JNeurosurg76:152-155,1992
Relief of akinetic mutism from obstructive hydrocephalus using bromocriptine and ephedrine Case report BRITI ANDERSON, M.D.
Neurology Section, Keesler Technical Training Center Medical Center, Keesler Air Force Base, Mississippi v The case of a 20-year-old man with obstructive hydrocephalus who suffered multiple shunt failures and shunt revisions is presented. The patient gradually developed a clinical syndrome of akinetic mutism. This behavioral syndrome failed to respond to shunt revisions, but did improve after the administration of a combination of bromocriptine and ephedrine. KEY WORDS
A
•
hydrocephalus
• akinetic mutism
mutism is an infrequent but profound complication of recurrent obstructive hydrocephalus. 4 This case suggests that the syndrome may be secondary to rapid ventricular expansion with damage to ascending monoamine projections. In the patient presented here, the behavioral characteristics failed to improve with cerebroventricular shunting, but did respond to administration of a combination of bromocriptine and ephedrine. KINETIC
Case Report
This 20-year-old man was evaluated at another institution for headache and diplopia. There was no relevant medical history, and a general physical examination was normal. Neurological examination revealed only papilledema and a left sixth cranial nerve palsy. Computerized tomography (CT) and magnetic resonance imaging of the brain disclosed hydrocephalus in a pattern consistent with aqueductal stenosis (Fig. 1). A cerebroventricular peritoneal shunt was placed on the right, with resolution of the headache and diplopia. Seven months later, the patient went to bed complaining of headache and did not awaken the next morning. Computerized tomography of the brain showed recurrent ventriculomegaly. The shunt was revised and 3 days later the patient was fully oriented, answered questions with short, appropriate responses, and could walk with stand-by support. The following day, the patient was noted to be mute, but no other 152
• bromocriptine
• ephedrine
changes were noted. He still obeyed commands, but would not respond verbally. A CT scan showed recurrent ventriculomegaly. A second shunt revision was performed and 2 days later the patient could move all extremities well and answer questions correctly with monosyllables. The next day, the patient was alert and responded to complex commands, but would not talk. Ten days after this, the examination had not altered, CT showed a decrease in the size of the ventricles, and the patient was discharged. Two days later, the patient was noted to have decorticate posturing; an emergency CT scan showed that the ventricles were again dilated and a third complete shunt revision was performed. One week after this shunt revision, the patient was transferred to Keesler Technical Training Center Medical Center. Examination. On examination, the patient would make no verbalizations. He looked to each side and blinked upon command, but no other commands were obeyed. Cranial nerve examination showed a coarse nystagmus in the direction of gaze and deficient upward gaze. Motor examination showed spasticity of all four extremities, with some slight withdrawal in response to pain. Deep-tendon reflexes were hyperreactive, more on the right side than the left, and there were bilateral Babinski signs as well as suck, snout, palmomental, and glabellar reflexes. One week after admission, the patient became comatose and was observed to have intermittent flexion of the arms and shaking of the left leg. A J. Neurosurg. / Volume 76/ January, 1992
Akinetic mutism from obstructive hydrocephalus
FIG. I. Computerized tomography scans showing the size of the lateral ventricles at the times of shunt malfunctions before (upper) and following (lower) shunt revisions. From left to right, the images represent scans obtained at initial presentation, following the first shunt malfunction, the second shunt malfunction, and the third shunt malfunction. Clinical symptoms range from headache (left) to coma (right); note the relative degree of ventriculomegaly and its lack of correlation with the clinical symptoms. The circle artifact and out-of-focus image are on the scans sent to our hospital.
CT scan performed at that time showed ventriculomegaly and again the patient was taken to surgery. Operations. The shunt was removed and a ventriculostomy tube placed for external drainage. Cerebrospinal fluid pressure was maintained at 4 cm H 20 for 5 days. During this time, the patient improved minimally, the only change being a return of the sleep-wake cycle and an infrequent sense that the patient would track objects with his eyes. He obeyed no commands, he would not speak, and pain produced no change in facial expression; there was some slow, incomplete withdrawal of the stimulated extremity. After 5 days of external drainage, the patient underwent a sixth operation. A ventriculoatrial shunt was placed, with the shunt catheter in the right temporal horn of the lateral ventricle.
