Altered Behavior Associated with Damage to the Ventromedial Hypothalamus: A Distinctive Syndrome

Behavioural Neurology, Jul 2018

An adult manifested a tetrad of neurobehavioral findings consisting of episodic rage, emotional lability, hyperphagia with obesity, and memory impairment with intellectual decline following surgical removal of a craniopharyngioma. Post-mortem investigation of the topography of the lesion as well as review of previously reported cases suggest that this tetrad represents a specific neurobehavioral syndrome referable to damage to the ventromedial hypothalamus.

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Altered Behavior Associated with Damage to the Ventromedial Hypothalamus: A Distinctive Syndrome

Altered Behavior Associated with Datnage to the Ventrotnedial Hypothalatnus: a Distinctive Syndrotne FREDERICK G. FLYNN 1 ' JEFFREY L. CUMMINGS 1 UWAMIE TOMIYASU 0 1 0 Laboratory Service (Neuropathology), West Los Angeles Veterans Administration Medical Center; , , 2Departments 1 , , 2Neurobehavior Unit An adult manifested a tetrad of neurobehavioral findings consisting of episodic rage, emotional lability, hyperphagia with obesity, and memory impairment with intellectual decline following surgical removal of a craniopharyngioma. Post-mortem investigation of the topography of the lesion as well as review of previously reported cases suggest that this tetrad represents a specific neurobehavioral syndrome referable to damage to the ventromedial hypothalamus. - alternating with childlike whining and crying. He began to eat excessively, had difficulty with memory, and became depressed. The patient was placed on desipramine for depression and haloperidol for agitation. Within 10 months of surgery the patient's agitation had evolved into intermittent episodes of impulsive violence. During these times the patient engaged in verbal abuse of family, hospital staff, and other patients. Over the ensuing one-and-a-half years the patient impulsively destroyed the contents of a garage, a pool table, door windows (including one that was reinforced by wire), door bolts, bedroom windows, water fountains, fire extinguishers and numerous pieces of furniture. Caretakers were often injured during at­ tempts to intervene, although the unprovoked violence was rarely directed specifically at individuals. Various combinations of haloperidol (to 120 mg/d) , chlorpromazine (to 3000 mg/d) , lithium carbonate (to 1200 mg/d) , and propranolol (to 320 mg/d) failed to control the violent outbursts. During a one-and-a-half year period the patient required physical restraint by tying all 4 limbs on over 30 occasions. Hyperphagia led to a weight gain of nearly 100 pounds. Attempts to restrict his caloric intake often precipitated violent outbursts. Mental status examination 2 years after the surgery revealed an alert patient whose affect was flat and whose psychomotor speed was slightly slowed. Digit span was 6 forward and 3 backwards. Memory testing revealed an immediate recall of 3 out of 3 words, but none of the 3 were recalled after 3 minutes. The patient's inability to learn was corroborated by nursing personnel and housestaff. In addition to the difficulty remembering new information, he was unable to adapt to new routines or retain instructions. Remote memory remained intact with the exception of a brief period of retrograde amnesia preceding the patient's surgery. In addition to his severe amnesia, the patient also had minor deficits of calculation, word list generation, abstract thinking, and frontal systems tasks. The patient's general neurologic examination demonstrated an incongruous left inferior quadrantanopsia, a flattened left nasal-labial fold, left pronator drift, and a left plantor extensor response. A CT scan (Fig. 1) demonstrated right temporal lobe as well as right hypothalamic defects, and the third ventricle was slightly enlarged. There was no radiologic evidence of recurrent tumor. The patient became increasingly immobile due to excessive weight and hypersomnolence. He was found pulseless and apneic and attempts to resuscitate him failed. The cause of death was massive bilateral pulmonary emboli with acute corpulmonale and pulmonary edema. Examination of the brain revealed a 4·5 x 3·5 