Treatment of Acute Cerebral Ischemia with Intravenous Aminophylline William J. Estrin, M D
I recently observed a patient with symptoms of cerebral ischemia who improved promptly after intravenous injection of aminophylline. A 63-year-old right-handed man with chronic intrinsic asthma since childhood awoke with marked right hemiparesis and expressive aphasia. Ten hours later the patient had an asthmatic attack that was treated with 250 mg of intravenous aminophylline. Thirty seconds after the injection the patient spoke his first understandable words: “Boy, that feelsgood!” Within afew minutes his hemiparesis improved to the point that writing was attempted. Thirty minutes after injection the patient’s speech and writing were easily understood, and only mild hemiparesis remained. T h e following morning, neurological examination was normal except for mild hesitancy of speech, occasional circumlocutions, and a slight right pronator drift. Extensive laboratory studies included ophthalmodynamometry, supraorbital artery Doppler examination, and arch aortogram with selective left carotid arteriogram; all findings were normal. Of the 205 patients in the world literature to whom aminophylline has been administered during acute cerebral ischemia, prompt amelioration of the neurological deficit has occurred in more than half [21. T h e most recent clinical series reported improvement in two-thirds of 67 patients treated with intravenous aminophylline after suffering acute strokes [31. Human and animal investigations have established that: (1)aminophylline is a potent cerebral vasoconstrictor in cats and man [ 4 ] ; (2) aminophylline has a protective role in cerebral ischemia, since it decreases mortality and cerebral edema in embolized rats [ 11; ( 3 ) aminophylline selectively increases cerebral blood flow in man to ischemic areas [51. Although aminophylline is also an effective inhibitor of platelet aggregation and, like other methylxanthines, significantly increases turnover of brain norepinephrine and dopamine, its most pertinent effect is believed to be increasing cerebral blood flow to ischemic areas through selective vasoconstriction of cerebral blood vessels in nonischemic areas. That aminophylline dilates virtually all vessels except those in the brain and will even dilate cerebral vessels when it is locally applied in large doses suggests that cerebral vasoconstriction is not directly related to aminophyllineinduced increases in cyclic adenosine monophosphate (CAMP) by phosphodiesterase inhibition; that is, cerebral vasodilation will always result when cAMP is sufficiently increased (as with papaverine and locally applied aminophylline). One possibility is that low doses of methylxanthines or From the Department of Neurology, St. Margaret Hospital, Spring Valley, IL 61362.
372 Annals of Neurology
Vol 3 N o 4
April 1978
methylxanthines with less inhibition of phosphodiesterase cause cerebral vasoconstriction while higher doses (or more potent phosphodiesterase inhibitors) cause vasodilation, implying a bimodal action. Low-dose aminophylline, which is structurally quite similar to CAMP, may compete with cAMP for receptor sites and thereby cause smooth muscle contraction and cerebral vasoconstriction. Perhaps this constriction of normal vessels paradoxically reduces cerebral ischemia in abnormal areas by a “reverse steal” mechanism.
References 1.
2.
3. 4.
5.
Kogure K: A n effect of aminophylline on experimental cerebral ischemia (abstract). Arch Neurol 32:952, 1975 Manzier F Trearment of incipient apoplexy with inrravenous aminophylline. Acta Med Scand 146:362-374, 1953 Olivarius BD: Apoplexia Cerebri. Copenhagen, 1964 Regli F, Yamaguchi T, Waltz AG: Responses of surface arteries and blood flow of ischemic and non-ischemiccerebral cortex to aminophylline, ergoromine tartrate and acerazolamide. Stroke 2~461-470,1971 Skinhoj E, Paulson OB: The mechanism ofaction ofaminophylline upon cerebral vascular disorders. Acta Neurol Scand 46: 129- 140, 1970
Phy sostigmine in Wilson Disease Daniel Tarsy, MD, John F. Mahoney, MD, and Jeffrey L. Cummings, M D Physostigmine, a centrally active anticholinesterase, has occasionally been given to patients with extrapyramidal disorders to study the effect of potentiating central cholinergic mechanisms. W e report a striking effect of physostigmine in a patient with Wilson disease. A 29-year-old man was evaluated for dysarthria, dysphagia, gait disturbance, and psychological depression of several years’ duration. Neurological abnormalities included facial masking, hypophonia, dysarthria, dystonic neck posturing, flexion of the upper extremities, bradykinesia, tongue cremor, and a fine postural tremor of the outstretched hands. A diagnosis of Wilson disease was confirmed by the presence of Kayser-Fleischer corneal rings, low serum ceruloplasmin, and elevated urinary copper. Following intravenous administration of physostigmine salicylate, 1 mg, the fine postural tremor of the upper extremities showed a great increase in amplitude and assumed a classic “wing-beating”appearance; this was associated with a coarse tremor of the upper trunk. Facial masking and flexion posture of the arms and trunk From the Department of Neurology, Boston Veterans Administration Hospital and Boston University School of Medicine, and the Division of Neurology, New England Deaconess Hospital and
Harvard Medical School, Boston, MA. Address reprint requests to Dr Tarsy, Department of Neurology, Boston Veterans Administration Hospital, 150 S Huntington Ave, Bosron, MA 02130.
