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Subacute diencephalic angioencephalopathy
Journal of the Neurological Sciences, 1980, 45: 73-81 © Elsevier/North-Holland Biomedial Press
73
SUBACUTE D I E N C E P H A L I C A N G I O E N C E P H A L O P A T H Y . Report of an Additional Case
HANNAH KINNEY, PETER C. BURGER and F. STEPHEN VOGEL Department of Pathology, Duke University Medical Center, Durham, NC 27710 (U.S.A.)
(Received 2 August, 1979) (Accepted 15 August, 1979)
SUMMARY The following report plesents an additional example of subacute diencephalic angioencephalopathy. The patient, a 68-year-old man, unexplicably withdrawn and asocial throughout his life, presented with an altered mental status of relatively recent onset. His illness was marked by progressive dementia and ended in death within 7 weeks. The neuropathologic findings were essentially identical to those described in the previous case in both theil histology and topographic localization within the thalamus. The etiology, pathogenesis, arid reason for the localization of this entity are unknown. Nevertheless, the lesion underscores the major role of the thalamus in cognitive function, emotional behavior, and awareness.
INTRODUCTION Extensive bilateral lesions of the thalamus may present as a progressive dementia ind!stinguishable from that produced by diffuse cerebral cortical disease. In 1974 DeGirolami et al. described a bilateral, symmetrical lesion in the thalamus of a 60-yearold man who died following an I 1-week course of such a progressive dementia (DeGirolami et al. 1974). The lesion, termed subacute diencephalic angioencephalopathy, was apparently unique, and neither its etiology nor pathogenesis was clear. The following report describes a second example of this entity, and discusses briefly the functional role of the thalamus in cognitive function. Address correspondence to: Dr. Hannah Kinney, Department of Pathology, Duke University Medical Center, Box 3712, Durham~ NC 27710, U.S.A.
74 CASE REPORT
Clinical presentation The patient, a 68-year-old white man, was admitted to Duke Hospital on 16 April, 1978 with an altered mental status of 3 days' duration. The past medical history was significant for life-long abnormal behavior, although it was unclear whether this had resulted from mental retardation or a psychiatric disorder. No similar behavior had been noted in any of 11 siblings, l i e was described by a sister as withdrawn and taciturn. Although he appeared to understand the speech of others, his verbal communication was limited to two or three word sentences and he normally communicated by head nodding. He never demonstrated psychotic behavior nor focal neurological deficits. Supported by Medicaid and Welfare, he lived alone in a trailer and managed his own needs. He never worked regularly nor married. No other medical problems were reported and he was not known to abuse alcohol or drugs. The patient was in his usual state until 14 April when he was found sweating and dyspneic. He was alert but uncommunicative. He was taken to a hospital, where his level of consciousness fluctuated between alertness and extreme lethargy. He was transferred to Duke University Hospital two days later. On admission, the patient appeared acutely ill with normal vital signs and mild dehydration. Auscultation of the chest revealed diffuse rales and rhonchi; otherwise, the general physical examination was unremarkable. The patient was drowsy and did not respond to questions except to give his name. There was a mild left ptosis; the remainder of the cranial nerve examination was normal. Gross sensory, motor, and cerebellar testing did not reveal a lateralized deficit. Gait could not be tested. The deep tendon reflexes were 2 + except for depressed ankle jerks; positive snout, suck, and palmomental reflexes were noted. The fundi could not be visualized because of cataracts. Initial laboratory data included normal peripheral blood count, electrolytes, arterial blood gases, chest X-ray, ~ind skull series. LDH, SGOT, and alkaline phosphatase were mildly elevated. ~'fie-sedimentation rate was 52 mm/hr. The spinal tap on admission had an opening pressure of 200 mm of water, 23 red blood cells, 0 white blood cells, a protein of 73 mg/100 ml, and a glucose of 110 mg/10ffml. Bacterial cultures and an India ink preparation were negative. The initial impression was that the patient's alteration in mental status reflected a metabolic encephalopathy secondary to dehydration and bronchitis, and he was treated accordingly with ampicillin and fluids. He received 100 mg of thiamine on the 2nd and 3rd hosptial days. The patient initially became more alert, but later the level of consciousness began to fluctuate. Occasionally, he sat on the edge of his bed and responded appropriately to simple commands, although