cm surgical defect in the right temporal lobe. This lesion did not involve the amygdala or parahippocampal gyrus. There was a 1·8 x 1'2 x 1'5 cm cavity in the infundibular area. It involved most of the right rostral hypothalamus as well as the left ventromedial hypothalamus (Fig. 2). The following specific nuclei were involved: ventromedial, anterior, paraventricular, dorsomedial, supraoptic, lateral, tuberal, and posterior. The latter 4 nuclei were less affected than the anterior and medial groups. There was also involvement of the descending columns of the fornix (particularly on the right). The post-surgical cavity extended superiorly into the right internal capsule, the massa intermedia, and the dorsal medial thalamus. The right lateral and third ventricles were enlarged. Microscopi­ cally, the tissue surrounding the cavity consisted of a gliotic scar. Chronic inflammatory cells were seen in the thalamus and medial globus pallidus. The pituitary was small but intact. No recurrent tumor or radiation-induced necrOSIS were seen . Discussion Direct invasion of the hypothalamus has been reported to produce endoc­ rine, neurologic, and behavioral abnormalities in various combinations (Bauer, 1954; Bray and Gallagher, 1975) . However, direct invasion of the hypothalamus by tumour producing the tetrad of (1) episodic rage, (2) emotional lability, (3) hyperphagia with obesity, and (4) intellectual deterioration have been described in only four previous cases (Table 1) 1 2 A-?nA-A~ (Collins, 1942; Haugh and Markesberry, 1983; Killeffer and Stern, 1970; Reeves and Plum, 1969) . In the current patient these features were the most conspicuous aspects of the clinical presentation. While present in the 4 cases noted above, the tetrad of behavioral findings was not emphasized or recognized as a specific syndrome with localizing significance. In all patients in whom the neurobehavioral syndrome discussed here was described, the principal site of brain injury involved the ventromedial hypothalamic nuclei. Bauer (1954) reviewed 60 cases of hypothalamic lesions previously reported in the literature. Fifty-one of these cases were due to tumors. Twenty-one of the patients had associated psychiatric manifestations, and behavioral changes represented the initial symptoms in 7. In this series, the psychiatric features observed included rage, emotional lability, or abnormal sexual behavior. Another retrospective study (Bray and Gallagher, 1975) of 69 patients with hypothalamic obesity disclosed 20 per cent to have associated behavioral changes, but the nature of these changes was not discussed. These large reviews suggest that behavioral alterations are common with hypothalamic lesions, but that the specific syndrome discussed here is relatively infrequent. The 4 components of the neurobehavioral syndrome have been described primarily in conjunction with hypothalamic injury, but may also occur with lesions in other areas. When all 4 behavioral features are simultaneously present, a lesion in the ventromedial hypothalamus is almost invariably found. Episodic rage due to hypothalamic lesions has been reported in both animal and human studies. Hess (1956) demonstrated that stimulation of the perifornical area of the hypothalamus made docile animals enraged. Bard (1928) showed that the expression of rage was independent of the cortex, occurring even when all tissue rostral to the posterior hypothalamus was removed. Akert (1959) suggested that the ventromedial hypothalamus suppresses other hypothalamic regions, and lesioning these nuclei releases inhibition and produces rage behavior. All reported human cases of episodic rage due to tumors of the hypothalamus involved the ventromedial nuclei (Table 1). In addition to rage attacks, the current case had marked oscillations between inappropriate laughter and crying, as well as occasional childlike remorse after his violent outbursts. This lability has been observed pre­ viously in patients with ventromedial nuclear involvement (Reeves and Plum, 1969; Killeffer and Stern, 1970; Beal et at., 1981) . The patient~ lacked signs of pseudobulbar palsy and the changes in affect reflected emotional fluctuations and impaired mood control. The ventromedial hypothalamic region has also been