Movement Disorders Vol. 5 , No. 3, 1990, pp. 219-224. 0 1990 Movement Disorder Society
Hypoxic-Ischemic Damage of the Basal Ganglia Case Reports and a Review of the Literature Kathleen Hawker and Anthony E. Lang Toronto Western Hospital Movement Disorders Clinic, Toronto, Ontario, Canada
Summary: Three cases of movement disorders secondary to hypoxic-ischemic encephalopathy are reported. Despite similarities among the clinical events, the neurological syndromes produced were dissimilar. Cerebral hypoxiaischemia typically produces lesions of the globus pallidus that may result in an akinetic rigid syndrome. Due to its unique blood supply, vascular insuf3ciency is found to be a major factor. Lesions in the putamen also occur, and these tend to be associated with dystonia. Recent evidence supports a specific neuronal sensitivity in the striatum, possibly due to afferent excitatory amino acid connections. These two components and changes in the levels of neurotransmitters during hypoxia-ischemia may interact to produce varied clinical outcomes. These factors must also be considered when planning therapeutic interventions. Key Words: Hypoxic-ischemic encephalopathy-Basal ganglia.
A variety of movement disorders have been observed after hypoxic-ischemic insults. These include parkinsonism, chorea, tics, athetosis, various forms of dystonia, and acute and chronic myoclonic syndromes (1-6). A wide diversity of etiologies such as carbon monoxide, hydrogen disulfide and cyanide poisoning, anesthetic accidents, and cardiorespiratory arrest may produce some such syndromes (1,2,7-9). The origin of tics remains uncertain. Myoclonus may originate from a wide variety of CNS sources, while the other movement disorders are more closely linked to dysfunction of the basal ganglia. In radiological and pathological studies, lesions have been reported in the striatum, the substantia nigra reticulata, and, most commonly, the globus pallidus interna and medial segment of the globus pallidus externa (2,7-10). We present three cases of nonmyoclonic posthypoxic-ischemic movement disorders with a dis-
cussion of possible pathophysiologies accounting for the underlying basal ganglia damage. CASE REPORTS Case 1
A 58-year-old woman suffered an acute asthmatic attack followed by cardiorespiratory arrest in January 1985. Immediately after the event, she was noted to have decorticate posturing and remained in coma for 1 week. She gradually regained consciousness over several weeks. Neurological examination revealed her to be dyslexic but of normal intellect. There was marked dystonic posturing of her limbs. The rest of her examination was normal. Examination 1 year later again revealed normal intellect but moderate dyslexia. Her speech was low and monotonous, and tongue movements were slow and tremulous. Hypometric saccades were noted. The rest of the cranial nerves were normal. Motor examination revealed marked dystonic rigidity of all her limbs. There was marked dystonic posturing of her extremities and she had difficulty performing voluntary tasks because of this (see video-
A videotape segment accompanies this article. Address correspondence and reprint requests to Dr. A. E. Lang, Toronto Western Hospital Movement Disorders Clinic, 25 Leonard Ave, Suite 101, Toronto, Ontario, Canada, M5T 2R2.
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tape segment 1). Power appeared intact. Deep tendon reflexes were normal and symmetrical. Her plantar reflexes were equivocal bilaterally. Cerebellar and sensory testing were within normal limits. A computerized tomography (CT) scan of the head showed bilateral symmetrical hypodensities in the putamen (Fig. 1). Case 2
A 36-year-old woman developed a sudden respiratory arrest after a hysterectomy. She remained ventilated and comatose for 3 days, followed by a gradual increase in her level of consciousness. She was noted to be severely rigid and akinetic at this time. Examination 18 years later (see videotape segment 2) revealed a 54-year-old woman with normal intellect. Speech was monotonous and limited to a whisper, while tongue movements were very slow and tremulous. There was mild to moderate rigidity and a mild postural tremor of the limbs. Neck rigidity was marked. Intermittent low-amplitude spontaneous myoclonic jerks were present in her limbs, FIG. 2. Case 2. CT scan shows hypodense lesions in the globus pallidus bilaterally. There is an additional low-density lesion in the region of the anterior limb of the internal capsule on the right.
and she was markedly bradykinetic in all her limbs. Strength and coordination were otherwise intact, and the sensory examination was normal. Deep tendon reflexes were symmetrical and normal. Plantar reflexes were flexor. When walking, the patient exhibited decreased arm swing and a tendency to freeze while turning. There was marked postural instability. Her handwriting demonstrated micrographia. A CT scan of her head showed bilateral low densities in the globus pallidus (Fig. 2). Treatment with trihexyphenidyl and levodopdcarbidopa in varying doses resulted in a mild improvement. Attempts to withdraw levodopa resulted in an increase in parkinsonian disability. Case 3
FIG. 1. Case 1. CT scan shows bilateral symmetrical linear hypodensities in the putamen.