Postoperative Course. Two days after shunt placement, bromocriptine therapy was begun. After 7 days, the dosage was increased to 27.5 mg bromocriptine orally every 6 hours. The patient would now blink and look to each side upon command. At II days following the operation, a course of ephedrine was started enterally, 25 mg 3 times daily. On Day 12, he would look, on command, from the examiner's hand to the examiner's nose and would blink in recognition of the names of his wife and daughter. On Day 14, the dosage of 1. Neurosurg. / Volume 76/ January, 1992
ephedrine was increased to 37.5 mg every 4 hours, and the patient began to squeeze fingers and wiggle his toes on command. On Day 15, the ephedrine dosage was 50 mg every 4 hours, and the patient could hold up the correct number of fingers to command. The following day, at a dose of 50 mg ephedrine every 3 hours, the patient could blink correct responses to "yes" and "no" questions. He whispered a request for a glass of water and, appropriately, "Happy New Year." The patient continued at this level until postoperative Day 20, when a decision was made to evaluate the contribution of the bromocriptine by withdrawing it. After the dose had been decreased by one-third, the patient stopped all speech, but continued to obey simple commands. At one-half the dose, the patient would squeeze hands only. The dose was then increased to 75 mg/day and the patient resumed following simple commands. At daily doses of 100 mg bromocriptine and 400 mg ephedrine, the patient said "Hello." The following day, he wrote his name and ate pizza and the next day he verbally answered questions. The ephedrine was then gradually increased to a total of 525 mg/day, and the bromocriptine was maintained at 100 mg/day. On examination, he then responded verbally to questions. He knew the month, year, and place, and could recall three of three items if prompted. There was no aphasia or anomia. He could recognize affect, but his expression
153
B. Anderson was aprosodic. Serial 7 tests were performed correctly to 86 and then he erred. Cranial nerve examination was normal, except for poor upward gaze and saccadic eye movements when following. Motor evaluation showed persistence of increased tone, with a coarse action tremor; he could walk with support. Sensory testing was normal, including graphesthesia. Over the subsequent 2 weeks, further improvement occurred. The patient was able to draw doodle art, feed himself, and walk with minimal assistance; he was discharged to a nursing home in Alabama. Three months later, a conversation with his wife revealed that he was continuing to do well. He was walking and feeding himself; on weekends, he would return home and, for entertainment, was allowed to drive a car on back roads. He was noted by the family to have some problems with memory, but no side effects from the medications had been noted and the dosage had not been altered. Six months later, the patient deteriorated markedly in his behavioral performance and was transferred to this institution, where a CT scan showed return of ventriculomegaly. A shunt revision was performed, with behavioral improvement. At this time, another attempt was made to withdraw the bromocriptine. This resulted in abrupt behavioral deterioration, with decreased spontaneous movement and a hesitancy to answer questions. Reinstitution of bromocriptine improved all features to the baseline prior to his most recent shunt malfunction. No cause for the multiple shunt malfunctions has been discerned. Discussion The term "akinetic mutism" was used by Cairns, et
ai.,2 to describe a behavioral state where a patient
appears awake but does not move or speak. The observation of this clinical syndrome as a consequence of obstructive hydrocephalus was first made by Messert, et al.,4 in 1966 and has been reported only infrequently since then. Daly and Love 3 successfully treated a patient with akinetic mutism, probably not due to hydrocephalus, with methylphenidate. Ross and StewartS used bromocriptine therapy successfully on a patient with akinetic mutism secondary to a tumor. There have been two reported cases of obstructive hydrocephalus where akinetic mutism and parkinsonism, not responsive to shunting, improved with dopaminergic stimulation. 1.9 Our case is the first with a requirement for both a dopamine agonist and a sympathomimetic, and when combined with previous reports, suggests a possible mechanism of induction of the akinetic mute state. The syndrome does not result from simple elevation of intracranial pressure, as was shown by Cairns, et al,,2 and is apparent to those treating pseudotumor cerebri patients, who can suffer pronounced elevations of intracranial pressure and be far from mute. Also, the syndrome is not due to simple dilation of the cerebroventricular system. As can be seen in Fig. 1, equivalent