without speech. Most of the time, however, he lay almost motionless, completely uncommunicative and with little apparent awareness of his surroundings. Rarely, he was unresponsive even to deep pain. During these unresponsive periods, Cheyne-Stokes' respirations developed, as did "trembling" of all 4 extremities. Neither seizures nor myoclonus were present. Because he was unable to swallow, hydration with intravenous fluids was required. He became progressively obtunded with fewer periods of alertness. Two EEG's and a CT scan were normal. A repeat lumbar puncture showed an opening pressure of 100 mm of water, 10 red cells, 0 white cells, a protein of 65 mg/100 ml, and a glucose of 78 mg/100 ml. CSF cryptococcal antigen, VDRL, and cultures for bacteria and fungus were also negative. A serum ceruloplasmin, thyroid screen HAA, B12 and folate levels were all normal. An LE preparation, serum complement level, anti-DNA antibodies, F A N A , serum VDRL, and rheumatoid factor were also negative. Serum immunoelectrophoresis was normal except for a low IgD. Repeat sedimentation rates were 70 and 99 ram/hr. Skin tests demonstrated complete anergy. On 22 April the patient was seen by a psychiatrist who expressed the opinion that a structural lesion was most likely, but that withdrawal reaction to illness and psychotic depression were possible alternatives. A two-week trial of haloperidol and a sodium amytal infusion produced no response. The patient became increasingly difficult to manage. He was markedly diaphoretic on many occasions in spite of rectal temperatures between 37 °C and 38 °C. Three barium swallows demonstrated an immobile esophagus. Because of repeated aspiration, a tracheostomy was performed on 12 May. The patient's caloric intake could not be maintained despite multiple attempts at tube feedings and he continuously lost weight. He developed gram-negative pneumonia, urinary tract infection, and sepsis which were treated successfully with gentamycin. Muscle tone was slightly increased in the lower extremities. Brief treatment with levodopa and carbi dopa for possible Parkinson's disease did not alter this condition. Because of increasing concern over malnutrition, a gastrostomy and feeding jejunostomy were performed on 6 June. The patient developed pneumonia and died 24 hr after surgery. During his 7 week hospitalization, he had lost about 20 ~ of his body weight.
75
Figs. 1 and 2. In a cross-section (Fig. 1) and a whole mount histological section (Fig. 2, I-I and E-LFB) through the mid-thalamus is a granular, microcystic lesion which is bilaterally and symmetrically confined to the thalamus.
76
Generalpathology At autopsy the patient was thin but not emaciated. The heart and aorta were free of atherosclerosis. There was mild hepatic centrilobular necrosis and diffuse fatty infiltration. Bilateral gram-negative pneumonia and sepsis were the immediate cause of death. Examination of the eye showed only bilateral cataracts. There was no optic atrophy or papilledema.
Neuropathology The brain weighed 1350 g. No anatomical defects were found to explain the patient's life-long abnormal behavior. The arteries were free of atherosclerosis and there were no vascular anomalies. The walls of the deep veins were slightly thickened; however, venous occlusion due to thrombosis or other causes was not present. The superficial venous system was normal. The cortex and the underlying white matter were unremarkable. The ventricles were of normal size. The cerebellum and lower brain stem were normal. The spinal cord was not examined. The abnormal macroscopic findings were restricted to the thalamus and rostral quadrigeminal plate (Fig. I). Here, an extensive soft, red-brown, granular, and focally microcystic lesion was found which was striking in its bilateral symmetry. At the level of the dorsal median nucleus, enlargement of the right thalamus produced a slight bulge into the 3rd ventricle. Although the lesion involved the entire thalamus, the degree of involvement was not uniform. The anterior and reticular nuclei and the lateral geniculate bodies were minimally involved; the dorsal median, ventral posterior medial and lateral, paramedian, lateral dorsal, lateral posterior, and centrum medianum nuclei, and the medial geniculate bodies were moderately involved ; and the pulvinar was severely affected. The lesion extended caudally to involve the left syperior colliculus and the adjacent periaqueductal grey matter. The hypothalamus, subthalamus, pineal gland, basal ganglia, and hippocampi were all unremarkable.
Fig. 3. Necrosis with gitter cells containing myelin break-down products is prominent in the noncystic, and presumably more recent, areas of involvement. H and E, x 400.
77
Fig. 4. Many small unidentifiable vessels are markedly thickened. H and E, × 400.