implicated in feeding behavior. Bilateral lesions of this region lead to excessive eating, whereas stimulation results in starvation (Akert, 1959) . The production of hypothalamic hyperphagia is not limited to lesions of the ventromedial area (Rabin, 1972; Gold, 1973) . Gold (1973) suggested that lesions in the ascending noradrenergic bundle rostral to the ventromedial hypothalamus can produce hyperphagia; Ahlskog et at. (1975 ) hypothesized that these two areas play independent roles in feeding behavior and that simultaneous lesions in both result in more extreme hyperphagia than a lesion in either the noradrenergic bundle or ventromedial nuclei alone. Another cardinal element of this syndrome is intellectual decline. Memory loss is the most prominent feature. The current patient demon­ strated an amnestic pattern of memory disturbance with poor ability to learn new information, retrograde amnesia, and intact recollection of remote material. Similar memory disorders have been described in the patients reported previously with similar syndromes (Table 1). Patients with more extensive brain involvement may develop dementia during the course of their illness (Reeves and Plum, 1969; Killefer and Stern, 1970; Beal et at., 1981) . Lesions of the mammillary bodies, fornix, dorsomedial nucleus of the thalamus, and hippocampus have all been implicated in the production of amnestic syndromes. The descending columns of the fornix are especially susceptible to damage when the ventromedial nuclei are involved. This was noted in the present patient as well as several others (Reeves and Plumb, 1969; Haugh and Markesbery, 1983) . Although involvement of mammillary bodies and fornices may be responsible for the memory deficit, a primary role in memory for the ventromedial hypothalamus itself has been postu­ lated (Beal et at., 1981; Reeves and Plum, 1969) . Animal studies have Tumor Type Hypothalamic invol­ vement Other structures in­ volved ;r:I o '"'1 r-' ~ Z ~ ...., ~ f"' Clinicopathological comparison ofpatients with tumors who manifested the hypothalamic neurobehavioral tetrad Present Case ( Adult) Collins (1942) (Adult) Reeves and Plum (1969) (Adult) Killeffer and Stern ( 1970) (Child) Haugh and Markesbery (Adult) Craniopharyngioma Craniopharyngioma Hamartoma Craniopharyngioma Astrocytoma Most affected: Right: VM, ANT, PV,DM Lift: VM Less affected: Right: SO, LAT, TUB, Post Right: IC, DMT, MI, descending col­ umns of fornix Lift: Descending col­ umns of fornix (only slightly in­ volved) All hypothalamic nuclei Bilateral: VM, DM, SO (caudal aspect only) All hypothalamic nuclei except MB (intact remnants) Floor of the third ventricle Descending columns of fornix (bilaterally) lvlost affected: Right: VM, DM, PV, ANT, MED, SC Less affected: Right: Post Lift: CVM, SC, PD, ANT, PV Third ventricle LT,AC Right fornix Episodic rage Emotional lability Hyperphagia Memory impairment & intellectual decline Diabetes insipidus H ypothyroidism Hypoadrenalism Episodic rage Emotional lability Hyperphagia Memory impairment & intellectual decline Diabetes insipidus Hypothyroidism Amenorrhea Hyperglycemia Poikilothermia Sleep disturbance Episodic rage Emotional lability Hyperphagia Memory impairment & intellectual decline Diabetes insipidus H ypothryoidism Hypoadrenalism Hyperglycemia Poikilothermia Episodic rage Emotional lability Hyperphagia Memory impairment & intellectual decline Diabetes insipidus Hypothyroidism Hypoadrenalism Precocious puberty Hyperglycemia Poikilothermia Sleep disturbance Episodic rage Emotional lability Hyperphagia Memory impairment & intellectual de­ cline Hypothyroidism Amenorrhea Hypothermia Reversal of sleep­ wake cycle Visual hallucinations AC = anterior commissure; ANT = anterior; DM = dorsomedial; DMT = dorsomedial thalamus; IC = internal capsule; LAT = lateral; LT = lamina terminalis; MB = mammillary bodies; ME = median eminence; MED = medial; MI = massa intermedia; PO = preoptic; POST = posterior; PV = paraventricular; SC = suprachiasmatic; SO = supraoptic; TUB = tuberal Neurobehavioral changes Endocrine changes Miscellaneous changes Code: > t..".,' t':I :;d t':I o t:l:l t':I ::c > < (3 :;>;: > Z o < t':I .Z.., :;d o ~ t':I o ;; t""' ::c ~ ~ ..., ::c > ~ ~ c: en demonstrated that amygdalofugal pathways