Movement Disorders, Vol. 5 , N o . 3, 1990
A 47-year-old man suffered two myocardial infarctions following a heart transplant for idiopathic hypertrophic subaortic stenosis. During this time, he sustained episodes Of hypotension and suffered cerebral ischemia of uncertain duration. Neurolog-
BASAL GANGLIA HYPOXIC-ISCHEMIC DAMAGE
ically, he was obtunded but gradually regained consciousness after 3 weeks. At that time, a postural tremor of his arms was noted as were mild memory difficulties. Examination 2 years later revealed a normal mental status. The patient was dysarthric but the rest of the cranial nerves were intact. There was mild rigidity and a marked postural tremor in all limbs, maximal in the upper extremities. Power was normal. Dystonic posturing of both feet was noted. Mild bradykinesia was also present. Deep tendon reflexes were symmetrical, and the toes were extensor. Sensation and coordination were normal. Over the following 2 years, action tremor, limb rigidity, and dystonia became gradually increased. Pain secondary to the dystonic posturing of the left foot became a major source of disability. Trials of levodopdcarbidopa, trihexyphenidyl, propranolol, carbamazepine, dantrolene, and diazepam proved ineffective. A CT scan of the head showed a linear right putamenal and a possible small left putamenal hypodensity (Fig. 3).
FIG. 3. Case 3. CT scan shows a linear low-density lesion in the right putamen and possibly a small hypodensity in the posterior left putamen.
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DISCUSSION Clinical-Anatomical-Neurotransmitter Correlates All three of our cases suffered hypoxic-ischemic insults to the brain; however, the clinical outcomes and CT scans were dissimilar. The most common pathological correlate of the parkinsonian syndrome produced by hypoxia-ischemia, both in animal models and humans, is necrosis of the globus pallidus (8,ll). A loss of the functional integrity of the cortico-striato-pallido-thalamo-cortical loop that occurs with necrosis of the globus pallidus, with consequent disinhibition of the thalamic inputs to the supplementary motor area, may produce an akinetic-rigid syndrome (12). The pathophysiology of hypoxia-ischemia-induced dystonia seems to involve more “proximal” basal ganglia circuitry; particularly the putamen. A variety of etiologies, such as trauma, cerebrovascular and neurodegenerative diseases, encephalitides, and neuronal storage diseases, have all been documented to produce this clinical-anatomical association (13). How these lesions result in this pronounced motor disturbance is unclear. While some authors cite a loss of striosomes in the putamen (14), others implicate a striatal catecholamine imbalance with increased norepinephrine and reduced dopamine levels (15). [‘8F]Fluoro-~-dopapositron emission tomography in some patients with dystonia due to putaminal lesions has confirmed the presence of alterations in nigrostriatal dopaminergic terminals (16). Finally, overlap syndromes, combining both dystonia and parkinsonism, have been described, with lesions in the globus pallidus and the putamen documented on magnetic resonance imaging (MRI) (3). Neurotransmitter levels within the basal ganglia may also be altered after a hypoxic-ischemic insult. In experimental animals, a marked depression of dopamine (17,18), with little change in norepinephrine or serotonin, has been documented. Low levels of homovanillic acid in the cerebrospinal fluid were demonstrated in a patient with a post-cardiac arrest parkinsonian syndrome although lesions were only seen in the globus pallidus and putamen on CT and MRI (19). The mild but definite benefit obtained with levodopa in our case 2 and in other reported cases (20) also supports the possible contribution of alterations in dopaminergic pathways originating in the mesencephalon. However, it is unlikely that changes in dopamine levels could completely ac-
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count for the clinical abnormalities in any of these patients since response to dopaminergic agents is suboptimal. Dopamine may also be involved in the pathogenesis of hypoxic-ischemic damage, possibly through an enhancement of the excitotoxic effects of glutamate (see below) (21,22). Elevated levels of DOPAC and homovanillic acid have been documented in the early postischemic period (21,22). Depletion of striatal dopamine by lesioning the substantia nigra in advance of cerebral ischemia reduces the extent of striatal neuronal damage (21,22,23). y-Aminobutyric acid (GABA) levels have been shown to be decreased (24), possibly as a consequence of necrosis of the medium-sized spiny striatal neurons. Secondary changes in projection areas (25) and aberrant sprouting of neurons following injury (26,27) also may alter specific neural and neurotransmitter relationships in the basal ganglia.