154
degrees of cerebroventricular dilation occurred both early and late in our patient's course, and were associated with widely disparate clinical states, ranging from headache to coma. A review of prior cases reveals that the syndrome usually develops after multiple shunt revisions for shunt failure. I.4.9 This suggests the possibility that the brain resembles a balloon stretched by hand to make it easier to inflate: the repeated bouts of ventricular dilation and relaxation may somehow alter the physical characteristics of the tissue to permit expansion at lower pressures and more rapid dilation. This rapid dilation could then exceed the rapidity with which compensatory mechanisms may work and resultant damage could then occur. The damage may well be maximal in regions adjacent to the third ventricle, again as suggested in their seminal paper by Cairns, et al. 2 In this region, there are monoaminergic projection fibers from the brain stem. 6 .8 Lesioning of these structures in animals can produce a behavioral syndrome, such as akinetic mutism, which can be reversed with dopamine agonists. 7 This was the basis for Ross and StewartS using bromocriptine therapy on their patient. We added ephedrine when bromocriptine alone failed in our patient because noradrenergic fibers also pass adjacent to the third ventricle and, with their wide projections, are thought to participate in the mediation of arousal. 6 Ephedrine has both direct and indirect sympathomimetic effects.lo It seems probable that this patient's response was due to the medicine, given the two attempts to remove bromocriptine, both of which resulted in behavioral decline. While the occurrence of the full syndrome of akinetic mutism may present itself infrequently to the neurosurgeon, a somewhat abulic apathetic individual who has undergone multiple shunt revision is not rare. It remains to be learned how much of the behavioral apathy in these cases is a consequence of incomplete damage to ascending monoaminergic projection systems which may be responsive to replacement therapies. Acknowledgments Gregory Walker, M.D., and Judith Williamson, M.D., both contributed significantly to the clinical care of this patient. Sue Currin provided excellent secretarial support. References I. Berger L, Gauthier S, Leblanc R: Akinetic mutism and parkinsonism associated with obstructive hydrocephalus. Can J Neurol Sci 12:255-258, 1985 2. Cairns H, Oldfield RC, Pennybacker JB, et al: Akinetic mutism with an epidermoid cyst of the 3rd ventricle. (With a report of the associated disturbance of brain potentials.) Brain 64:273-290, 1941 3. Daly DD, Love JG: Akinetic mutism. Neurology 8: 238-242, 1958 4. Messert B, Henke TK, Langheim W: Syndrome of aki-
J. Neurosurg. / Volume 76/ January, 1992
Akinetic mutism from obstructive hydrocephalus
5. 6. 7.
8.
9.
netic mutism associated with obstructive hydrocephalUS. Neurology 16:635-649, 1966 Ross ED, Stewart RM: Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 31:1435-1439,1981 Saper CB: Function of the locus coeruleus. Trends Neurosci 10:343-344, 1987 Ungerstedt U: Brain dopamine neurons and behavior, in Schmitt FO, Worden FG (eds): The Neurosciences Third Study Program. Cambridge, Mass: MIT Press, 1974, pp 695-703 Ungerstedt U: Functional dynamics of central monoamine pathways, in Schmitt FO, Worden FG (OOs): The Neurosciences Third Study Program. Cambridge, Mass: MIT Press, 1974, pp 979-988 Watahiki Y, Narita S, Kurahashi K, et al: [Akinetic mutism from recurrent hydrocephalus: successful treat-
J. Neurosurg. / Volume 76/ January, 1992
ment with levodopa, bromocriptine, and trihexyphenidyl.] No To Shinkei 39:977-982, 1987 (Jpn) 10. Weiner N: Norepinephrine, epinephrine, and the sympathomimetic amines, in Gilman AG, Goodman LS, Rall TW, et al (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed 7. New York: Macmillan, 1985, pp 145-180 Manuscript received March 18, 1991. Accepted in final form June 17, 1991. Opinions expressed herein are those of the author and do not purport to express views of the Department of the Air Force or the Department of Defense. Address reprint requests to: Britt Anderson, M.D., Department of Neurology, University of Alabama, UAB Station, Birmingham, Alabama 35294-0007.
