J Neurosurg 73:774-776, 1990
Hemiparkinsonism as a complication of an Ommaya reservoir Case report WILLIAM P. CHESHIRE, M.D., AND ALBERT L. EHLE, M . D .
Department of Neurology, University of North Carolina, Chapel Hill, North Carolina ~" The authors describe the case of a 28-year-old woman who developed the following symptoms in her right hand: a lasting resting tremor, transient focal rigidity, and paresthesia. These deficits occurred following treatment with intrathecal methotrexate via an Ommaya reservoir which was placed too deeply, resulting in trauma to the contralateral mesencephalon. KEY WORDS methotrexate
9 O m m a y a reservoir
T
HE intraventricular Ommaya reservoir 12 is a preferred method for delivery of intrathecal chemotherapy in terms of therapeutic efficacy and patient comfort. The most common complication is infection, estimated to occur in 3% to 15% of patients t4 or once in every 153 reservoir-months. 3 Less frequent problems include reservoir malfunction, hemorrhage, and focal seizuresJ l Pericatheter necrosis and leukoencephalopathy have been reported in patients who received intrathecal methotrexate, particularly when combined with irradiation. T M 1,15,18To our knowledge, parkinsonism has not been described as an outcome of intraventricular reservoir placement or the drugs injected by this means. Case Report
This 28-year-old woman with acute lymphoblastic leukemia underwent placement of an Ommaya reservoir via a nondominant right frontal approach as a route for intrathecal methotrexate delivery. Its position was not confirmed radiographically. Upon aspiration, resistance was consistently encountered, but periodic injection of methotrexate met no resistance until 16 months later when fluid could not be withdrawn and the reservoir, if depressed, took many hours to refill. Computerized tomography (CT) at that time demonstrated the path of the catheter from the Ommaya reservoir at Kocher's point 7 traversing the third ventricle to its tip lodged in the left mesencephalon (Fig. 1).
774
9 ventricular catheter
9 parkinsonism
9
Function of the catheter was restored after it was withdrawn 3.5 cm; during this maneuver unusual resistance was encountered. Methotrexate injections were resumed 2 months later. Postoperatively, the patient noticed paresthesia and stiffness of the right hand and right perioral area; these resolved over 6 weeks but were succeeded 4 months later by a persistent 3 to 5 cycle/ sec resting tremor of the right hand, chiefly of the thumb and index finger, involving at times the forearm and right foot, and disappearing with intention. Magnetic resonance imaging revealed a small signal-void focus in the former path of the catheter tip (Fig. 2) and showed no signs of leukoencephalopathy. Physical examination, which took place after anticholinergic therapy had been initiated, did not disclose other features of parkinsonism such as bradykinesia, rigidity, abnormality of gait, loss of postural reflexes, or autonomic dysfunction. No ballismus, chorea, or ataxia was present. No deficits were detected in language, attention, memory, strength, sensation, or ocular motility. There was no family history of parkinsonism, and serum ceruloplasmin was normal. The patient had undergone no irradiation. Parenteral and oral medications had included Adriamycin (doxorubicin hydrochloride), vincristine, prednisone, cyclophosphamide, actinomycin D, 6-mercaptopurine, and carmustine. The tremor failed to improve after cessation of the antiemetic drugs metoclopramide and thiethylperazine. Three years later, the patient's leukemia is in remission.
J. Neurosurg. / Volume 73/November, 1990
Hemiparkinsonism after Ommaya reservoir placement
FIG. 1. Diagnostic studies performed prior to catheter withdrawal. A: Lateral skull roentgenogram showing the 11cm extent of the intraventricular catheter from the Ommaya reservoir at Kocher's point to its tip in the contralateral mesencephalon. B: Computerized tomography scan demonstrating the position of the catheter tip. The tremor has not progressed but has reduced in intensity with trihexyphenidyl. Discussion
Posttraumatic parkinsonism has been described following penetrating injury to nigrostriatal tracts, but such cases are rare because midbrain injury is often fatal. 4J~ In our patient the trauma was exceptionally limited and, aside from transient paresthesia, was confined to the motor system. It is of interest that no symptoms were noted for more than a year following insertion of the catheter but occurred after it was withdrawn from the midbrain. This may be attributed to disruption of tissue ingrowth in catheter fenestrations or to increased methotrexate exposure to tissue within the hollow catheter track which ordinarily would not have been brought into contact with intrathecally injected agents. The site of injury resembles the electrolytic lesions induced in monkeys by Ward, et al., w in 1948, particularly those of their monkeys TM1 and BR12 which developed Parkinson-like tremors immediately following focal ablation within the mesencephalic tegmentum in locations that approximate the signal void area seen in Fig. 2A. More extensive than our patient's lesion, theirs extended into the pontine tegmentum. Monkeys TM6 and BR14 probably failed to develop tremor because the lesions were more medially placed and insufficiently destroyed the substantia nigra or its outflow to the striatum. The small artificial mesencephalic cavity left in the wake of the catheter tip would have allowed methotrexate to pool in direct proximity to the substantia nigra. Unlike the immediate tremor produced experimentally in monkeys by Ward, et al., ~9 our patient did not experience tremor until several months after catheter withdrawal and after intrathecal methotrexate was reJ. Neurosurg. / Volume 73 / November, 1990
FIG. 2. Magnetic resonance studies following catheter withdrawal. Consecutive horizontal T~-weighted images through rostral (A) and more caudal (B) portions of the mesencephalon demonstrating the former path of the catheter passing through the plane of the substantia nigra and terminating in the lateral tegmentum of the mesencephalon. (Apparent blurring is due to enlargement of these 1.0-tesla images.)