Pathogenesis of Neural Damage Numerous theories concerning the pathogenesis of hypoxic-ischemic damage in the basal ganglia have been suggested. Most investigators have been proponents of vascular theories of damage. The internal segment and the medial compartment of the outer segment of the globus pallidus are supplied by the pallidal branches of the anterior choroidal artery while the head of the caudate and putamen receive their supply from the lenticulostriate artery (8). The early proposal of Lindenberg (28) of anterior choroidal artery compression against the rostra1 tentorium secondary to brain swelling was discounted by later authors who noted that lesions were not always consistent with that vascular territory (9). Selective hypoperfusion related to the specific vascular pattern of the globus pallidus was considered the most likely explanation for the sensitivity of this structure to hypoxic-ischemic insult (29,30). Other experimental evidence that ischemia of certain parts of the brain persisted after reperfusion led Chiang et al. (31) to propose the “no-reflow” theory. Earlier observations of the poorly anastomosing, linear arterioles supplying the globus pallidus (32) causing precarious vascularization (30) added weight to the vascular theory of basal ganglia damage. In addition, different combinations of acidosis, hypotension, and hypoxia may explain varying patterns of damage (30). For example, although a leukoencephalopathy is usually associated with carbon monoxide poisoning (30), as well as certain other
Movement Disorders, Vol. 5 , No. 3, 1990
intoxications, this is due to the prolonged acidemia and hypoxemia with a mild degree of hypotension rather than being a direct toxic effect on the white matter (10,15). The more common association with these metabolic disturbances may explain the apparent preferential changes in the basal ganglia in carbon monoxide poisoning when compared to hypoxic-ischemic states. Numerous other authors, however, have noted specific areas of damage that do not relate to vascular territories. Vogt and Vogt (33,34) first proposed the “pathoclisis” theory in 1922. Subsequently, it has been postulated that the high oxidative metabolism of the neostriatum (35) provides an intrinsic metabolic susceptibility contributing to the propensity to hypoxic-ischemic damage. That two morphologically distinct patterns of hypoxic-ischemic brain damage exist was first proposed by Scholz (36). He divided them into those attributable to the unique vascular patterns of specific parts of the brain and those explained by specific properties of the cells themselves; the latter he called “topistic” patterns. A predilection for either pattern seemed to be due to certain pathophysiological conditions. Boundary or watershed lesions appeared to occur (37,38) with severe hypotension or in combination with severe metabolic acidosis (1 1). Topistic patterns (39) predicted that certain cell groups were preferentially susceptible to hypoxiaischemia, including the CA1 hippocampal cells, the Purkinje cells of the cerebellum, the neocortical neurons in layers 3 , 5, and 6, and the small and medium sized striatal neurons (40). An episode of transient ischemia followed by survival for several days tended to produce these lesions. The discovery of the afferent input of the excitatory amino acid (41) glutamate to all of these areas has provided a common denominator. The excitotoxic properties of the accumulation of this amino acid, which may be potentiated by dopamine (22,23), during hypoxia-ischemia result in neuronal death because of an influx of calcium (42,43). This effect is probably mediated through the action of glutamate on Nmethyl-D-aspartate (NMDA) receptors (42). In the basal ganglia, there are extensive glutamatergic afferents from the cortex projecting to the striatum. Afferents from the subthalamic nucleus to the substantia nigra reticulata and globus pallidus are postulated to use glutamate as well (14). However, minimal to absent excitatory amino acid receptors are found in the globus pallidus (44) although substantially higher levels are found in neonatal animals
BASAL GANGLIA H YPOXIC-ISCHEMIC DAMAGE (40). High levels are found in the striatum, while lower numbers exist in the substantia nigra reticulata (44). In the striatum, the predominant glutamate receptor is the NMDA type. It is uncertain which receptors predominate in the substantia nigra reticulata. However, if these are also of the NMDA type, it could be postulated that hypoxia-ischemia induced excitatory neurotoxic effects in this structure similar to those proposed for the striatum. However, the literature fails to differentiate the distribution of NMDA receptors in the subdivisions of the striatum (i.e., putamen versus caudate). This makes it difficult to correlate receptor location with clinicopathological features . The discovery of neuronal susceptibility secondary to neuroexcitotoxins may constitute a rationale for early treatment with excitatory amino acid antagonists ( 4 9 , dopamine blockade, or GABA agonists (46). Although it is unlikely, because of the effects mediated by the ischemia in the globus pallidus, that this modality will entirely prevent morbidity, it may improve the final outcome. Further elucidation of specific short- and long-term changes in neurotransmitter systems after hypoxic-ischemic insult may aid in designing specific therapeutic regimens to ameliorate symptoms after hypoxicischemic damage. The poor response of the resultant movement disorders to standard symptomatic pharmacotherapy, as seen in our patients, further emphasizes the need for advances in therapeutics, which must include protective or preventative interventions.