155
Relief of akinetic mutism from obstructive hydrocephalus using bromocriptine and ephedrine Case report BRITI ANDERSON, M.D.
Neurology Section, Keesler Technical Training Center Medical Center, Keesler Air Force Base, Mississippi v The case of a 20-year-old man with obstructive hydrocephalus who suffered multiple shunt failures and shunt revisions is presented. The patient gradually developed a clinical syndrome of akinetic mutism. This behavioral syndrome failed to respond to shunt revisions, but did improve after the administration of a combination of bromocriptine and ephedrine. KEY WORDS
A
•
hydrocephalus
• akinetic mutism
mutism is an infrequent but profound complication of recurrent obstructive hydrocephalus. 4 This case suggests that the syndrome may be secondary to rapid ventricular expansion with damage to ascending monoamine projections. In the patient presented here, the behavioral characteristics failed to improve with cerebroventricular shunting, but did respond to administration of a combination of bromocriptine and ephedrine. KINETIC
Case Report
This 20-year-old man was evaluated at another institution for headache and diplopia. There was no relevant medical history, and a general physical examination was normal. Neurological examination revealed only papilledema and a left sixth cranial nerve palsy. Computerized tomography (CT) and magnetic resonance imaging of the brain disclosed hydrocephalus in a pattern consistent with aqueductal stenosis (Fig. 1). A cerebroventricular peritoneal shunt was placed on the right, with resolution of the headache and diplopia. Seven months later, the patient went to bed complaining of headache and did not awaken the next morning. Computerized tomography of the brain showed recurrent ventriculomegaly. The shunt was revised and 3 days later the patient was fully oriented, answered questions with short, appropriate responses, and could walk with stand-by support. The following day, the patient was noted to be mute, but no other 152
• bromocriptine
• ephedrine
changes were noted. He still obeyed commands, but would not respond verbally. A CT scan showed recurrent ventriculomegaly. A second shunt revision was performed and 2 days later the patient could move all extremities well and answer questions correctly with monosyllables. The next day, the patient was alert and responded to complex commands, but would not talk. Ten days after this, the examination had not altered, CT showed a decrease in the size of the ventricles, and the patient was discharged. Two days later, the patient was noted to have decorticate posturing; an emergency CT scan showed that the ventricles were again dilated and a third complete shunt revision was performed. One week after this shunt revision, the patient was transferred to Keesler Technical Training Center Medical Center. Examination. On examination, the patient would make no verbalizations. He looked to each side and blinked upon command, but no other commands were obeyed. Cranial nerve examination showed a coarse nystagmus in the direction of gaze and deficient upward gaze. Motor examination showed spasticity of all four extremities, with some slight withdrawal in response to pain. Deep-tendon reflexes were hyperreactive, more on the right side than the left, and there were bilateral Babinski signs as well as suck, snout, palmomental, and glabellar reflexes. One week after admission, the patient became comatose and was observed to have intermittent flexion of the arms and shaking of the left leg. A J. Neurosurg. / Volume 76/ January, 1992
Akinetic mutism from obstructive hydrocephalus
FIG. I. Computerized tomography scans showing the size of the lateral ventricles at the times of shunt malfunctions before (upper) and following (lower) shunt revisions. From left to right, the images represent scans obtained at initial presentation, following the first shunt malfunction, the second shunt malfunction, and the third shunt malfunction. Clinical symptoms range from headache (left) to coma (right); note the relative degree of ventriculomegaly and its lack of correlation with the clinical symptoms. The circle artifact and out-of-focus image are on the scans sent to our hospital.
CT scan performed at that time showed ventriculomegaly and again the patient was taken to surgery. Operations. The shunt was removed and a ventriculostomy tube placed for external drainage. Cerebrospinal fluid pressure was maintained at 4 cm H 20 for 5 days. During this time, the patient improved minimally, the only change being a return of the sleep-wake cycle and an infrequent sense that the patient would track objects with his eyes. He obeyed no commands, he would not speak, and pain produced no change in facial expression; there was some slow, incomplete withdrawal of the stimulated extremity. After 5 days of external drainage, the patient underwent a sixth operation. A ventriculoatrial shunt was placed, with the shunt catheter in the right temporal horn of the lateral ventricle.