to the ventromedial hypothala­ mus are important in the acquisition of new memory and lesions in these regions may contribute to the memory deficit (Gold and Proulx, 1972; Schwartz and Teitelbaum, 1974) . Treatment of the behavioral manifestations associated with ventrome­ dial hypothalamic lesions has been largely unsuccessful. Large doses of neuroleptics, beta-adrenergic blocking agents, and lithium carbonate failed to alter the behavior of the current patient. In some patients, these agents-­ alone or in combination with antidepressants, benzodiazepines, or testoster­ one antagonists--have ameliorated the aggressive episodes (Sheard, 1984; Goldstein, 1974) . Psychotherapy and behavioral modification approaches have consistently failed to improve behavior (Goldstein, 1974). Pharmaco­ logic studies in animals suggest that rage and appetite are mediated by cholinergic mechanisms and can be manipulated by cholinergic agonists and antagonists (Myers, 1964; Smith et at., 1970; Yoburn and Glusman, 1984) . Such observations may eventually lead to more efficacious treatment. Amygdalotomy (Naraboyashi, 1963; Heimburger et at., 1966) , posterior hypothalamotomy (Sano et at., 1970) , and thalamotomy (Andy and Jurko, 1972) have been shown to diminish aggressive behavior in animals and humans. While controversial as therapeutic interventions, their success attests to the importance of these structures in mediating aggressive beha­ VIOr. Other abnormalities exhibited by the current patient and others with hypothalamic lesions include diabetes insipidus, hypothyroidism, hypoadre­ nalism, sleep abnormalities, and disturbances of temperature regulation. Diabetes insipidus is seen with lesions of the supraoptic and paraventricular complex as well as the infundibular stalk (Rodeck, 1967) . Interference with thyroid releasing factor due to lesions of the anterior hypothalamus as well as reduction in adrenocorticotropic hormone production from injury to the ventral hypothalamus may result in hypothyroidism and hypoadrenalism, respectively (Reichlin, 1963) . Abnormalities of sleep have been reported with lesions of the basal diencephalon, and Jouvet (1967) proposed that this region subserves behavioral arousal. Poikilothermia has been produced by bilateral caudal and lateral hypothalamic lesions, and heat loss can be interrupted by lesions in the preoptic or lateral anterior hypothalamus (Akert, 1959) . Behavioral disturbances associated with hypothalamic tumors have previously been reported, but their importance has been underemphasized. Behavioral disturbances may be the initial manifestations of hypothalamic involvement and may dominate the clinical syndrome. The tetrad of episodic rage, emotional lability, hyperphagia with obesity, and mental impairment represent a specific neurobehavioral syndrome associated with hypothalamic dysfunction. Evidence from this case as well as those pre­ viously reported suggests that when this tetrad is present the ventromedial hypothalamus is invariably involved. AcknowledgeIIlents This project was supported by the Veterans Administration. Norene Hiekel typed the manuscript. MEDIATORS INFLAMMATION World Journal Hindawi Publishing Corporation ht p:/ www.hindawi.com Practice Hindawi Publishing Corporation ht p:/ www.hindawi.com Hindawi Publishing Corporation ht p:/ www.hindawi.com Hindawi Publishing Corporation ht p:/ www.hindawi.com Journal of Hindawi Publishing Corporation ht p:/ www.hindawi.com Immunology Research PPAR Research Hindawi Publishing Corporation ht p:/ www.hindawi.com Submit your manuscr ipts Obesity Endocrin Ophthalmology Stem Cells International Hindawi Publishing Corporation ht p:/ www.hindawi.com Evidence-Based Complementary Alternative Medicine and Hindawi Publishing Corporation ht p:/ www.hindawi.com Journal of Oncology Disease nal and Mathematical Methods Behavioural AIDS Oxidative Ahlskog , J. E. , Randall , P. K. and Hoebel , B. G. ( 1975 ). Hypothalamic hyperphagia: dissociation from hyperphagia following destruction of noradrenergic neuroma . Science , 190 , 399 - 40 I. Akert , K. ( 1959 ). Physiology and pathophysiology of the hypothalamus; In "Introduction to Stereotaxis with an Atlas of the Human Brain" , (Eds G. Schaltenbrand and P. Bailey) , Volume 1 . Grune