A whole mount histological preparation of the brain at the mid-thalamic level demonstrated the lesion's striking symmetry and patchy nature (Fig. 2). Contiguous anatomic structures such as the internal capsule were pale, consistent with the effect of edema. Microscopically the lesion was characterized by parenchymal necrosis with edema and hemorrhage associated with prominent vascular thickening. In the most severely involved areas, such as the pulvinar, the neurons had almost completely disappeared. In other regions, particularly in the medial and lateral thalamic nuclei, persistent necrotic neurons suggested a more recent ischemic insult as their nuclei were pyknotic and their cytoplasm intensely eosinophilic. Axonal spheroids were present. Neuronal loss was accompanied by a mild proliferation of reactive fibrillary astrocytes. Macrophages had infiltrated the necrotic areas and phagocytized debris (Fig. 3). Within their cytoplasm, myelin products stained blue with luxol fast blue. In the pulvinar, there were severe changes with prominent neuronal loss, less phagocytic activity, and more fibrillary gliosis, suggestive of a later stage in the evolution of the lesion. In less severely involved areas, such as the anterior nuclei and the lateral geniculate bodies, the neurons appeared normal but prominent vacuolization of the neuropil and minimal fibrillary gliosis were present. Hemorrhage was located primarily around small blood vessels, but also scattered in small loci throughout the parenchyma. In the periventricular and rostral periaqueductal areas, ring hemorrhages were present (Fig. 5). The striking changes in the small- and medium-sized blood vessels were most marked in the areas of the thalamus with the most severe necrosis. The vascular changes were characterized mainly by a proliferation of fibroblasts and endothelial cells. This thickening caused considerable narrowing of the lumen; however, despite multiple serial sections, complete occlusion was not found. Occasionally, lymphocytes were scattered in the adventitia; neither necrosis of the wall nor neutrophilic infiltration was present. Prominent hyalinization characterized the walls of other vessels (Fig. 4). Special stains did not show amyloid. An occasional small vessel contained a small fibrin thrombus. Endothelial hyperplasia and proliferation were marked in many small blood vessels. In other areas of the brain, the blood
78
Fig. 5. Adjacent to the 3rd ventricle are markedly thickened vessels suggestive of medium-sized veins. Note the multiple hemorrhages. H and E, × 33.
Fig. 6. Thickening of unequivocal venous channels, as here in both internal cerebral veins (arrows), underscores a venous component of this disease. Masson, × 15.
79 vessels demonstrated a similar thickening of the walls; however, this was not as severe as within the thalamus nor was it associated with necrosis. The blood vessels in the other organs were unremarkable. Because of the alteration of the vessels by fibrosis, it was often impossible to distinguish veins from arteries. Comparison of the veins and arteries in and around the 3rd ventricle suggested that at least some of these abnormal vessels were veins (Fig. 5). The internal cerebral veins and their large feeding tributaries were unequivocally involved with thickening of both the intima and adventitia (Fig. 6). In contrast, the medium-sizedarteries adjacent to the internal cerebral veins were normal with intact internal elastic membranes and mediae. Special stains failed to demonstrate microorganisms within the thalamic parenchyma or blood vessels. Viral inclusions were not identified by light microscopy. Electron microscopy of the dorsal median nucleus was unrevealing. Senile plaques and neurofibrillary tangles were not present in the cerebral cortex, hippocampus, or thalamus. Microscopically, the hypothalamus, subthalamus, epithalamus, brain stem, cerebral cortex, hippocampus, basal ganglia, andcerebellumwereallunremarkable. DISCUSSION The patient was a 68-year-old man who presented with an altered mental status of relatively acute onset. It was unclear whether his past abnormal behavior resulted from mental retardation or a psychiatric disorder. His acute illness was marked by progressive neurological deterioration which ended in severe malnutrition, superimposed infection, and death within seven weeks. At autopsy a lesion was found in the thalamus. The distribution and character of this lesion appear distinctive and, to our knowledge, have been described in only one prior case. In both patients the gross brain findings were almost exclusively within the thalamus where the lesion was soft, granular, microcystic, and remarkable for its bilateral symmetry. Microscopically, it was characterized by patchy parenchymal necrosis and proliferative vascular change. The pathologic similarities between these two cases are so compelling that comparison of the clinical features is warranted in an attempt to define what is presumably a clinico-pathologic entity. Both patients were white, middle-aged (60 and 68 years) men, and in good general health at the apparent onset of illness. Both presented with altered mental status of relatively brief daration, deteriorated rapidly, and died from infection within weeks. The dementia was characterized in the previous patient by a decrease in intellectual function with loss of memory,judgement, and abstract reasoning, as well as a deterioration in emotional behavior with flat and inappropriate affect and emotional lability. The neurological illness in our patient was unfortunately obscured by his poorly defined long-term deficit in cognitive and social functions and the inability of the patient and his family to give a precise history. Nevertheless, it is clear that his mental status deteriorated during the few weeks prior to death. Mutism was shared by both. The striking fluctuations in consciousness and derangements in autonomic function, so conspicuous in our patient, were absent in the former case. On neurological examination, neither patient had lateralizing deficits in motor, sensory, or cerebellar function. A fine resting tremor and terminal myoclonus were present in the Boston case, "tremulousness" only in ours. Seizures were not present in either. Cranial nerve function was remarkable only for minor abnormalities in oculomotor function. Reflexes were normal except for frontal release signs in our patient. Significant laboratory data shared by both patients included minimally elevated spinal
