opean sychiatry and Neurological Eur Arch Psychiatr Neurol Sci (1988) 237:218-222 Archives of Sciences © Springer-Verlag 1988 Akinetic Mutism Associated with Bicingular Lesions: Clinicopathological and Functional Anatomical Correlates Gyorgy Nemeth, Katalin Hegediis, and Lisz 16 Molnar Department of Neurology and Psychiatry, University Medical School, H-4012 Debrecen, Hungary Summary The clinical symptoms and neuropathological findings of three patients suffering from akinetic mutism were summarized The patients showed almost absolute mutism and immobility and were unable to communicate in any way The neurological signs varied from case to case The pathological features common to all of the cases were bilateral lesions of the rostral part of the anterior cingulate gyri which overlapped onto the neighboring supplementary motor area, while differing as regards other damage With the help of more recent neurobiochemical findings we tried to analyze the pathomechanism of akinetic mutism on the basis of the structures damaged There seems to be an anatomic correspondence between the mesolimbocortical dopaminergic system and the circumscribed bilateral lesions of the medial prefrontal cortex The study suggests that damage of the mesolimbocortical dopaminergic terminal fields in the anteromedial frontal cortex is essential for this specific type of akinetic mutism. Key words: Akinetic mutism Cingulate gyri - Mesolimbocortical dopaminergic system Introduction Akinetic mutism (AM) was the term given by Cairns et al to the clinical picture observed in a patient with an epidermoid cyst of the third ventricle l6 l The patient showed almost absolute mutism and immobility except for eye movements as well as complete absence of communication Akinetic mutism differs from coma, the apallic syndrome, and the locked-in syndrome with which it has often been confused. Offprint requests to: L Molnar Pathophysiologically coma and apallic syndrome are other types of disturbances of consciousness and have to be distinguished from AM On the other hand in the locked-in syndrome the patient's awareness is fully preserved which can be demonstrated by voluntary blinking and eye movements l34 l. The condition of AM has been reported in a variety of articles related to different localizations of lesions including bilateral damage of the globus pallidus l8, 10 l, the diencephalic-mesencephalic reticular formation l9, 16, 19, 31, 36, 37, 38 l, or the basis of the brainstem l8, 35, 36l Clinico anatomical cases of bilateral lesions of the cingulate gyrus have rarely been reported, to our knowledge 14 cases have been described l1, 3, 5, 11, 12, 17, 22, 28, 32, 33, 39l The clinical consequences have always been AM. A total of 23 cases of clinically recognized AM have been autopsied during the last 10 years in our Department, and in 3 of them common pathological lesions were localized in the cingulate gyri and the neighboring area The criteria of AM were total immobility (but not plegia) except for eye movements and blinking and complete absence of all types of communication The 3 cases reported in this paper met the criteria of AM The nature and extent of lesions in the cingulate gyri responsible for AM are still disputed In our study we have been especially attentive not only to clinicopathological observations but to both the crucial clinical problems of behavior and their impact on some aspects of research in neurotransmission. Case Reports and Neuropathological Findings Only cases 2 and 3 will be described in greater detail as case 1 presented no circumscribed lesions in order to draw any relevant conclusions. 219 Fig 2 71-year-old woman Bilateral softening in territory of the anterior cerebral arteries Fig 1 58-year-old man Bilateral tumorous infiltration of the frontal lobes which involves both cingulate gyri Heidenhain x1 Case 1 A 58-year-old man with a 3-week history of progressive drowsiness and instability of gait was admitted to our Department on March 19, 1977 The findings of a general physical examination performed on admission were normal Neurological examination revealed rigid muscle tone, normal tendon reflexes without pyramidal signs and normal eye movements He did not move spontaneously and showed only very few but adequate responses to painful stimuli He was unable to speak, and there was no possibility of communication with him although he seemed to be alert The EEG showed diffuse 10 cycles/s activity but was areactive to various stimuli The patient remained immobile and in spite of the total absence of any initiative, either motor or verbal, he continued to give the impression of following every activity taking place around him with an alert look In this state he died suddenly 4 days after admission. PathologicalFindings: general autopsy disclosed thrombosis of the right femoral vein, massive pulmonary thromboembolism, and massive sclerosis of the arteries The brain weighed 1,420 g. It was edematous with bilateral tonsillar herniation Frontal section of the brain revealed at the level of the frontal poles of the lateral ventricles a massive bilateral tumorous infiltration which had spread to both the cinguli gyrus and midline regions and extended caudally at the level of the corpus mamillare. Microscopic examination of the tumor mass revealed the characteristic features of glioblastoma multiforme (Fig 1). Case 2 A 71-year-old woman with a 3-year history of left hemiparesis and hypertension was hospitalized on August 18, 1981 The day before admission she became unable to speak and to move her right limbs On admission her blood pressure was 270/150 Hgmm, and general physical examination revealed no abnormalities Neurological examination revealed bilateral optic atrophy, she made no sound and lay inert, and there were no movements of a