Schizophrenia Research 64 (2003) 87 – 89 www.elsevier.com/locate/schres Letter to the Editors Auditory hallucinations and cognitive impairment in a patient with a lesion restricted to the hippocampus The hippocampus has been postulated to play an important role in the pathogenesis of schizophrenia. However, explicit evidence of this role is lacking. We describe a man who developed auditory hallucinations and cognitive impairment after suffering a lesion specific to the hippocampus. Case report A 58-year-old right-handed man, who had been a diligent welder, noticed that he was forgetful of dayto-day events without any precipitating event. The impairment gradually worsened and, several weeks later, he even became unable to find his way around his home. He visited our department, presenting with memory dysfunction and auditory hallucinations. No focal neurological abnormalities were evident. Routine serological and CSF examinations, and brain CT were normal. On T1-weighted MRI, there were no apparent ventricular enlargements or dilation of gyri. However, MRI with a fluid attenuated inversion recovery (FLAIR) method revealed high-intensity areas restricted to the hippocampi with the left more marked than the right (Fig. 1A). Although limbic encephalitis was suspected, neither anti-viral (herpes simplex virus and cytomegalovirus) nor anti-neoplastic (Hu, Yo, Ri) antibodies were detected. Since bilateral hippocampal lesions on MRI were not enhanced by gadolinium, ischemic insults were considered the plausible cause. He was unable to recall what he had been doing even several minutes previously, whereas he was able to recall public and social events that had occurred before the onset of illness. He had auditory verbal hallucinations of a derogatory and commanding nature. These halluci- nations were deemed to have persisted from the inception of illness; his wife noted that parallel to the development of disturbed memory, he often behaved as if he were conversing with somebody while he was alone. On neuropsychological tests, he obtained a full-scale IQ of 81 (verbal, 80; performance, 84). Although, on the Benton Visual Retention Test, the number of Correct was within the normal range, the Error score was 6 due to consistent omission of the figure on the right, suggesting a left-sided lesion. The revised Wechsler Memory Scale (WMS-R) revealed a significant impairment in the delayed recall of both logical and visual stimuli, while immediate retrieval was relatively preserved. The Auditory Verbal Learning Test showed a disturbance in the learning effect despite normal immediate reproductions. Performance was also poor in the Wisconsin Card Sorting Test (WCST), in which he achieved five categories with seven perseverative errors (total errors of 18). We repeated MRI scanning every 2 months after the initial examination. While, 6 months later, the highintensity signal became unrecognizable on FLAIR imaging, reduced hippocampal volume was, instead, evident on T1-weighted image and again more conspicuous on the left than the right side (Fig. 1B). At this time, we also re-examined neuropsychological functions. The results on the tests were almost identical to those obtained from previous assessments, except for a marked improvement in the delayed reproduction of visual stimuli (from the 22nd to 77th percentile) in the WMS-R and a further decline in the performance of WCST (the number of category achieved, 0; perseverative errors, 9; and total errors, 26). On the following consecutive assessments of both MRI scans and cognitive performance, these abnormalities remained unchanged. The auditory hallucinations that had lasted for a few months subsided soon after the start of psycho- 0920-9964/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0920-9964(02)00386-9 88 Letter to the Editors Fig. 1. (A) Fluid attenuated inversion recovery MRI (the left brain is shown on the right) shows restricted high-intensity areas in the bilateral hippocampi with the left side more conspicuous. (B) T1-weighted MRI taken a year after the onset of the illness shows a reduction in hippocampal volume that was more evident on the left than the right. tropic agents. The patient managed to resume work after 6 months of treatment, but required close assistance from his colleagues because of his memory impairment, particularly in the domain of delayed recall. This case showed a relatively acute course of an amnestic syndrome and auditory hallucinations associated with lesions localized exclusively to the bilateral hippocampal structures. Although a number of amnestic cases with lesions involving hippocampal structures Letter to the Editors have been reported (Chun and Phelps, 1999; RempelClower et al., 1996), there is no previous report of a case, such as ours, with a lesion circumscribed in the hippocampus and with symptoms of auditory verbal hallucinations that are the most common type of hallucinations in patients with schizophrenia. More interestingly, the patient’s hippocampal lesions were associated with poor performance on the WCST, which is thought to be related to malfunction in the left dorsolateral – prefrontal cortex and has been frequently reported in patients with schizophrenia (Bertolino et al., 2000). It follows, therefore, that impaired performance on the WCST observed in schizophrenic patients may be ascribed, in part, to a deficit in the hippocampus, especially on the left side, in addition to that of the prefrontal region itself. The etiology of his symptoms remain unclear. Since several studies have reported a high prevalence of hallucinations in patients with probable Alzheimer’s disease (AD), auditory hallucinations and cognitive dysfunction observed in our case might be regarded as symptoms of AD. However, this is unlikely because the onset of disturbances in the present case was acute, the cognitive impairments were not progressive, the patient’s memory impairment was considered to be associated with a lesion specific to the hippocampus as revealed by MRI scan, and the patient did not show cognitive disturbances typical of AD such as aphasia, agnosia, alexia, or aplaxia. To our knowledge, this is the first report to provide clear evidence that the hippocampus mediates the formation of symptoms characteristic of schizophrenia, i.e., auditory verbal hallucinations and cognitive dysfunction. Dr. Takei would like to thank the Theodore and Veda Stanley Foundation for financial support. 89 References Bertolino, A., Esposito, G., Callicott, J.H., et al., 2000. Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia. Am. J. Psychiatry 157, 26 – 33. Chun, M.M., Phelps, E.A., 1999. Memory deficits for implicit contextual information in amnesic subjects with hippocampal damage. Nat. Neurosci. 2, 844 – 847. Rempel-Clower, N.L., Zola, S.M., Squire, L.R., et. al., 1996. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci. 16, 5233 – 5255. Katsuaki Suzuki a Nori Takei a,b,c,* Takao Toyoda a Yasuhide Iwata a,c Ryoichi Hoshino a Yoshio Minabe a Norio Mori a a Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan b Stanley Research Center in Japan, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan c Institute of Psychiatry, London, UK 15 April 2002 * Corresponding author. Email address: ntakei@hama-med.ac.jp.