and Stratton, New York. Andy , O.J. andJurko , M. F. ( 1972 ). Lesions in the centromedian and intralaminar nuclei; In "Psychosurgery" (Eds E. Hitchcock, L. Laitiren and K. Voernet) , Charles C. Thomas, Springfield, IL. Bard , P. ( 1928 ). A diencephalic mechanism for the expression of rage, with special reference to the sympathetic nervous system . American Journal oj Physiology , 84 , 490 - 515 . Bauer , H. G. ( 1954 ). Endocrine and other clinical manifestations of hypothalamic disease . Journal of Clinical Endocrinology , 14 , 13 - 31 . Beal , M. F. , Kleinman , G. M. , Ojemann , R. G. , et al. ( 1981 ). Gangliocytoma of third ventricle: hyperphagia, somnolence, and dementia . Neurology , 31 , 1224 - 1228 . Bray , G. A. and Gallagher , T. F. ( 1975 ). Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a review of the literature . Medicine , 54 , 301 - 330 . Collins , V. P. ( 1942 ). Effects of destruction of the hypothalamus by tumor . Archives oj Neurology and Psychiatry , 48 , 774 - 788 . Gold , R. M. ( 1973 ). Hypothalamic obesity: the myth of the ventromedial nucleus . Science , 182 , 488 - 490 . Gold , R. M. and Proulx , D. M. ( 1972 ). Bait-shyness impairment by ventromedial hypothalamic lesions . Journal of Comparative Physiology and Psychology , 79 , 201 - 209 . Goldstein , M. ( 1974 ). Brain research and violent behavior . Archives oj Neurology , 30 , 1 - 34 . Haugh , R. M. and Markesbery , W. R. ( 1983 ). Hypothalamic astrocytoma: syndrome of hyperphagia, obesity, and disturbances of behavior and endocrine and autonomic function . Archives of Neurology , 40 , 560 - 563 . Heimburger , R. F. , Whitlock , C. C. and Kalsbeck , J. E. ( 1966 ). Stereotaxic amygdalotomy for epilepsy with aggressive behavior . Journal ofthe American Medical Association , 198 , 741~ 745 . Hess , W. R. ( 1956 ). "Hypothalamus and Thalamus" . Georg Thieme , Stuttgart, Germany. Jouvet , M. ( 1967 ). Neurophysiology of the states of sleep . Physiology Review , 47 , 117 - 177 . Killefl"er, F.A. and Stern , W.E. ( 1970 ). Chronic effects of hypothalamic injury . Archives of Neurology , 22 , 419 - 429 . Myers , R. D. ( 1964 ). Emotional and autonomic responses following hypothalamic chemical stimulation . Can:adian Journal of Psychology (Revue Canadienne de Psychologie) , 18 , 7 - 15 . Narabayashi , H. , Nagao , T. , Saito , Y. et al. ( 1963 ). Stereotaxic amygdalotomy for behavior disorders . Archive of Neurology , 9 , 1 - 16 . Rabin , B. M. ( 1972 ). Ventromedial hypothalamic control of food intake and satiety: a reappraisal . Brain Research , 43 , 317 - 342 . Reeves , A. G. and Plum , F. ( 1969 ). Hyperphagia, rage, and dementia accompanying a ventromedial hypothalamic neoplasm . Archives of Neurology , 20 , 616 - 624 . Reichlin , S. ( 1963 ). Neuroendocrinology. New England Journal oj Medicine , 269 , 1182 - 119 ; 1246 - 12 .50, 1296 - 1303 . Rodeck , H. ( 1967 ). Physiology and pathology of the hypothalamo-hypophyseal system; In "Introduction to Clinical Neuroendocrinology" , (Ed. E. Bajrisz) Williams and Wilkins , Baltimore. Sano , K. , Mayanagi , Y. , Sekino , H. et al. ( 1970 ). Results of stimulation and destruction of the posterior hypothalamus in man . Journal oj Neurosurgery , 33 , 689 - 707 . Schwartz , M. and Teitelbaum , P. ( 1974 ). Dissociation between learning and remembering in rats with lesions in the lateral hypothalamus . Journal of Comparative Physiology and Psychology , 87 , 384 - 398 . Sheard , M. H. ( 1984 ). Clinical pharmacology of aggressive behavior . Clinical Neuropharmacology , 7 , 173 - 183 . Smith , D. E. , King , M. B. and Hoebel , B. G. ( 1970 ). Lateral hypothalamic control of killing: evidence for cholinoceptive mechanism . Science , 167 , 900 - 901 . Yoburn , B. C. and Glusman , M. ( 1984 ). The effects of intrahypothalamic hemicholinium-3 on muricide, irritability, and feeding . Pharmacology, Biochemistry and Behavior , 20 , 829 - · 833. Volume 2014 Volume 2014 Journal of Hindawi Publishing Corporation ht p:/ www .hindawi.com


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Frederick G. Flynn, Jeffrey L. Cummings, Uwamie Tomiyasu. Altered Behavior Associated with Damage to the Ventromedial Hypothalamus: A Distinctive Syndrome, Behavioural Neurology, DOI: 10.3233/BEN-1988-1107