0022-3018/85/1731-0610$02.00/0 THE JOURNAL OF NERVOUS AND MENTAL DISEASE Copyright © 1985 by The Williams & Wilkins Co, Vol. 173, No. 10 Printed in U.S.A. Psychiatric Manifestations of Right Hemisphere Infarctions BRUCE H. PRICE, M.D., anD MARSEL MESULAM, M.D.' Five right-handed patients (aged 45 to 78 years) developed acute psychotic disturbances in conjunction with infarcts in the right hemisphere. Their presentation was marked by agitation, inattention, suspiciousness, paranoid delusions, hallucinations, and lack of ap- propriate concern. Several of these patients initially received primary psychiatric diagnoses. Although neurological findings indicative of right hemisphere involvement could also be elicited, these were generally overshadowed by the more dramatic behavioral alterations. The electroencephalogram and computerized axial tomography were positive in most cases. These cases demonstrate that the possibility of a right hemisphere lesion needs to be entertained in patients who present with an atypical psychotic episode. We treated five right-handed patients whose clinical presentation raised the possibility of primary psychi- atric disease but whose test results also indicated infarcts in the right hemisphere. One purpose of this report is to alert the physician to the psychiatric presentations of cerebrovascular disease; another is to advance some thoughts on the potential anatomical substrates of these conditions. Case Reports Case 1 A 66-year-old right-handed engineer with no prior neurological or psychiatric disease but with a history of adult onset diabetes mellitus, chronic obstructive lung disease, and alcoholism, suddenly became restless and sleepless. He fixated on numbers and money and was convinced that he would win the lottery so that “all my children would be set free for life.” He lost 30 Ibs over the ensuing month and was hospitalized even- tually, where he remained agitated and accused the nurses of trying to poison him. In addition, he was convinced he had terminal cancer and would soon die. The admitting diagnosis was psychotic depression. The medical and neurological exams were free of diagnostic abnormalities. The EEG was unremarka- ble, but a computerized axial tomography (CAT) scan revealed a right parietal infarction. He was treated with imipramine, haloperidol, benztropine, and psy- chotherapy, but his agitated and delusional state per- sisted. Over the next several months he received other diagnoses, including major depression with suicidal potential and panic reaction. Section of Neuroscience and Behavioral Neurology, Charles A. Dana Research Institute, Beth Israel Hospital, 330 Brookline Ave- nue, Boston, Massachusetts 02215. Send reprint requests to Dr. Price. The preparation of this manuscript was supported in part by the Javits Neuroscience Investigator Award. The authors want to thank Leah Christie and Rick Plourde for expert secretarial and photo- graphic assistance. Approximately 3 months later, he experienced two episodes of transient left upper extremity sensory- motor symptoms. On examination at that time, his blood pressure was 180/120 mm Hg. He was oriented but mildly inattentive and did not appear to show concern for his condition. Spontaneous gait demon- strated a diminished left arm swing. A minimal left pronator drift, mild weakness of the left wrist exten- sors and interossei, brisk left upper extremity deep tendon reflexes, and left-sided extinction upon double stimultaneous tactile stimulation were seen. Impaired visual-spatial skills were also demonstrated. Routine admission studies were normal. A repeat EEG showed focal right posterior temporal and occipital slowing. The CAT scan at this time demonstrated a small lacunar infarct in the right anterior internal capsule as well as the previously seen larger infarct in the right posterior parietal region (Figure 1, left). His behavioral difficulties gradually remitted over 3 months. Though his mild left body findings persist, he has experienced no further episodes and has re- turned to his previous job with success over the past 2 years. He remains only on antihypertensive and antiplatelet medications. Comment. It is likely that the infarction in the right parietal region seen in the first CAT scan was respon- sible for the initial psychotic behavior, although the temporal relationship between these two events re- mains unresolved. The additional lacunar stroke sev- eral months later brought him to neurological atten- tion. It is interesting that this second cerebrovascular event was not associated with a new psychotic episode. Case 2 A 35-year-old right-handed woman office manager with no prior medical or psychiatric history experi- enced the abrupt onset of left hemiparesis and slurred speech which cleared over 3 weeks. Birth control pills were implicated. They were withdrawn, and she had CEREBRAL INFARCTION AND PSYCHOSIS 611 Fic. 1. CAT scans of patient 1 (left) and patient 2 (right). The left side of the head is on the left side of the scan. The arrowhead points to the site of infarction. no further cerebrovascular events. She was essentially well again for 10 years when, at the age of 45, she experienced the first of four acute psychotic episodes over the ensuing 8 months. Each episode