LEGENDS TO THE VIDEOTAPE SEGMENT 1. This segment demonstrates clinical features in case 1 with severe post-hypoxicischemic dystonia due to bilateral putamenal lesions. SEGMENT 2. This segment demonstrates severe post-hypoxic-ischemic parkinsonism in case 2 due to bilateral globus pallidus lesions. REFERENCES 1. Carella F, Grassi MP, Savoiardo M, Contri P, Rapuzzi B, Mangoni A. Dystonic-parkinsonian syndrome after cyanide poisoning: clinical and MRI findings. J Neurol Neurosurg Psychiutr 1988;51 :1345-1 348. 2. Davous P, Rondot P, Marion MH, Gueguen B. Severe chorea after acute carbon monoxide poisoning. J Neurol Neurosurg Psychiutr 1986;49:206-208. 3. Keane JR, Young JA. Blepharospasm with bilateral basal ganglia infarction. Arch Neurol 1985;42:1206-1208. 4. Klawans HL, Stein RW, Tanner CM, Goetz CG. A pure parkinsonian syndrome following acute carbon monoxide intoxication. Arch Neurol 1982;39:302-304. 5. Pulst SM, Walshe TM, Romero JA. Carbon monoxide poi-
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soning with features of Gilles de la Tourette’s syndrome. Arch Neurol 1983;40:44344. 6. Schwartz A, Hennerici M, Wegener OH. Delayed choreoathetosis following acute carbon monoxide poisoning. Neurology 1985;35:98-99. 7. Matuso F, Cummins JW, Anderson RE. Neurological sequelae of massive hydrogen sulfide inhalation. Arch Neurol 1979;36:451-452. 8 . Jellinger K. Exogenous lesions of the pallidum. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology. Amsterdam: Elsevier Science, 1986:465-491. 9. Murray RS, Stensaas SS, Anderson RE, Matuso F. Bilateral basal ganglia necrosis following diffuse hypoxic-ischemic injury. Arch Neurol 1987;44:897. 10. Brierley JB. Comparison between effects of profound arterial hypotension, hypoxia, and cyanide on the brain of macaca mulatta. Adv Neurol 1975;10:213-221. 1 1 . Ginsberg MD, Hedley-Whyte T, Richardson EP. Hypoxicischemic leukoencephalopathy in man. Arch Neurol 1976; 33~5-14. 12. Deniau JM, Chevalier G. Disinhibition as a basic process in the expression of striatal functions. 11. The striatonatonigral influence on thalamocortical cells of the ventromedial thalamic nucleus. Bruin Res 1985;334:227-233. 13. Calne DB, Lang AE. Secondary dystonia. Adv Neurol 1988;50:9-33. 14. Penney JB, Young AB. Striatal inhomogeneities and basal ganglia function. Movement Disord 1986;1:3-15. 15. Yebenes JG, Vazquez A, Martinez A, et al. Biochemical findings in symptomatic dystonias. Adv Neurol1988;50: 167175. 16. Lang AE, Garnett ES, Firnau G, Namias C, Talalla A. Positron tomography in dystonia. Adv Neurol 1988;50:249-253. 17. Mc Namara MC, Gingras-Leatherman JL, Lawson EE. Effect of hypoxia in brainstem concentration of biogenic amines in postnatal rabbits. Develop Bruin Res 1986;25:253258. 18. Silverstein F, Johnston MV. Effects of hypoxia-ischemia on monoamine metabolism in the immature brain. Ann Neurol 1984;15:342-347. 19. Verslegers W, Crols R, van den Kerchove M, de Potter W, Appel B, Lowenthal A. Parkinsonian syndrome after cardiac arrest: radiological and neurochemical changes. Clin Neurol Neuosurg 1988;90(2):177- 179. 20. Ringel SP, Klawans HL. Carbon monoxide-induced parkinsonism. J Neurol Sci 1972;16:245-251. 21. Globus MYT, Ginsberg MD, Harik SI, Busto BS, Dietrich WD. Role of dopamine in ischemic striatal injury: metabolic evidence. Neurology 1987;37:1712-1219. 22. Lindvall 0, Auer RN, Siesjo BK. Selective lesions of mesostriatal dopamine neurons ameliorate hypoglycemic damage in the caudate-putamen. Exp Bruin Res 1986;63:382-386. 23. Globus MYT, Ginsberg MD, Dietrich WD, Busto R, Scheinberg P. Substantia nigra lesion protects against ischemic damage in the striatum. Neurosci Lett 1987;80:251-256. 24. Onodera H, Sat0 G, Kogure K. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia. Demonstration by quantitative receptor autoradiography. J Cereb Blood Flow Metub 1987;7:82-88. 25. Pearson RCA, Neal JW, Powell TPS. Bilateral morphological changes in the substantia nigra of the rat following unilateral damage of the striatum. Brain Res 1987;400:127-132. 26. Burke RE, Fahn S, Gold AP. Delayed-onset dystonia in patients with “static” encephalopathy. J Neurol Neurosurg Psychiutr 1980;43:789-797. 27. Norton SN, Culver B. A golgi analysis of caudate neurons in rats exposed to carbon monoxide. Bruin Res 1977;132:455465. 28. Lindenberg R. Compression of brain arteries as pathogenetic
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29. 30. 31. 32. 33. 34. 35. 36. 37.