voluntary character A painful stimulus produced weak, slow withdrawal of the left limbs On the left side the tendon reflexes were slightly increased, and there were no pyramidal signs The flexor muscle tone was increased in all four limbs There was no possibility of achieving any type of communication The patient made no voluntary, only automatic eye movements Cisternal puncture yielded clear CSF with no abnormalities The EEG presented thetaalpha waves bilaterally without focal signs, and was areactive to various stimuli Fluctuations occurred in this AM state. After a few days there was an incomplete manifestation: the patient responded at times, though slowly and imperfectly, by speech and voluntary movements This condition was observed for 2 days, and she remained in this AM state until she died of bronchopneumonia 15 days after admission. Pathological Findings: general autopsy disclosed extensive bilateral bronchopneumonia Except for severe dilatation of ventricles, and coronary sclerosis, her heart showed no abnormality The brain weighed 1,255 g There was severe arteriosclerosis of the circle of Willis The left anterior cerebral artery was occluded with a thrombus and the right anterior cerebral artery was severely stenotic On the right side old infarcted cystic lesions were present in the anterior cingulate gyrus, the caudal part of the superior frontal gyrus, leaving undamaged the frontal pole and the frontal basal areas On the left side infarction had destroyed the parasagittal area of the frontal lobe extending more caudally, partly overlapping the posterior cingulate gyrus On this side the precentral and postcentral gyri were damaged, too (Fig 2). Case 3 A 62-year-old man with a typical picture of AM was admitted to our Department on September 12, 1978 Some 15 days earlier he had been hospitalized with acute hypertension (300/100 Hgmm), massive bloody CSF and in a comatose state On admission to our clinic his blood pressure was 180/ 100 Hg mm, and general examination was negative Neurological examination revealed anisocoric pupils (left > right), right flaccid hemiplegia without pyramidal signs, and bilateral grasping reflexes Lumbar puncture yielded xanthochromic CSF In the angiogram of the left common carotid artery an aneurysm was observed at the beginning of the anterior cerebral artery An EEG was not performed The patient remained immobile and presented a state of total inertia except for the 220 Discussion Fig 3 62-year-old man Circumscribed hemorrhages due to rupture of an aneurysm of the right anterior cerebral artery Fig 4 The same 62-year-old man as in Fig 3 Circumscribed infarction with hemorrhagic components in the territory of the left anterior cerebral artery eyes which from time to time followed movements in the environment, thereby showing that he was alert Only repeated verbal stimuli elicited a reply in the form of incomprehensible monosyllables In this state he died suddenly 5 days after admission. Pathological Findings: severe arteriosclerosis, right bronchopneumonia, thrombosis of the right femoral vein, and massive pulmonary thromboembolism The brain weighed 1,310g An extended subarachnoid hemorrhage was present over both the cerebral hemispheres On the right anterior cerebral artery 3 mm distally from the anterior communicating artery an aneurysm was found On the mesial surface of both frontal lobes about 1 cm wide hemorrhages could be seen On the right side only the rostral part of the anterior cingulate gyrus located around the genu of the corpus callosum was affected, leaving undamaged the caudal part of the anterior cingulate gyri On the left side the hemorrhage destroyed at the level of genu a very circumscribed area of the anterior cingulate gyrus beneath the cingulate sulcus The lesion overlapped slightly onto the neighboring cortical areas involving the supplementary motor area (Brodmann 32) rostrally (Figs 3, 4). As previously mentioned the term AM has sometimes been used too extensively and improperly. Kemper and Romanul l20l and Molnar l29l stress the necessity of separating conditions which differ from AM Generally the term AM designates a special type of disturbance of consciousness In the available literature on most of the anatomical observations of AM associated with the bilateral anterior cingulate gyri (Brodmann area 24) however, the lesions were too extensive or multiple, therefore preventing a well-defined clinicopathological relationship In all of the cases to date the lesions involved other brain structures, too: the territory of the anterior cerebral artery most frequently the medial surface of the superior frontal gyri and some parts of the limbic system such as the septum pellucidum, fornix, gyrus rectus, and the gyrus orbitalis The destruction of the anterior portion of the caudate nuclei, the corpus callosum, the asymmetrical or unilateral invading of the globus pallidus and putamen and the anterior-medial thalamic nuclear groups was also observed. The circumscribed lesions and common features of our cases, especially cases 2 and 3, partly supported the fact that the damage must be localized in the anterior part of the cingulate gyri bilaterally In case 2 the lesions were most similar to those which can be found in the literature but slightly more restricted Although in case 3 there was a massive subarachnoid hemorrhage which would explain the sudden onset of the illness and the comatose state on the first day, but not the AM state, which developed later Comparing the three cases the only common pathological features were: ( 1) the lesion of the rostral part of the cingulate gyri just around the genu corporis callosi, and (2) the damage of the adjacent frontal lobe namely the supplementary motor area. After cingulectomies or cingulotomies some degree of