80 fluid protein and normal radiographic studies. The EEG in the previous patient was twice abnormal; in the present patient it was twice normal. The etiology of this distinctive thalamic lesion remains unknown. The association, however, of vascular thickening and parenchymal necrosis suggests a cause and effect relationship. The bilaterality and deep central location of the lesion further raises the possibility of occlusion of the deep venous system (Hassler 1966; Peele 1977). Further support comes from the clear involvement with proliferative change in the internal cerebral veins, their large feeding veins, and the veins lining the 3rd ventricle, as noted above. Still, complete occlusion by proliferative change or thrombosis in the deep cerebral veins was not found, either grossly or microscopically. Arterial occlusion seems less likely. The bilateral symmetry of the lesion would necessitate occlusion of two major arteries or a single vessel common to both thalami, i.e. the basilar artery. Such occlusions were not present. Occasionally, a thalamoperforating branch may distribute bilaterally to the thalamus, and occlusion cause a bilateral infarct (Castaigne et al. 1966), but no such anomalies were present in this case. Furthermore, branches of those vessels supplying necrotic areas also supply noninvolved areas. For example, parts of the thalamus (e.g. the ventral part of the medial formation) and the red nucleus are both supplied by branches of the thalamo-perforating vessels (Martin 1969): the medial formation was involved; the red nucleus was spared. The angiopathy cannot be classified with any of the recognized infectious or immune vasculitides. In the present patient, however, the finding of complete anergy raises the possibility of pathogenetic immunological factors. Immunofluorescent studies would be of interest on fresh thalamic tissue and serum in future cases. Clearly, other causes of this disorder, such as infectious or metabolic-nutritional insults, cannot be excluded, as discussed by DeGirolami et al. The disease in the present patient provides insight into the functional role of the thalamus. During his hospitalization, different observers localized the lesion to the frontal lobes, limbic system, or basal ganglia. At one point, even functional illness was considered and psychiatric consultation sought. Yet extensive bilateral lesions of the thalamus can also present as a profound disorder of intellect and awareness. Such lesions include vascular (Castaigne et al. 1966; Martin 1969), degenerative (Sterne 1939; Schulman 1957; Martin 1975), and neoplastic processes (McKissock and Paine 1958, Tori et al. 1961 ; Smyth and Sterne 1978). In both cases identified as subacute diencephalic angioencephalopathy, the dementia was presumably an expression of the thalamic lesion. With appreciation of the broad and vital role of the thalamus in many aspects of CNS function, it is easy to understand how dementia might result from destruction of this subcortical structure. Unfortunately in the present patient a precise clinicalanatomic correlation cannot be made. As impediments, the patient's acute and terminal illness were obscured by his lifelong abnormal neurological state and by the inability of both his family and himself to give a reliable and complete history. It seems fair, however, to state that the terminal illness was characterized by derangements in intellect, emotional behavior, awareness, consciousness, and motor function and that they were associated with the destructive lesion restricted to the thalamus and its environs.
81 Interestingly, these d e r a n g e m e n t s could not be distinguished clinically from those due to diffuse cerebral cortical disease. ACKNOWLEDGEMENTS The authors acknowledge the excellent help of Drs. Cheryl Szpak a n d Michael K a u f m a n a n d Mr. B e r n a r d Lloyd in the p r e p a r a t i o n of this report. We also t h a n k Dr. E d w a r d P. Richardson, Boston, M A for his helpful review of this material.
REFERENCES Castaigne, P., A. Buge, J. Cambier, R. Escourolle, P. Brunet and J. Decos (1966) Demence thalamique d'origine vasculaire par ramollissement bilat6ral limite au territoire du p6dicule r~tro-mammillaire, Rev. neurol., 114: 87-107. DeGirolami, U., M. L. Haas and E. P. Richardson (1974) Subacute diencephalic angioencephalopathy - - A clinico-pathological case study, J. neurol. Sci., 22: 197-210. Hassler, O. (1966) Deep cerebral venous system in man - - A microangiographic study of areas of drainage and its anastomosis with the superficial cerebral veins, Neurology (Minneap.), 16: 504-511. Martin, J. J. (1969) Thalamic syndromes. In: P. J. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 2 (Localization in Clinical Neurology), North-Holland Publ. Co., Amsterdam, pp. 469-496. Martin, J. J. (1975) Thalamic degenerations. In: P. J. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Yol. 21 (System Disorders and Atrophies, Part I), North-Holland Publ. Co., Amsterdam, pp. 587-604. McKissock, W. and K. W. E. Paine 0958) Primary tumors of the thalamus, Brain, 81 : 41-63. Peele, T. L. (1977) The Neuroanatomic Basis for Clinical Neurology, McGraw-Hill Company, New York, pp. 287-315. Schulman, S. (1957) Bilateral symmetrical degeneration of the thalamus, J. Neuropatk. exp. Neurol., 16: 446-480. Smyth, G. E. and Karl Sterne 0938) Tumors of the thalamus - - A clinicopathological study, Brain, 61 : 339-374. Sterne, K. (1939) Severe dementia associated with bilateral symmetrical degeneration of the thalamus, Brain, 62: 157-171. Tori, D., G. Schisand and B. Liljequist (1961) Primary tumors of the region of the thalamus, J. Neurosurg., 18 : 730-740.