factor for tissue necrosis and their areas of predilection. J Neurol Exp Neurol 1955;14:223-243. Ginsberg MD. Carbon monoxide intoxication. Clinical features, neuropathology and mechanisms of injury. Clin Toxicol 1985;23(4-6):281-288. Ginsberg MD, Myers RE, Mc Donagh BF. Experimental carbon monoxide encephalopathy in the primate. Arch Neurol 1974;30:202-216. Chiang J, Kowada M, Ames 1 1 1 A, Wright RL, Majno G. Cerebral ischemia. Am J Puthol 1968;52(1-3):455476. Kolisko A. Die Symmetrische encephalomalacie in den linsenkernen nach kohlenoxydvergiftung. Beitr Gerichtel Med 1914;2:1-16. Vogt C, Vogt 0. Zurlehre der erkrankingen des stiaren systems. J Psychiutr Neurol 1920;3:627-846. Vogt C, Vogt 0. Erkranjungen der grobhirnrinde im lichte der topidyk, pathoklise und pathoarchitektonig. J Psycho1 Neurot 1922;28:1-171. Fahn S. Biochemistry of the basal ganglia. Adv Neurol 1976;14:60-89. Scholz W. Selective neuronal necrosis and its topistic patterns in hypoxemia and oligemia. J Neuroputhol 1953; 12:249-26 1. Adams JH, Brierley JB, Connor RCR, Treip CS. The effects of systemic hypotension on the human brain. Clinical and neuropathological observations in 1 1 cases. Bruin 1966; 89:235-268.
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38. Brierley JB. Cerebral hypoxia. In: Blackwood W, Corsellis JAN, eds. Greenfields neuroputhology. New York: Wiley & Sons, 1977:43-85. 39. Pulsinellia WA. Selective neuronal vunerality: morphological and molecular characteristics. Prog Bruin Res 1985; 63:29-37. 40. Westerberg E, Monaghan DT, Cotman CW, Wieloch T. Excitatory amino acid receptors and ischemic brain damage in the rat. Neurosci Lett 1987;73:119-124. 41. Ascher P, Nowak L. Electrophysiological studies of NMDA receptors. Trends Neurosci 1987;10:284-293. 42. Rothman S, Olney J. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 1986;19:105111. 43. Cotman CW, Iversen LL. Excitatory amino acids in the brain: focus on NMDA receptors. Trends Neurosci 1987; 10:263-272. 44. Fonnum F, Paulsen RH, Fosse VM, Engelsen B. Synthesis and release of amino acid transmitters. Adv Exp Med B i d 1986 ;203:285-293. 45. Meldrum B . Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 1985;68:113-122. 46. Saji M, Reis DJ. Delayed transneuronal death of substantia nigra neurons prevented by gamma-aminobutyric acid agonist. Science 1987;2:66-69.
Hypoxic-Ischemic Damage of the Basal Ganglia Case Reports and a Review of the Literature Kathleen Hawker and Anthony E. Lang Toronto Western Hospital Movement Disorders Clinic, Toronto, Ontario, Canada
Summary: Three cases of movement disorders secondary to hypoxic-ischemic encephalopathy are reported. Despite similarities among the clinical events, the neurological syndromes produced were dissimilar. Cerebral hypoxiaischemia typically produces lesions of the globus pallidus that may result in an akinetic rigid syndrome. Due to its unique blood supply, vascular insuf3ciency is found to be a major factor. Lesions in the putamen also occur, and these tend to be associated with dystonia. Recent evidence supports a specific neuronal sensitivity in the striatum, possibly due to afferent excitatory amino acid connections. These two components and changes in the levels of neurotransmitters during hypoxia-ischemia may interact to produce varied clinical outcomes. These factors must also be considered when planning therapeutic interventions. Key Words: Hypoxic-ischemic encephalopathy-Basal ganglia.