was accom- panied by multiple visual and auditory hallucinations, such as seeing Shriner comic cars and faces in fire- places. She had the delusions of being poisoned and killed, accompanied by feelings of panic and depres- sion. The episodes began and ended rather abruptly and lasted from 1 day to 1 week. She required psychi- atric hospitalization and received various diagnoses, such as acute schizophrenia, schizoid personality, and atypical depressive disorder. She continued to func- tion well between psychotic episodes. Neurological examination 1 year later revealed the presence of brisk deep tendon reflexes and slowness of individual finger movements on the left, as well as impaired visual-spatial skills. A CAT scan revealed an old infarct in the white matter of the right frontal region (Figure 1, right). An EEG showed paroxysmal independent bitemporal epileptiform activity during drowsiness and sleep. She was placed on phenobarbital and has had no recurrences over the subsequent 2 years. Comment. Since there is no evidence of recurrent stroke, it is likely that the psychotic episodes repre- sented seizure phenomena. This is supported by her epileptic EEG and the apparent beneficial response to an anticonvulsant. Although the EEG focus was in the temporal lobes, this may well represent daughter foci secondary to electrical instability around the zone of the frontal infarction (Morrell, 1969; Morrell, in press; Morrell, et al., 1975). Naturally, the possibility that this woman had additional limbic lesions or a totally independent condition of temporal lobe epi- lepsy cannot be ruled out. Case 3 A 61-year-old right-handed woman was admitted to - the psychiatry ward for agitation, anorexia with weight loss, suicidal ideation, and inappropriate be- havior, such as threatening to kill her husband, pulling down all her house plants, and attempting to set her house on fire. Past medical history was remarkable for atherosclerotic cardiovascular disease, chronic ob- structive lung disease, left mastectomy for carcinoma, one transient episode of left monocular blindness, and another involving left upper extremity numbness and weakness. During the hospitalization she was noted to be confused and incontinent. Neurological exam revealed brisker left upper extremity reflexes, left upper ex- tremity clumsiness, and left dystonic posturing with stressed gait. She was markedly inattentive and diso- riented, showed a lack of appropriate concern, was perseverative, and had impaired visual-spatial skills. A CAT scan was unremarkable, and the EEG showed a mildly slow background of 7 Hz. No toxic or meta- bolic causes could be determined. She was discharged 612 PRICE AND MESULAM on haloperidol, isosorbide, digoxin, dipyridamole, the- ophylline, and nitroglycerin. She was readmitted 5 months later due to her hus- band’s inability to care for her at home. She was still mildly inattentive and displayed left-sided extinction during double simultaneous visual stimulation. Her visual-spatial skills remained impaired. A repeat CAT scan showed no change, but the EEG showed parox- ysms of right posterior temporal sharp theta waves with occasional involvement of homologous areas in the left. Her behavior improved spontaneously, and she has experienced no recurrence. Comment. The abrupt onset of a confusional state accompanied by psychotic features, incontinence, and left-sided motor findings makes the diagnosis of an idiopathic affective disorder highly improbable. It is more likely that the behavioral picture resulted from structural injury to the right side of the brain. Case 4 A 78-year-old right-handed woman with long-stand- ing hypertension and a recent subendocardial infarct became abruptly confused and was admitted to the hospital. She refused to drink for fear of being poi- soned, would take off other patients’ surgical head dressings, and would intermittently scream “My fam- ily thinks I have Hitler’s papers under my head .... People are out to kill me .... I am Hitler ... ’'m covered with worms.” On occasion, she became as- saultive towards family members and staff. These spells were mixed with periods of relative lucidity. Neurological exam revealed inattentiveness, persev- eration, lack of appropriate concern, mild left hemi- paresis, and tactile extinction on the left. Impaired visual-spatial skills and dysgraphia were also noted. Toxic and metabolic factors were ruled out. The CSF examination was unremarkable. A CAT scan was nor- mal. The EEG showed intermittent rhythmic sharp theta waves of medium to high voltage, with phase reversal in the right parietal region. A trial of diphen- ylhydantoin did not result in clinical improvement. During one of her agitated delusional episodes, she fell and sustained a pelvic fracture. Haloperidol was needed for behavioral management. Over the 1 year since onset, she has remained confused, with episodic exacerbations of her agitated and delusional behavior. Comment. This elderly patient without prior psy- chiatric history was at high risk for stroke. The abrupt onset of psychotic behavior was associated with neu- rological and EEG findings that point to a right hem- isphere lesion. Case 5 A 76-year-old right-handed male plumber without prior psychiatric history