73
SUBACUTE D I E N C E P H A L I C A N G I O E N C E P H A L O P A T H Y . Report of an Additional Case
HANNAH KINNEY, PETER C. BURGER and F. STEPHEN VOGEL Department of Pathology, Duke University Medical Center, Durham, NC 27710 (U.S.A.)
(Received 2 August, 1979) (Accepted 15 August, 1979)
SUMMARY The following report plesents an additional example of subacute diencephalic angioencephalopathy. The patient, a 68-year-old man, unexplicably withdrawn and asocial throughout his life, presented with an altered mental status of relatively recent onset. His illness was marked by progressive dementia and ended in death within 7 weeks. The neuropathologic findings were essentially identical to those described in the previous case in both theil histology and topographic localization within the thalamus. The etiology, pathogenesis, arid reason for the localization of this entity are unknown. Nevertheless, the lesion underscores the major role of the thalamus in cognitive function, emotional behavior, and awareness.
INTRODUCTION Extensive bilateral lesions of the thalamus may present as a progressive dementia ind!stinguishable from that produced by diffuse cerebral cortical disease. In 1974 DeGirolami et al. described a bilateral, symmetrical lesion in the thalamus of a 60-yearold man who died following an I 1-week course of such a progressive dementia (DeGirolami et al. 1974). The lesion, termed subacute diencephalic angioencephalopathy, was apparently unique, and neither its etiology nor pathogenesis was clear. The following report describes a second example of this entity, and discusses briefly the functional role of the thalamus in cognitive function. Address correspondence to: Dr. Hannah Kinney, Department of Pathology, Duke University Medical Center, Box 3712, Durham~ NC 27710, U.S.A.
74 CASE REPORT
Clinical presentation The patient, a 68-year-old white man, was admitted to Duke Hospital on 16 April, 1978 with an altered mental status of 3 days' duration. The past medical history was significant for life-long abnormal behavior, although it was unclear whether this had resulted from mental retardation or a psychiatric disorder. No similar behavior had been noted in any of 11 siblings, l i e was described by a sister as withdrawn and taciturn. Although he appeared to understand the speech of others, his verbal communication was limited to two or three word sentences and he normally communicated by head nodding. He never demonstrated psychotic behavior nor focal neurological deficits. Supported by Medicaid and Welfare, he lived alone in a trailer and managed his own needs. He never worked regularly nor married. No other medical problems were reported and he was not known to abuse alcohol or drugs. The patient was in his usual state until 14 April when he was found sweating and dyspneic. He was alert but uncommunicative. He was taken to a hospital, where his level of consciousness fluctuated between alertness and extreme lethargy. He was transferred to Duke University Hospital two days later. On admission, the patient appeared acutely ill with normal vital signs and mild dehydration. Auscultation of the chest revealed diffuse rales and rhonchi; otherwise, the general physical examination was unremarkable. The patient was drowsy and did not respond to questions except to give his name. There was a mild left ptosis; the remainder of the cranial nerve examination was normal. Gross sensory, motor, and cerebellar testing did not reveal a lateralized deficit. Gait could not be tested. The deep tendon reflexes were 2 + except for depressed ankle jerks; positive snout, suck, and palmomental reflexes were noted. The fundi could not be visualized because of cataracts. Initial laboratory data included normal peripheral blood count, electrolytes, arterial blood gases, chest X-ray, ~ind skull series. LDH, SGOT, and alkaline phosphatase were mildly elevated. ~'fie-sedimentation rate was 52 mm/hr. The spinal tap on admission had an opening pressure of 200 mm of water, 23 red blood cells, 0 white blood cells, a protein of 73 mg/100 ml, and a glucose of 110 mg/10ffml. Bacterial cultures and an India ink preparation were negative. The initial impression was that the patient's alteration in mental status reflected a metabolic encephalopathy secondary to dehydration and bronchitis, and he was treated accordingly with ampicillin and fluids. He received 100 mg of thiamine on the 2nd and 3rd hosptial days. The patient initially became more alert, but later the level of consciousness began to fluctuate. Occasionally, he sat on the edge of his bed and responded appropriately to simple commands, although without speech. Most of the time, however, he lay almost motionless, completely