A variety of movement disorders have been observed after hypoxic-ischemic insults. These include parkinsonism, chorea, tics, athetosis, various forms of dystonia, and acute and chronic myoclonic syndromes (1-6). A wide diversity of etiologies such as carbon monoxide, hydrogen disulfide and cyanide poisoning, anesthetic accidents, and cardiorespiratory arrest may produce some such syndromes (1,2,7-9). The origin of tics remains uncertain. Myoclonus may originate from a wide variety of CNS sources, while the other movement disorders are more closely linked to dysfunction of the basal ganglia. In radiological and pathological studies, lesions have been reported in the striatum, the substantia nigra reticulata, and, most commonly, the globus pallidus interna and medial segment of the globus pallidus externa (2,7-10). We present three cases of nonmyoclonic posthypoxic-ischemic movement disorders with a dis-
cussion of possible pathophysiologies accounting for the underlying basal ganglia damage. CASE REPORTS Case 1
A 58-year-old woman suffered an acute asthmatic attack followed by cardiorespiratory arrest in January 1985. Immediately after the event, she was noted to have decorticate posturing and remained in coma for 1 week. She gradually regained consciousness over several weeks. Neurological examination revealed her to be dyslexic but of normal intellect. There was marked dystonic posturing of her limbs. The rest of her examination was normal. Examination 1 year later again revealed normal intellect but moderate dyslexia. Her speech was low and monotonous, and tongue movements were slow and tremulous. Hypometric saccades were noted. The rest of the cranial nerves were normal. Motor examination revealed marked dystonic rigidity of all her limbs. There was marked dystonic posturing of her extremities and she had difficulty performing voluntary tasks because of this (see video-
A videotape segment accompanies this article. Address correspondence and reprint requests to Dr. A. E. Lang, Toronto Western Hospital Movement Disorders Clinic, 25 Leonard Ave, Suite 101, Toronto, Ontario, Canada, M5T 2R2.
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tape segment 1). Power appeared intact. Deep tendon reflexes were normal and symmetrical. Her plantar reflexes were equivocal bilaterally. Cerebellar and sensory testing were within normal limits. A computerized tomography (CT) scan of the head showed bilateral symmetrical hypodensities in the putamen (Fig. 1). Case 2
A 36-year-old woman developed a sudden respiratory arrest after a hysterectomy. She remained ventilated and comatose for 3 days, followed by a gradual increase in her level of consciousness. She was noted to be severely rigid and akinetic at this time. Examination 18 years later (see videotape segment 2) revealed a 54-year-old woman with normal intellect. Speech was monotonous and limited to a whisper, while tongue movements were very slow and tremulous. There was mild to moderate rigidity and a mild postural tremor of the limbs. Neck rigidity was marked. Intermittent low-amplitude spontaneous myoclonic jerks were present in her limbs, FIG. 2. Case 2. CT scan shows hypodense lesions in the globus pallidus bilaterally. There is an additional low-density lesion in the region of the anterior limb of the internal capsule on the right.
and she was markedly bradykinetic in all her limbs. Strength and coordination were otherwise intact, and the sensory examination was normal. Deep tendon reflexes were symmetrical and normal. Plantar reflexes were flexor. When walking, the patient exhibited decreased arm swing and a tendency to freeze while turning. There was marked postural instability. Her handwriting demonstrated micrographia. A CT scan of her head showed bilateral low densities in the globus pallidus (Fig. 2). Treatment with trihexyphenidyl and levodopdcarbidopa in varying doses resulted in a mild improvement. Attempts to withdraw levodopa resulted in an increase in parkinsonian disability. Case 3
FIG. 1. Case 1. CT scan shows bilateral symmetrical linear hypodensities in the putamen.
Movement Disorders, Vol. 5 , N o . 3, 1990
A 47-year-old man suffered two myocardial infarctions following a heart transplant for idiopathic hypertrophic subaortic stenosis. During this time, he sustained episodes Of hypotension and suffered cerebral ischemia of uncertain duration. Neurolog-
BASAL GANGLIA HYPOXIC-ISCHEMIC DAMAGE
ically, he was obtunded but gradually regained consciousness after 3 weeks. At that time, a postural tremor of his arms was noted as were mild memory difficulties. Examination 2 years later revealed a normal mental status. The patient was dysarthric but the rest of the cranial nerves were intact. There was mild rigidity and a marked postural tremor in all limbs, maximal in the upper extremities. Power was normal. Dystonic posturing of both feet was noted. Mild bradykinesia was also present. Deep tendon reflexes were symmetrical, and the toes were extensor. Sensation and coordination were normal. Over the following 2 years, action tremor, limb rigidity, and dystonia became gradually increased. Pain secondary to the dystonic posturing of the left foot became a major source of disability. Trials of levodopdcarbidopa, trihexyphenidyl, propranolol, carbamazepine, dantrolene, and diazepam proved ineffective. A CT scan of the head showed a linear right putamenal and a possible small left putamenal hypodensity (Fig. 3).