suddenly became confused. He was unable to drive to his son’s house for Thanks- giving, became increasingly inattentive and irritable, but remained indifferent to his difficulties, merely complaining of a stuffy nose. On admission, he was inattentive, perseverative, and impaired on visual- spatial tasks. Left-sided visual extinction was elicited during double simultaneous visual stimulation, and a left pronator drift was also noted. During the hospi- talization, he thought there was a plot against him and refused all tests and medications. He was agitated and combative, repeatedly dressed and attempted ‘to escape, and claimed there was no reason for him to be there. He stated that he was in a prison or hotel and that “you are all murderers .... you’re torturing me ... I want to call the police.” He would continually disturb other patients, make inappropriate verbal and physical sexual gestures, and felt he was going to die. Tests for toxic and metabolic causes were negative. An EEG showed 6 Hz background slowing without focal features. A CAT scan revealed no focal lesions. The echocardiogram and Holter monitor were normal, as were noninvasive carotid studies. Past medical his- tory was remarkable for a myocardial infarct and congestive heart failure. The left-sided body findings cleared over the next month, but his behavioral and cognitive difficulties remained. Comment. This patient had an atypical psychiatric presentation in conjunction with findings suggestive of a right hemisphere lesion. Discussion We have described five right-handed patients be- tween the ages of 45 and 78 years who attracted psychiatric attention in conjunction with signs of structural injury to the right hemisphere. Although focal findings were present, the intensity of the be- havioral changes far exceeded the abnormalities noted in the examination of cognitive and sensory-motor functions. Some of the patients were initially diag- nosed as having agitated depression or other psychotic conditions. An alternative diagnostic consideration was toxic metabolic encephalopathy. No patient had a prior psychiatric history, but cardiovascular risk factors were commonly present. Many of these patients experienced agitation, inat- tention, persecutory delusions, hallucinations, lack of appropriate concern, and mood distrubances, which included dysphoria, hypomania, generalized anxiety, and panic. These behavioral manifestations did not fit any well-established primary psychiatric entity, especially in view of the age of onset and the absence of an obvious precipitating life experience. All patients also had some cognitive and sensory-motor impair- ment consistent with right hemisphere injury. How- CEREBRAL INFARCTION AND PSYCHOSIS 613 ever, these could easily be overlooked in the context of the more salient psychiatric features. Either the CAT scan or the EEG provided confirmation of a structural lesion in the right hemisphere in several of the cases. Except for case 2, the behavioral disorders most likely coincided with the stroke onset. The hallucina- tions, agitation, and confusion persisted in cases 4 and 5. Only case 2 was attributable to a seizure disorder 10 years after her stroke. The emergence of severe psychiatric manifestations as a consequence of organic brain disease is well known in clinical practice. However, in most such cases, metabolic or toxic encephalopathies are usually implicated (Wolff and Curran, 1935). In fact, the term organic psychosis was once popular as a synonym for toxic metabolic encephalopathy. Our patients show that similar behavioral syndromes can also emerge in conjunction with focal brain disease. Accurate diag- nosis in such cases is of obvious benefit to institute appropriate management. Patients similar to ours have been described previ- ously. In 1979, Guard et al. reported 10 patients with right temporal softening secondary to strokes or trauma. The clinical presentations were characterized by disorientation, agitation, inattention, flight of ideas, and blunted intellect. Four had visual halluci- nations, six displayed visual-spatial difficulties, one had symptoms suggestive of a manic-depressive ill- ness, and six had focal left-sided neurological findings. The EEGs, brain scans, angiograms, and dichotic lis- tening tests helped to confirm the diagnosis in all cases. Levine and Finkelstein (1982) reported eight pa- tients with the acute onset of psychotic behavior 1 month to 11 years after right temporoparietooccipital stroke or trauma. As in the case of our patients, the onset was abrupt, and the clinical manifestations in- cluded hallucinations, delusions, agitation, a fluctuat- ing course, mild left body findings, impoverished vis- ual-spatial skills, and an absence of prior psychiatric history. They suggested that the pathophysiology of the psychosis may be related to epilepsy. Peroutka et al. (1982) reported a similar patient who presented with hallucinations and delusions 2 days after a right temporoparietooccipital infarction. Although the ele- mentary neurological examination of this patient was normal, diminished visual-spatial skills were demon- strated. The EEG was not epileptic. Only two of our six patients (case 2 and perhaps case 4) had epilepti- form activity on the