uncommunicative and with little apparent awareness of his surroundings. Rarely, he was unresponsive even to deep pain. During these unresponsive periods, Cheyne-Stokes' respirations developed, as did "trembling" of all 4 extremities. Neither seizures nor myoclonus were present. Because he was unable to swallow, hydration with intravenous fluids was required. He became progressively obtunded with fewer periods of alertness. Two EEG's and a CT scan were normal. A repeat lumbar puncture showed an opening pressure of 100 mm of water, 10 red cells, 0 white cells, a protein of 65 mg/100 ml, and a glucose of 78 mg/100 ml. CSF cryptococcal antigen, VDRL, and cultures for bacteria and fungus were also negative. A serum ceruloplasmin, thyroid screen HAA, B12 and folate levels were all normal. An LE preparation, serum complement level, anti-DNA antibodies, F A N A , serum VDRL, and rheumatoid factor were also negative. Serum immunoelectrophoresis was normal except for a low IgD. Repeat sedimentation rates were 70 and 99 ram/hr. Skin tests demonstrated complete anergy. On 22 April the patient was seen by a psychiatrist who expressed the opinion that a structural lesion was most likely, but that withdrawal reaction to illness and psychotic depression were possible alternatives. A two-week trial of haloperidol and a sodium amytal infusion produced no response. The patient became increasingly difficult to manage. He was markedly diaphoretic on many occasions in spite of rectal temperatures between 37 °C and 38 °C. Three barium swallows demonstrated an immobile esophagus. Because of repeated aspiration, a tracheostomy was performed on 12 May. The patient's caloric intake could not be maintained despite multiple attempts at tube feedings and he continuously lost weight. He developed gram-negative pneumonia, urinary tract infection, and sepsis which were treated successfully with gentamycin. Muscle tone was slightly increased in the lower extremities. Brief treatment with levodopa and carbi dopa for possible Parkinson's disease did not alter this condition. Because of increasing concern over malnutrition, a gastrostomy and feeding jejunostomy were performed on 6 June. The patient developed pneumonia and died 24 hr after surgery. During his 7 week hospitalization, he had lost about 20 ~ of his body weight.
75
Figs. 1 and 2. In a cross-section (Fig. 1) and a whole mount histological section (Fig. 2, I-I and E-LFB) through the mid-thalamus is a granular, microcystic lesion which is bilaterally and symmetrically confined to the thalamus.
76
Generalpathology At autopsy the patient was thin but not emaciated. The heart and aorta were free of atherosclerosis. There was mild hepatic centrilobular necrosis and diffuse fatty infiltration. Bilateral gram-negative pneumonia and sepsis were the immediate cause of death. Examination of the eye showed only bilateral cataracts. There was no optic atrophy or papilledema.
Neuropathology The brain weighed 1350 g. No anatomical defects were found to explain the patient's life-long abnormal behavior. The arteries were free of atherosclerosis and there were no vascular anomalies. The walls of the deep veins were slightly thickened; however, venous occlusion due to thrombosis or other causes was not present. The superficial venous system was normal. The cortex and the underlying white matter were unremarkable. The ventricles were of normal size. The cerebellum and lower brain stem were normal. The spinal cord was not examined. The abnormal macroscopic findings were restricted to the thalamus and rostral quadrigeminal plate (Fig. I). Here, an extensive soft, red-brown, granular, and focally microcystic lesion was found which was striking in its bilateral symmetry. At the level of the dorsal median nucleus, enlargement of the right thalamus produced a slight bulge into the 3rd ventricle. Although the lesion involved the entire thalamus, the degree of involvement was not uniform. The anterior and reticular nuclei and the lateral geniculate bodies were minimally involved; the dorsal median, ventral posterior medial and lateral, paramedian, lateral dorsal, lateral posterior, and centrum medianum nuclei, and the medial geniculate bodies were moderately involved ; and the pulvinar was severely affected. The lesion extended caudally to involve the left syperior colliculus and the adjacent periaqueductal grey matter. The hypothalamus, subthalamus, pineal gland, basal ganglia, and hippocampi were all unremarkable.
Fig. 3. Necrosis with gitter cells containing myelin break-down products is prominent in the noncystic, and presumably more recent, areas of involvement. H and E, x 400.
77
Fig. 4. Many small unidentifiable vessels are markedly thickened. H and E, × 400.