Postoperative Course. Two days after shunt placement, bromocriptine therapy was begun. After 7 days, the dosage was increased to 27.5 mg bromocriptine orally every 6 hours. The patient would now blink and look to each side upon command. At II days following the operation, a course of ephedrine was started enterally, 25 mg 3 times daily. On Day 12, he would look, on command, from the examiner's hand to the examiner's nose and would blink in recognition of the names of his wife and daughter. On Day 14, the dosage of 1. Neurosurg. / Volume 76/ January, 1992
ephedrine was increased to 37.5 mg every 4 hours, and the patient began to squeeze fingers and wiggle his toes on command. On Day 15, the ephedrine dosage was 50 mg every 4 hours, and the patient could hold up the correct number of fingers to command. The following day, at a dose of 50 mg ephedrine every 3 hours, the patient could blink correct responses to "yes" and "no" questions. He whispered a request for a glass of water and, appropriately, "Happy New Year." The patient continued at this level until postoperative Day 20, when a decision was made to evaluate the contribution of the bromocriptine by withdrawing it. After the dose had been decreased by one-third, the patient stopped all speech, but continued to obey simple commands. At one-half the dose, the patient would squeeze hands only. The dose was then increased to 75 mg/day and the patient resumed following simple commands. At daily doses of 100 mg bromocriptine and 400 mg ephedrine, the patient said "Hello." The following day, he wrote his name and ate pizza and the next day he verbally answered questions. The ephedrine was then gradually increased to a total of 525 mg/day, and the bromocriptine was maintained at 100 mg/day. On examination, he then responded verbally to questions. He knew the month, year, and place, and could recall three of three items if prompted. There was no aphasia or anomia. He could recognize affect, but his expression
153
B. Anderson was aprosodic. Serial 7 tests were performed correctly to 86 and then he erred. Cranial nerve examination was normal, except for poor upward gaze and saccadic eye movements when following. Motor evaluation showed persistence of increased tone, with a coarse action tremor; he could walk with support. Sensory testing was normal, including graphesthesia. Over the subsequent 2 weeks, further improvement occurred. The patient was able to draw doodle art, feed himself, and walk with minimal assistance; he was discharged to a nursing home in Alabama. Three months later, a conversation with his wife revealed that he was continuing to do well. He was walking and feeding himself; on weekends, he would return home and, for entertainment, was allowed to drive a car on back roads. He was noted by the family to have some problems with memory, but no side effects from the medications had been noted and the dosage had not been altered. Six months later, the patient deteriorated markedly in his behavioral performance and was transferred to this institution, where a CT scan showed return of ventriculomegaly. A shunt revision was performed, with behavioral improvement. At this time, another attempt was made to withdraw the bromocriptine. This resulted in abrupt behavioral deterioration, with decreased spontaneous movement and a hesitancy to answer questions. Reinstitution of bromocriptine improved all features to the baseline prior to his most recent shunt malfunction. No cause for the multiple shunt malfunctions has been discerned. Discussion The term "akinetic mutism" was used by Cairns, et
ai.,2 to describe a behavioral state where a patient
appears awake but does not move or speak. The observation of this clinical syndrome as a consequence of obstructive hydrocephalus was first made by Messert, et al.,4 in 1966 and has been reported only infrequently since then. Daly and Love 3 successfully treated a patient with akinetic mutism, probably not due to hydrocephalus, with methylphenidate. Ross and StewartS used bromocriptine therapy successfully on a patient with akinetic mutism secondary to a tumor. There have been two reported cases of obstructive hydrocephalus where akinetic mutism and parkinsonism, not responsive to shunting, improved with dopaminergic stimulation. 1.9 Our case is the first with a requirement for both a dopamine agonist and a sympathomimetic, and when combined with previous reports, suggests a possible mechanism of induction of the akinetic mute state. The syndrome does not result from simple elevation of intracranial pressure, as was shown by Cairns, et al,,2 and is apparent to those treating pseudotumor cerebri patients, who can suffer pronounced elevations of intracranial pressure and be far from mute. Also, the syndrome is not due to simple dilation of the cerebroventricular system. As can be seen in Fig. 1, equivalent