EEG. Therefore, epilepsy does not appear to constitute a necessary feature in patients with this syndrome. Levine and Grek (1984) recently reported nine cases of delusions following right hemisphere infarction and concluded that delusions depend more on premorbid brain atrophy than on the exact location or size of the infarct. Since none of our patients had significant brain atrophy on CAT scan, this is also unlikely to constitute a necessary relationship. The fact that pa- tient 2 was only 45 years old and otherwise mentally intact also rules out the possibility that a background of age-related cognitive decline is essential for the emergence of these syndromes. There are other settings in which cerebrovascular disease may present predominantly as a behavioral or psychiatric syndrome. For example, some right hemi- sphere infarcts may give rise to an isolated confusional state without the florid psychiatric symptomatology described in these patients (Mesulam, e¢ al., 1976). In patients with medial temporooccipital lesions in either hemisphere, severe agitated delirium may emerge, but these are almost invariably associated with marked visual field deficits (Horenstein, et al., 1967, Medina, et al., 1977). In still other patients, acute left prefrontal lesions may present as apathy and withdrawal (Mesulam, 1979). Furthermore, the initial presentation of Wernicke’s aphasia is charac- terized by what appears to be an incoherent word salad in a patient who may have no primary neurolog- ical findings. Many such patients may also show in- termittent agitation and suspiciousness, so that an adequate examination of language may not be possible during the acute phase (Benson and Geschwind, 1975). In such patients, the demonstration that axial com- mands can be followed perfectly while limb commands cannot be performed is diagnostic of the condition. Thus, even when elementary sensory-motor findings are hard to detect, subdued, or even absent, there are several settings in which the clinician must suspect the presence of cerebrovascular disease when faced with a patient in whom the clinical picture appears to be dominated by psychiatric symptomatology. It is interesting that each of our patients as well as those of Guard et al. (1979), Levine and Finkelstein (1982), and Peroutka et al. (1982) had right hemi- sphere injury. It is not clear if this indicates that damage to the right hemisphere is more closely asso- ciated with this type of psychiatric disturbance or whether similar disturbances are equally frequent after left hemisphere injury but become masked by the prominent aphasic symptoms. Our initial impres- sion, shared by several other investigators as well (Gainotti, 1979), is that right hemisphere injury is more frequently implicated than left hemisphere in- jury as the cause of salient psychiatric disturbances. It would be useful to find out what proportion of individuals with right hemisphere infarcts develops psychotic symptoms. Furthermore, it is of interest to determine if this indicates a unique lesion site or, 614 PRICE AND MESULAM perhaps, a set of special vulnerabilities in the form of preexisting brain disease or psychiatric profile. Our cases do not support advanced age, atrophy, epilepsy, or concomitant left hemisphere dysfunction as neces- sary prerequisites. The pathophysiology of the psychotic behavior in our patients is obscure. The brain is not only the organ of cognition, perception, and action but also that of affect and thought. The proper balance among thought, experience, and affect is indispensable to mental health. It is not surprising that certain lesions of the brain can disrupt this balance in a way that may lead to severe behavioral disturbances which ap- pear to represent psychotic episodes. Usually, the lim- bic parts of the brain are implicated in psychiatric disease. However, many patients with the type of acute psychotic symptoms described in this report have lesions located in frontal, parietal, or lateral temporal cortex. Recent evidence indicates that the high-order association areas in the prefrontal and posterior pa- rietal regions receive direct, monosynaptic limbic sys- tem inputs (Barbas and Mesulam, 1981; Mesulam, et al., 1977). It is conceivable, therefore, that lesions in such areas of the brain disrupt the interaction between high-order association cortex and limbic structures and that the behavioral manifestations of this include psychotic episodes. Conclusion Five right-handed patients developed psychotic fea- tures in conjunction with right hemisphere infarcts. Although subtle neurological signs could be elicited, their psychiatric features were most salient. Cardio- vascular risk factors were usually present. Several patients received primary psychiatric diagnoses and inappropriate treatments. CAT scans and EEGs were helpful in most cases. In patients who present with an acute atypical psychotic episode, focal brain disease must be considered. References Barbas H, Mesulam M-M (1981) Organization of afferent input to subdivisions of area 8 in the rhesus monkey. J Comp Neurol 200:407-431. Benson DF, Geschwind N (1975) Psychiatric conditions associated with focal lesions of the central nervous system. 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