-4927/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2005.05.007 264 M. Mimura et al. / Psychiatry Research: Neuroimaging 139 (2005) 263–267 with major depression and admitted to another hospital. Occasional interruptions of medication led to more than five exacerbations of depression. No manic episodes occurred, and no family history of mood disorder was obtained. In February 2003, the patient developed insomnia and loss of appetite following the death of a relative. A change of medication did not improve her depressed mood. She later was hospitalized at our institution in June 2003. On admission, the patient showed a severely depressed mood, with psychomotor retardation, anxiety, irritability, and delusions of guilt. Her initial score on the Hamilton Depression Rating Scale (HDRS) was 28, and her score on the Zung Self-rating Depression Scale was 66. T2-weighed magnetic resonance imaging (MRI) on admission demonstrated multiple small lacunae in the subcortical white matter (Fig. 1, upper row). Treatment with milnacipran, a dual-action antidepressant, at 100 mg/day did not improve her depressed state. She remained hypoactive and pessimistic, and she retained delusions of guilt. The HDRS score on hospital day 46 was 23, showing no overall change in severity of depression. On hospital day 57, the patient suddenly developed left hemiplegia. Emergency computed tomography (CT) demonstrated a right-sided infarct in the territory of the middle cerebral arteries (MCA) consistent with a right internal carotid artery embolism. She received conservative treatment. Milnacipran was discontinued. Her mental status showed drastic change as consciousness level cleared. Even in the face of left hemiplegia, her depressed mood and psychomotor retardation no longer were evident. Instead, she was in a manic state characterized by mood elevation, a cheerful and talkative manner, frequent joking, and enjoyment of pleasurable activities. Inflated self-esteem had replaced previous delusions of guilt. The follow-up HDRS score was 6. Her score on the Young Mania Scale was 21. Since she still was not ambulant, no treatment was required for her manic state. Subsequent MRI confirmed the previous CT findings (Fig. 1, bottom row). Fig. 1. T2-weighed MRI pre- (top row) and post-stroke (bottom row). M. Mimura et al. / Psychiatry Research: Neuroimaging 139 (2005) 263–267 3. Methods Single photon emission tomography (SPECT) was performed twice, on hospital day 4 and again 12 days after the stroke. Projection data were acquired after an i.v. bolus injection of 600 MBq of 99mTc-ECD using a two-headed gamma camera system (ECAM, Siemens, Hoffman Estates, IL). SPECT images were spatially normalized to standardized stereotactic space, smoothed using a 12-mm FWHM isotropic Gaussian kernel, and analyzed using the Easy Z-Score Imaging System (eZIS) (Matsuda et al., 2004). Each SPECT image was compared with the mean and SD of SPECT images of 20 age-matched healthy female controls (range, 71–80 years) using voxel-byvoxel Z-score analysis after normalization to global 265 mean voxel values; Z-score = ([control mean] [individual value]) / (control SD). The Z-score maps were displayed by projection with an averaged Z-score of 14-m thickness to a surface rendering of the anatomically standardized MRI template with a two-tailed view of a hot color scale (hyperperfusion, Z-score level z 2.0) and a cold color scale (hypoperfusion, Z-score level V 2.0). The extent threshold of the cluster size was set at z 300 voxels. 4. Results Analysis of the patient’s pre-stroke SPECT by eZIS demonstrated bilateral hypoperfusion in the medial and dorsolateral frontal cortices. Hypoperfusion Fig. 2. 99mTc-ECD SPECT analyses using the Easy Z-Score Imaging System (eZIS) pre- (top row) and post-stroke (bottom row). A color key indicates Z-scores. 266 M. Mimura et al. / Psychiatry Research: Neuroimaging 139 (2005) 263–267 in the anterior cingulate cortex was prominent. Hyperperfused areas also were found bilaterally in the lateral frontal, temporal (right more than left), and occipital lobes, and in the cerebellum (Fig. 2). The post-stroke SPECT demonstrated a large area of dense hypoperfusion in the right orbitofrontal, medial frontal, and dorsolateral frontal cortices corresponding to the lesion shown by MRI. Hypoperfusion was also present laterally in the opposite orbitofrontal cortex and in the cerebellum. The areas showing hypoperfusion before the stroke remained essentially unchanged, with additional hyperperfused areas apparent in the left hemisphere, including the medial portion of the orbitofrontal cortex, the superior temporal gyrus, and the paracentral areas. 5. Discussion The present report depicts a patient with poststroke mania, which ironically replaced recurrent and treatment-resistant depression present before the stroke. There was pre-stroke MRI evidence of small vessel disease. The patient was likely to have MRIdefined vascular depression poorly responsive to treatment before the stroke. Pre-stroke SPECT demonstrated prominent bilateral hypoperfusion in the frontal and the anterior cingulate cortices together with several hyperperfused areas that have been documented previously (Drevets et al., 1999). Her post-stroke mental state represented mania rather than euphoria, given her mood elevation and inflated self-esteem. In view of her disinhibition and anosognosia, organic mania of the patient could be regarded as part of a frontal lobe syndrome. As might be expected, eZIS analysis of SPECT images demonstrated hypoperfusion of more extensive areas than the lesions identified by MRI, including most of the right frontal lobes. Hypoperfusion was also present in the lateral portion of the left orbitofrontal cortex. Interestingly, however, our post-stroke SPECT results were unique: hyperperfusion was found in the medial portion of the left orbitofrontal cortex (ventromedial cortex), superior temporal gyrus, and paracentral areas. Regional functional neuroimaging studies of primary mania in resting states have documented increased activity in the anterior cingulate cortex, lateral prefrontal cortex, temporal lobe, and basal ganglia. Although orbitofrontal activity has generally been reported to be decreased, Blumberg et al. (2000) proposed that mania is associated with an imbalance with right lower than left, and ventral lower than dorsal, prefrontal activity. Similarly, Rubin et al. (1995) suggested a pattern of left N right regional cerebral blood flow in the inferior prefrontal cortex in mania. It is plausible that left orbitofrontal hyperperfusion as observed in the present patient may contribute to a similar regional imbalance. Recent functional neuroimaging studies also suggested right orbitofrontal pathology in mania. For example, Blumberg et al. (1999) demonstrated decreased right rostral and orbital prefrontal cortex activation in patients with mania using PET. HarmonJones et al. (2002) suggested that increased left frontal activity is a neurophysiological index of propensity to respond to rewards and that proneness toward manic symptoms is related to relatively increased left frontal activity. Such a functional imbalance between right and left orbitofrontal cortices, together with related cortical and subcortical areas, may be important in mania. However, great caution should be given to the interpretation of hyperperfusion in this patient and the function–perfusion relationship, especially during the subacute stage after stroke. Definitive conclusions await evidence from other patients with organic mania. References Benke, T., Kurzthaler, I., Schmidauer, C., Moncayo, R., Donnemiller, E., 2002. Mania caused by a diencephalic lesion. Neuropsychologia 40, 245 – 252. 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