A whole mount histological preparation of the brain at the mid-thalamic level demonstrated the lesion's striking symmetry and patchy nature (Fig. 2). Contiguous anatomic structures such as the internal capsule were pale, consistent with the effect of edema. Microscopically the lesion was characterized by parenchymal necrosis with edema and hemorrhage associated with prominent vascular thickening. In the most severely involved areas, such as the pulvinar, the neurons had almost completely disappeared. In other regions, particularly in the medial and lateral thalamic nuclei, persistent necrotic neurons suggested a more recent ischemic insult as their nuclei were pyknotic and their cytoplasm intensely eosinophilic. Axonal spheroids were present. Neuronal loss was accompanied by a mild proliferation of reactive fibrillary astrocytes. Macrophages had infiltrated the necrotic areas and phagocytized debris (Fig. 3). Within their cytoplasm, myelin products stained blue with luxol fast blue. In the pulvinar, there were severe changes with prominent neuronal loss, less phagocytic activity, and more fibrillary gliosis, suggestive of a later stage in the evolution of the lesion. In less severely involved areas, such as the anterior nuclei and the lateral geniculate bodies, the neurons appeared normal but prominent vacuolization of the neuropil and minimal fibrillary gliosis were present. Hemorrhage was located primarily around small blood vessels, but also scattered in small loci throughout the parenchyma. In the periventricular and rostral periaqueductal areas, ring hemorrhages were present (Fig. 5). The striking changes in the small- and medium-sized blood vessels were most marked in the areas of the thalamus with the most severe necrosis. The vascular changes were characterized mainly by a proliferation of fibroblasts and endothelial cells. This thickening caused considerable narrowing of the lumen; however, despite multiple serial sections, complete occlusion was not found. Occasionally, lymphocytes were scattered in the adventitia; neither necrosis of the wall nor neutrophilic infiltration was present. Prominent hyalinization characterized the walls of other vessels (Fig. 4). Special stains did not show amyloid. An occasional small vessel contained a small fibrin thrombus. Endothelial hyperplasia and proliferation were marked in many small blood vessels. In other areas of the brain, the blood
78
Fig. 5. Adjacent to the 3rd ventricle are markedly thickened vessels suggestive of medium-sized veins. Note the multiple hemorrhages. H and E, × 33.
Fig. 6. Thickening of unequivocal venous channels, as here in both internal cerebral veins (arrows), underscores a venous component of this disease. Masson, × 15.
79 vessels demonstrated a similar thickening of the walls; however, this was not as severe as within the thalamus nor was it associated with necrosis. The blood vessels in the other organs were unremarkable. Because of the alteration of the vessels by fibrosis, it was often impossible to distinguish veins from arteries. Comparison of the veins and arteries in and around the 3rd ventricle suggested that at least some of these abnormal vessels were veins (Fig. 5). The internal cerebral veins and their large feeding tributaries were unequivocally involved with thickening of both the intima and adventitia (Fig. 6). In contrast, the medium-sizedarteries adjacent to the internal cerebral veins were normal with intact internal elastic membranes and mediae. Special stains failed to demonstrate microorganisms within the thalamic parenchyma or blood vessels. Viral inclusions were not identified by light microscopy. Electron microscopy of the dorsal median nucleus was unrevealing. Senile plaques and neurofibrillary tangles were not present in the cerebral cortex, hippocampus, or thalamus. Microscopically, the hypothalamus, subthalamus, epithalamus, brain stem, cerebral cortex, hippocampus, basal ganglia, andcerebellumwereallunremarkable. DISCUSSION The patient was a 68-year-old man who presented with an altered mental status of relatively acute onset. It was unclear whether his past abnormal behavior resulted from mental retardation or a psychiatric disorder. His acute illness was marked by progressive neurological deterioration which ended in severe malnutrition, superimposed infection, and death within seven weeks. At autopsy a lesion was found in the thalamus. The distribution and character of this lesion appear distinctive and, to our knowledge, have been described in only one prior case. In both patients the gross brain findings were almost exclusively within the thalamus where the lesion was soft, granular, microcystic, and remarkable for its bilateral symmetry. Microscopically, it was characterized by patchy parenchymal necrosis and proliferative vascular change. The pathologic similarities between these two cases are so compelling that comparison of the clinical features is warranted in an attempt to define what is presumably a clinico-pathologic entity. Both patients were white, middle-aged (60 and 68 years) men, and in good general health at the apparent onset of illness. Both presented with altered mental status of relatively brief daration, deteriorated rapidly, and died from infection within weeks. The dementia was characterized in the previous patient by a decrease in intellectual function with loss of memory,judgement, and abstract reasoning, as well as a deterioration in emotional behavior with flat and inappropriate affect and emotional lability. The neurological illness in our patient was unfortunately obscured by his poorly defined long-term deficit in cognitive and social functions and the inability of the patient and his family to give a precise history. Nevertheless, it is clear that his mental status deteriorated during the few weeks prior to death. Mutism was shared by both. The striking fluctuations in consciousness and derangements in autonomic function, so conspicuous in our patient, were absent in the former case. On neurological examination, neither patient had lateralizing deficits in motor, sensory, or cerebellar function. A fine resting tremor and terminal myoclonus were present in the Boston case, "tremulousness" only in ours. Seizures were not present in either. Cranial nerve function was remarkable only for minor abnormalities in oculomotor function. Reflexes were normal except for frontal release signs in our patient. Significant laboratory data shared by both patients included minimally elevated spinal