I recently observed a patient with symptoms of cerebral ischemia who improved promptly after intravenous injection of aminophylline. A 63-year-old right-handed man with chronic intrinsic asthma since childhood awoke with marked right hemiparesis and expressive aphasia. Ten hours later the patient had an asthmatic attack that was treated with 250 mg of intravenous aminophylline. Thirty seconds after the injection the patient spoke his first understandable words: “Boy, that feelsgood!” Within afew minutes his hemiparesis improved to the point that writing was attempted. Thirty minutes after injection the patient’s speech and writing were easily understood, and only mild hemiparesis remained. T h e following morning, neurological examination was normal except for mild hesitancy of speech, occasional circumlocutions, and a slight right pronator drift. Extensive laboratory studies included ophthalmodynamometry, supraorbital artery Doppler examination, and arch aortogram with selective left carotid arteriogram; all findings were normal. Of the 205 patients in the world literature to whom aminophylline has been administered during acute cerebral ischemia, prompt amelioration of the neurological deficit has occurred in more than half [21. T h e most recent clinical series reported improvement in two-thirds of 67 patients treated with intravenous aminophylline after suffering acute strokes [31. Human and animal investigations have established that: (1)aminophylline is a potent cerebral vasoconstrictor in cats and man [ 4 ] ; (2) aminophylline has a protective role in cerebral ischemia, since it decreases mortality and cerebral edema in embolized rats [ 11; ( 3 ) aminophylline selectively increases cerebral blood flow in man to ischemic areas [51. Although aminophylline is also an effective inhibitor of platelet aggregation and, like other methylxanthines, significantly increases turnover of brain norepinephrine and dopamine, its most pertinent effect is believed to be increasing cerebral blood flow to ischemic areas through selective vasoconstriction of cerebral blood vessels in nonischemic areas. That aminophylline dilates virtually all vessels except those in the brain and will even dilate cerebral vessels when it is locally applied in large doses suggests that cerebral vasoconstriction is not directly related to aminophyllineinduced increases in cyclic adenosine monophosphate (CAMP) by phosphodiesterase inhibition; that is, cerebral vasodilation will always result when cAMP is sufficiently increased (as with papaverine and locally applied aminophylline). One possibility is that low doses of methylxanthines or From the Department of Neurology, St. Margaret Hospital, Spring Valley, IL 61362.
372 Annals of Neurology
Vol 3 N o 4
April 1978
methylxanthines with less inhibition of phosphodiesterase cause cerebral vasoconstriction while higher doses (or more potent phosphodiesterase inhibitors) cause vasodilation, implying a bimodal action. Low-dose aminophylline, which is structurally quite similar to CAMP, may compete with cAMP for receptor sites and thereby cause smooth muscle contraction and cerebral vasoconstriction. Perhaps this constriction of normal vessels paradoxically reduces cerebral ischemia in abnormal areas by a “reverse steal” mechanism.
References 1.
2.
3. 4.
5.
Kogure K: A n effect of aminophylline on experimental cerebral ischemia (abstract). Arch Neurol 32:952, 1975 Manzier F Trearment of incipient apoplexy with inrravenous aminophylline. Acta Med Scand 146:362-374, 1953 Olivarius BD: Apoplexia Cerebri. Copenhagen, 1964 Regli F, Yamaguchi T, Waltz AG: Responses of surface arteries and blood flow of ischemic and non-ischemiccerebral cortex to aminophylline, ergoromine tartrate and acerazolamide. Stroke 2~461-470,1971 Skinhoj E, Paulson OB: The mechanism ofaction ofaminophylline upon cerebral vascular disorders. Acta Neurol Scand 46: 129- 140, 1970
Phy sostigmine in Wilson Disease Daniel Tarsy, MD, John F. Mahoney, MD, and Jeffrey L. Cummings, M D Physostigmine, a centrally active anticholinesterase, has occasionally been given to patients with extrapyramidal disorders to study the effect of potentiating central cholinergic mechanisms. W e report a striking effect of physostigmine in a patient with Wilson disease. A 29-year-old man was evaluated for dysarthria, dysphagia, gait disturbance, and psychological depression of several years’ duration. Neurological abnormalities included facial masking, hypophonia, dysarthria, dystonic neck posturing, flexion of the upper extremities, bradykinesia, tongue cremor, and a fine postural tremor of the outstretched hands. A diagnosis of Wilson disease was confirmed by the presence of Kayser-Fleischer corneal rings, low serum ceruloplasmin, and elevated urinary copper. Following intravenous administration of physostigmine salicylate, 1 mg, the fine postural tremor of the upper extremities showed a great increase in amplitude and assumed a classic “wing-beating”appearance; this was associated with a coarse tremor of the upper trunk. Facial masking and flexion posture of the arms and trunk From the Department of Neurology, Boston Veterans Administration Hospital and Boston University School of Medicine, and the Division of Neurology, New England Deaconess Hospital and
Harvard Medical School, Boston, MA. Address reprint requests to Dr Tarsy, Department of Neurology, Boston Veterans Administration Hospital, 150 S Huntington Ave, Bosron, MA 02130.