FIG. 3. Case 3. CT scan shows a linear low-density lesion in the right putamen and possibly a small hypodensity in the posterior left putamen.
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DISCUSSION Clinical-Anatomical-Neurotransmitter Correlates All three of our cases suffered hypoxic-ischemic insults to the brain; however, the clinical outcomes and CT scans were dissimilar. The most common pathological correlate of the parkinsonian syndrome produced by hypoxia-ischemia, both in animal models and humans, is necrosis of the globus pallidus (8,ll). A loss of the functional integrity of the cortico-striato-pallido-thalamo-cortical loop that occurs with necrosis of the globus pallidus, with consequent disinhibition of the thalamic inputs to the supplementary motor area, may produce an akinetic-rigid syndrome (12). The pathophysiology of hypoxia-ischemia-induced dystonia seems to involve more “proximal” basal ganglia circuitry; particularly the putamen. A variety of etiologies, such as trauma, cerebrovascular and neurodegenerative diseases, encephalitides, and neuronal storage diseases, have all been documented to produce this clinical-anatomical association (13). How these lesions result in this pronounced motor disturbance is unclear. While some authors cite a loss of striosomes in the putamen (14), others implicate a striatal catecholamine imbalance with increased norepinephrine and reduced dopamine levels (15). [‘8F]Fluoro-~-dopapositron emission tomography in some patients with dystonia due to putaminal lesions has confirmed the presence of alterations in nigrostriatal dopaminergic terminals (16). Finally, overlap syndromes, combining both dystonia and parkinsonism, have been described, with lesions in the globus pallidus and the putamen documented on magnetic resonance imaging (MRI) (3). Neurotransmitter levels within the basal ganglia may also be altered after a hypoxic-ischemic insult. In experimental animals, a marked depression of dopamine (17,18), with little change in norepinephrine or serotonin, has been documented. Low levels of homovanillic acid in the cerebrospinal fluid were demonstrated in a patient with a post-cardiac arrest parkinsonian syndrome although lesions were only seen in the globus pallidus and putamen on CT and MRI (19). The mild but definite benefit obtained with levodopa in our case 2 and in other reported cases (20) also supports the possible contribution of alterations in dopaminergic pathways originating in the mesencephalon. However, it is unlikely that changes in dopamine levels could completely ac-
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count for the clinical abnormalities in any of these patients since response to dopaminergic agents is suboptimal. Dopamine may also be involved in the pathogenesis of hypoxic-ischemic damage, possibly through an enhancement of the excitotoxic effects of glutamate (see below) (21,22). Elevated levels of DOPAC and homovanillic acid have been documented in the early postischemic period (21,22). Depletion of striatal dopamine by lesioning the substantia nigra in advance of cerebral ischemia reduces the extent of striatal neuronal damage (21,22,23). y-Aminobutyric acid (GABA) levels have been shown to be decreased (24), possibly as a consequence of necrosis of the medium-sized spiny striatal neurons. Secondary changes in projection areas (25) and aberrant sprouting of neurons following injury (26,27) also may alter specific neural and neurotransmitter relationships in the basal ganglia.
Pathogenesis of Neural Damage Numerous theories concerning the pathogenesis of hypoxic-ischemic damage in the basal ganglia have been suggested. Most investigators have been proponents of vascular theories of damage. The internal segment and the medial compartment of the outer segment of the globus pallidus are supplied by the pallidal branches of the anterior choroidal artery while the head of the caudate and putamen receive their supply from the lenticulostriate artery (8). The early proposal of Lindenberg (28) of anterior choroidal artery compression against the rostra1 tentorium secondary to brain swelling was discounted by later authors who noted that lesions were not always consistent with that vascular territory (9). Selective hypoperfusion related to the specific vascular pattern of the globus pallidus was considered the most likely explanation for the sensitivity of this structure to hypoxic-ischemic insult (29,30). Other experimental evidence that ischemia of certain parts of the brain persisted after reperfusion led Chiang et al. (31) to propose the “no-reflow” theory. Earlier observations of the poorly anastomosing, linear arterioles supplying the globus pallidus (32) causing precarious vascularization (30) added weight to the vascular theory of basal ganglia damage. In addition, different combinations of acidosis, hypotension, and hypoxia may explain varying patterns of damage (30). For example, although a leukoencephalopathy is usually associated with carbon monoxide poisoning (30), as well as certain other
Movement Disorders, Vol. 5 , No. 3, 1990