80 fluid protein and normal radiographic studies. The EEG in the previous patient was twice abnormal; in the present patient it was twice normal. The etiology of this distinctive thalamic lesion remains unknown. The association, however, of vascular thickening and parenchymal necrosis suggests a cause and effect relationship. The bilaterality and deep central location of the lesion further raises the possibility of occlusion of the deep venous system (Hassler 1966; Peele 1977). Further support comes from the clear involvement with proliferative change in the internal cerebral veins, their large feeding veins, and the veins lining the 3rd ventricle, as noted above. Still, complete occlusion by proliferative change or thrombosis in the deep cerebral veins was not found, either grossly or microscopically. Arterial occlusion seems less likely. The bilateral symmetry of the lesion would necessitate occlusion of two major arteries or a single vessel common to both thalami, i.e. the basilar artery. Such occlusions were not present. Occasionally, a thalamoperforating branch may distribute bilaterally to the thalamus, and occlusion cause a bilateral infarct (Castaigne et al. 1966), but no such anomalies were present in this case. Furthermore, branches of those vessels supplying necrotic areas also supply noninvolved areas. For example, parts of the thalamus (e.g. the ventral part of the medial formation) and the red nucleus are both supplied by branches of the thalamo-perforating vessels (Martin 1969): the medial formation was involved; the red nucleus was spared. The angiopathy cannot be classified with any of the recognized infectious or immune vasculitides. In the present patient, however, the finding of complete anergy raises the possibility of pathogenetic immunological factors. Immunofluorescent studies would be of interest on fresh thalamic tissue and serum in future cases. Clearly, other causes of this disorder, such as infectious or metabolic-nutritional insults, cannot be excluded, as discussed by DeGirolami et al. The disease in the present patient provides insight into the functional role of the thalamus. During his hospitalization, different observers localized the lesion to the frontal lobes, limbic system, or basal ganglia. At one point, even functional illness was considered and psychiatric consultation sought. Yet extensive bilateral lesions of the thalamus can also present as a profound disorder of intellect and awareness. Such lesions include vascular (Castaigne et al. 1966; Martin 1969), degenerative (Sterne 1939; Schulman 1957; Martin 1975), and neoplastic processes (McKissock and Paine 1958, Tori et al. 1961 ; Smyth and Sterne 1978). In both cases identified as subacute diencephalic angioencephalopathy, the dementia was presumably an expression of the thalamic lesion. With appreciation of the broad and vital role of the thalamus in many aspects of CNS function, it is easy to understand how dementia might result from destruction of this subcortical structure. Unfortunately in the present patient a precise clinicalanatomic correlation cannot be made. As impediments, the patient's acute and terminal illness were obscured by his lifelong abnormal neurological state and by the inability of both his family and himself to give a reliable and complete history. It seems fair, however, to state that the terminal illness was characterized by derangements in intellect, emotional behavior, awareness, consciousness, and motor function and that they were associated with the destructive lesion restricted to the thalamus and its environs.
81 Interestingly, these d e r a n g e m e n t s could not be distinguished clinically from those due to diffuse cerebral cortical disease. ACKNOWLEDGEMENTS The authors acknowledge the excellent help of Drs. Cheryl Szpak a n d Michael K a u f m a n a n d Mr. B e r n a r d Lloyd in the p r e p a r a t i o n of this report. We also t h a n k Dr. E d w a r d P. Richardson, Boston, M A for his helpful review of this material.
REFERENCES Castaigne, P., A. Buge, J. Cambier, R. Escourolle, P. Brunet and J. Decos (1966) Demence thalamique d'origine vasculaire par ramollissement bilat6ral limite au territoire du p6dicule r~tro-mammillaire, Rev. neurol., 114: 87-107. DeGirolami, U., M. L. Haas and E. P. Richardson (1974) Subacute diencephalic angioencephalopathy - - A clinico-pathological case study, J. neurol. Sci., 22: 197-210. Hassler, O. (1966) Deep cerebral venous system in man - - A microangiographic study of areas of drainage and its anastomosis with the superficial cerebral veins, Neurology (Minneap.), 16: 504-511. Martin, J. J. (1969) Thalamic syndromes. In: P. J. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 2 (Localization in Clinical Neurology), North-Holland Publ. Co., Amsterdam, pp. 469-496. Martin, J. J. (1975) Thalamic degenerations. In: P. J. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Yol. 21 (System Disorders and Atrophies, Part I), North-Holland Publ. Co., Amsterdam, pp. 587-604. McKissock, W. and K. W. E. Paine 0958) Primary tumors of the thalamus, Brain, 81 : 41-63. Peele, T. L. (1977) The Neuroanatomic Basis for Clinical Neurology, McGraw-Hill Company, New York, pp. 287-315. Schulman, S. (1957) Bilateral symmetrical degeneration of the thalamus, J. Neuropatk. exp. Neurol., 16: 446-480. Smyth, G. E. and Karl Sterne 0938) Tumors of the thalamus - - A clinicopathological study, Brain, 61 : 339-374. Sterne, K. (1939) Severe dementia associated with bilateral symmetrical degeneration of the thalamus, Brain, 62: 157-171. Tori, D., G. Schisand and B. Liljequist (1961) Primary tumors of the region of the thalamus, J. Neurosurg., 18 : 730-740.