docility, indifference, and slight loss of depth in general interests and pursuits have been observed l 40, 41 l There is considerable discrepancy between the clinical picture of our cases and the postoperative states of the cingulectomized patients This discrepancy can be explained by two main facts First, in the absence of anatomical verfication in cingulectomies, the brain removal is imprecise and, possibly, often less extensive than our patients' cingulate lesion The second fact which may account for the intensive behavioral changes in our patients is the presence of associated lesions The most common clinical findings with lesions involving the supplementary motor area are the transient stage of apathy, akinesia, lack of drive and motivation, and disturbances of speech similar to transcortical motor aphasia 221 l18, 21 l Comparison of these facts suggests that simultaneous frontal (supplementary motor area) and limbic (cingulate) impairment is necessary to induce such a state as this type of AM Therefore, it may be suggested that the cingulate lesion, when added to a frontal lesion could produce more pronounced symptoms or a qualitatively different state such as AM than those of frontal lesions alone or vice versa. In true AM the akinesia and mutism appear without paralysis; therefore, the akinesis does not mean tetraplegia This is supported by our present and previous studies and some observations in the literature l6, 22, 31 l It must be emphasized that these findings have also been observed in other localizations of bilateral lesions causing AM These discrete lesions destroyed isolated stuctures, located within the pons or mesencephalon l8, 31, 36 l, diencephalon l 6l, or ventral pallidum l8, 10l, without involving the pyramidal tracts. The EEG in cases 1 and 2 showed diffuse bilateral theta-alpha waves areactive to various stimuli, similar to many other descriptions in the literature l7, 22, 31 l The EE Gs were independent regardless of the level and the site of the lesion causing AM This fact supports a neural mechanism for AM which does not depend on a special functional entity, at least pathophysiologically. Our observations are consistent with animal models and human data suggesting that this type of AM may be related to loss of dopaminergic input to the anterior cingulate cortex or related cortex such as the supplementary motor area It has been demonstrated that there are dopaminergic mesolimbocortical projections l23 l which also exist in humans l2l. One of them originates in the pars compacta of the substantia nigra and in the ventral tegmental area of the mesencephalon and courses through the medial forebrain bundles and ultimately ends in the anterior cingulate gyri and the anteromedial prefrontal cortex l 13, 15, 24 l In animals interruption of the dopaminergic axons traveling through the far-lateral hypothalamus in the medial forebrain bundles with 6-hydroxydopamine induced a behavioral syndrome similar to AM l26 l The impairments can be reversed by the systematic administration of the dopamine receptor stimulant apomorphine l25, 27 l Patients with bilateral, restricted ventral tegmental lesions in the mesencephalon l31l or with damage in the hypothalamus which involves both medial forebrain bundles l37l sparing the dorsal part of the upper brainstem tegmentum also exhibit the clinical picture of AM In the latter case after treatment with bromocriptine (direct dopamine receptor agonist) there was marked improvement and the authors con- cluded that if their patient's lesion involved the anterior cingulate gyri, he probably would not have responded to direct dopamine agonists because dopamine receptor targets would have been destroyed l37 l. Dopaminergic receptor activity in the anterior part of the cingulate gyri regulates movement, decodes various types of sensory stimuli, a process necessary for proper sensory motor integration, and thus makes the selection of meaningful behavior in a complex environment possible l4, 14, 30 l. If the data of our study are considered in their overall context three main observations emerge: 1 In all of our cases the affected regions are associated with those structures in which dopaminergic neurons of the mesolimbocortical system have been found. 2 On the other hand, no clear-cut anatomic observations can be made in humans concerning the extension of the medial surface lesion of the cortex which is necessary for the development of AM. 3 In lesions of different locations which result in AM those structures which play a role in the development of comatose states remain intact. After integration of the functional-anatomical and human clinicopathological data the problem is to distinguish disorders of elementary neurological functions from the disorders of consciousness The neurological signs e g , hemiparesis etc are accidental; they vary from case to case Consciousness as a form of cerebral integration depends more probably on the synergy of different systems in complex interactions which sort and regulate sensory information deriving from the body or the outer world or result from action which it has itself provoked. On the basis of pathogenesis AM is a specific type of disturbance of consciousness It seems that AM constitutes a single entity from the functional point of view but, since it can occur after different lesion sites, it is different from the anatomical point of view In AM a specific communicating system is damaged in isolation at various levels of the neuraxis The significance of the functional patterns demonstrable at different levels of the nervous system will be understood only if it is appreciated that they are characteristic of the entire specific communicating system from the brainstem level to the cortex. 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