154
degrees of cerebroventricular dilation occurred both early and late in our patient's course, and were associated with widely disparate clinical states, ranging from headache to coma. A review of prior cases reveals that the syndrome usually develops after multiple shunt revisions for shunt failure. I.4.9 This suggests the possibility that the brain resembles a balloon stretched by hand to make it easier to inflate: the repeated bouts of ventricular dilation and relaxation may somehow alter the physical characteristics of the tissue to permit expansion at lower pressures and more rapid dilation. This rapid dilation could then exceed the rapidity with which compensatory mechanisms may work and resultant damage could then occur. The damage may well be maximal in regions adjacent to the third ventricle, again as suggested in their seminal paper by Cairns, et al. 2 In this region, there are monoaminergic projection fibers from the brain stem. 6 .8 Lesioning of these structures in animals can produce a behavioral syndrome, such as akinetic mutism, which can be reversed with dopamine agonists. 7 This was the basis for Ross and StewartS using bromocriptine therapy on their patient. We added ephedrine when bromocriptine alone failed in our patient because noradrenergic fibers also pass adjacent to the third ventricle and, with their wide projections, are thought to participate in the mediation of arousal. 6 Ephedrine has both direct and indirect sympathomimetic effects.lo It seems probable that this patient's response was due to the medicine, given the two attempts to remove bromocriptine, both of which resulted in behavioral decline. While the occurrence of the full syndrome of akinetic mutism may present itself infrequently to the neurosurgeon, a somewhat abulic apathetic individual who has undergone multiple shunt revision is not rare. It remains to be learned how much of the behavioral apathy in these cases is a consequence of incomplete damage to ascending monoaminergic projection systems which may be responsive to replacement therapies. Acknowledgments Gregory Walker, M.D., and Judith Williamson, M.D., both contributed significantly to the clinical care of this patient. Sue Currin provided excellent secretarial support. References I. Berger L, Gauthier S, Leblanc R: Akinetic mutism and parkinsonism associated with obstructive hydrocephalus. Can J Neurol Sci 12:255-258, 1985 2. Cairns H, Oldfield RC, Pennybacker JB, et al: Akinetic mutism with an epidermoid cyst of the 3rd ventricle. (With a report of the associated disturbance of brain potentials.) Brain 64:273-290, 1941 3. Daly DD, Love JG: Akinetic mutism. Neurology 8: 238-242, 1958 4. Messert B, Henke TK, Langheim W: Syndrome of aki-
J. Neurosurg. / Volume 76/ January, 1992
Akinetic mutism from obstructive hydrocephalus
5. 6. 7.
8.
9.
netic mutism associated with obstructive hydrocephalUS. Neurology 16:635-649, 1966 Ross ED, Stewart RM: Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 31:1435-1439,1981 Saper CB: Function of the locus coeruleus. Trends Neurosci 10:343-344, 1987 Ungerstedt U: Brain dopamine neurons and behavior, in Schmitt FO, Worden FG (eds): The Neurosciences Third Study Program. Cambridge, Mass: MIT Press, 1974, pp 695-703 Ungerstedt U: Functional dynamics of central monoamine pathways, in Schmitt FO, Worden FG (OOs): The Neurosciences Third Study Program. Cambridge, Mass: MIT Press, 1974, pp 979-988 Watahiki Y, Narita S, Kurahashi K, et al: [Akinetic mutism from recurrent hydrocephalus: successful treat-
J. Neurosurg. / Volume 76/ January, 1992
ment with levodopa, bromocriptine, and trihexyphenidyl.] No To Shinkei 39:977-982, 1987 (Jpn) 10. Weiner N: Norepinephrine, epinephrine, and the sympathomimetic amines, in Gilman AG, Goodman LS, Rall TW, et al (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed 7. New York: Macmillan, 1985, pp 145-180 Manuscript received March 18, 1991. Accepted in final form June 17, 1991. Opinions expressed herein are those of the author and do not purport to express views of the Department of the Air Force or the Department of Defense. Address reprint requests to: Britt Anderson, M.D., Department of Neurology, University of Alabama, UAB Station, Birmingham, Alabama 35294-0007.
155