intoxications, this is due to the prolonged acidemia and hypoxemia with a mild degree of hypotension rather than being a direct toxic effect on the white matter (10,15). The more common association with these metabolic disturbances may explain the apparent preferential changes in the basal ganglia in carbon monoxide poisoning when compared to hypoxic-ischemic states. Numerous other authors, however, have noted specific areas of damage that do not relate to vascular territories. Vogt and Vogt (33,34) first proposed the “pathoclisis” theory in 1922. Subsequently, it has been postulated that the high oxidative metabolism of the neostriatum (35) provides an intrinsic metabolic susceptibility contributing to the propensity to hypoxic-ischemic damage. That two morphologically distinct patterns of hypoxic-ischemic brain damage exist was first proposed by Scholz (36). He divided them into those attributable to the unique vascular patterns of specific parts of the brain and those explained by specific properties of the cells themselves; the latter he called “topistic” patterns. A predilection for either pattern seemed to be due to certain pathophysiological conditions. Boundary or watershed lesions appeared to occur (37,38) with severe hypotension or in combination with severe metabolic acidosis (1 1). Topistic patterns (39) predicted that certain cell groups were preferentially susceptible to hypoxiaischemia, including the CA1 hippocampal cells, the Purkinje cells of the cerebellum, the neocortical neurons in layers 3 , 5, and 6, and the small and medium sized striatal neurons (40). An episode of transient ischemia followed by survival for several days tended to produce these lesions. The discovery of the afferent input of the excitatory amino acid (41) glutamate to all of these areas has provided a common denominator. The excitotoxic properties of the accumulation of this amino acid, which may be potentiated by dopamine (22,23), during hypoxia-ischemia result in neuronal death because of an influx of calcium (42,43). This effect is probably mediated through the action of glutamate on Nmethyl-D-aspartate (NMDA) receptors (42). In the basal ganglia, there are extensive glutamatergic afferents from the cortex projecting to the striatum. Afferents from the subthalamic nucleus to the substantia nigra reticulata and globus pallidus are postulated to use glutamate as well (14). However, minimal to absent excitatory amino acid receptors are found in the globus pallidus (44) although substantially higher levels are found in neonatal animals
BASAL GANGLIA H YPOXIC-ISCHEMIC DAMAGE (40). High levels are found in the striatum, while lower numbers exist in the substantia nigra reticulata (44). In the striatum, the predominant glutamate receptor is the NMDA type. It is uncertain which receptors predominate in the substantia nigra reticulata. However, if these are also of the NMDA type, it could be postulated that hypoxia-ischemia induced excitatory neurotoxic effects in this structure similar to those proposed for the striatum. However, the literature fails to differentiate the distribution of NMDA receptors in the subdivisions of the striatum (i.e., putamen versus caudate). This makes it difficult to correlate receptor location with clinicopathological features . The discovery of neuronal susceptibility secondary to neuroexcitotoxins may constitute a rationale for early treatment with excitatory amino acid antagonists ( 4 9 , dopamine blockade, or GABA agonists (46). Although it is unlikely, because of the effects mediated by the ischemia in the globus pallidus, that this modality will entirely prevent morbidity, it may improve the final outcome. Further elucidation of specific short- and long-term changes in neurotransmitter systems after hypoxic-ischemic insult may aid in designing specific therapeutic regimens to ameliorate symptoms after hypoxicischemic damage. The poor response of the resultant movement disorders to standard symptomatic pharmacotherapy, as seen in our patients, further emphasizes the need for advances in therapeutics, which must include protective or preventative interventions.
LEGENDS TO THE VIDEOTAPE SEGMENT 1. This segment demonstrates clinical features in case 1 with severe post-hypoxicischemic dystonia due to bilateral putamenal lesions. SEGMENT 2. This segment demonstrates severe post-hypoxic-ischemic parkinsonism in case 2 due to bilateral globus pallidus lesions. REFERENCES 1. Carella F, Grassi MP, Savoiardo M, Contri P, Rapuzzi B, Mangoni A. Dystonic-parkinsonian syndrome after cyanide poisoning: clinical and MRI findings. J Neurol Neurosurg Psychiutr 1988;51 :1345-1 348. 2. Davous P, Rondot P, Marion MH, Gueguen B. Severe chorea after acute carbon monoxide poisoning. J Neurol Neurosurg Psychiutr 1986;49:206-208. 3. Keane JR, Young JA. Blepharospasm with bilateral basal ganglia infarction. Arch Neurol 1985;42:1206-1208. 4. Klawans HL, Stein RW, Tanner CM, Goetz CG. A pure parkinsonian syndrome following acute carbon monoxide intoxication. Arch Neurol 1982;39:302-304. 5. Pulst SM, Walshe TM, Romero JA. Carbon monoxide poi-
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