sumed. The reason for this is uncertain but could have been the addition of chemical to mechanical injury. Exposure of methotrexate to divided tissue might have been capable of inducing parkinsonism, interrupting dopaminergic projection to the striatum by inhibition of the biosynthesis of tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase. The susceptibility of this biopterin pathway to degeneration has been postulated to explain idiopathic parkinsonism, although administration of exogenous tetrahydrobiopterin has been therapeutically disappointingfl '9'17 Fortunately, leukovorin rescue was not part of our patient's protocol, since intrathecal injections of folic acid in rats have resulted in excessive stimulation and eventual injury of nigral gamma-aminobutyric acid (GABA)ergic and dopaminergic neurons. 8 Asymmetric tremor, this patient's major symptomatic feature, is not typical of juvenile onset Parkinson's disease. Its course did not correlate with administration of metoclopramide or thiethylperazine, drugs which are known to reversibly precipitate or unmask evolving parkinsonism. We conclude that our patient's tremor was a complication of trauma combined with metabolic insult to the substantia nigra. Paresthesia may be explained by trauma to the medial and ventral trigeminal lemnisci, which also lie in the catheter's path. The fascination of this unusual case lies in its anatomically discrete lesion and definable clinical correlate. It also emphasizes the importance of routine postoperative CT verification of intraventricular catheter placement prior to injection of cytotoxic agents. In cases such as this, ultrasonic guidance represents a potential method of observing catheter position intraoperatively, when immediate recognition of unforeseen difficulties would allow prompt correction to be made. 1'13 References
1. Chandler WF, Knake JE, McGillicuddy JE, et al: Intraoperative use of real-time ultrasonography in neurosurgery. J Neurosurg 57:157-163, 1982 775
W. P. Cheshire and A. L. Ehle 2. Curtius HC, Niederwieser A, Levine R, et al: Therapeutic efficacy of tetrahydrobiopterin in Parkinson's disease, in Hassler RG, Christ JF (eds): Advances in Neurology. Vol
40: Parkinson-Specific Motor and Mental Disorders, Role of Pallidum: Pathophysiological, Biochemical, and Therapeutic Aspects. New York: Raven Press, 1984, pp
463-466 3. Dinndorf PA, Bleyer WA: Management of infectious complications of intraventricular reservoirs in cancer patients: low incidence and successful treatment without reservoir removal. Cancer Drug Deliv 4:105-117, 1987 4. Factor SA, Sanchez-Ramos J, Weiner WJ: Trauma as an etiology of Parkinsonism: an historical review of the concept. Move Dis 3:30-36, 1988 5. Glass JP, Lee YY, Bruner J, et al: Treatment-related leukoencephalopathy. A study of three cases and literature review. Medicine 65:154-162, 1986 6. Lemann W, Wiley RG, Posner JB: Leukoencephalopathy complicating intraventricular catheters: clinical, radiographic and pathologic study of 10 cases. J Neurooncol 6: 67-74, 1988 7. Mapstone TB, Ratcheson RA: Techniques of ventricular puncture, in Wilkins RH, Rengachary SS (eds): Neurosurgery. New York: McGraw-Hill, 1985, Vol 1, pp 151-155 8. McGeer EG, McGeer PL: Substantia nigra cell death from kainic acid or folic acid injections into the pontine tegmentum. Brain Res 298:339-342, 1984 9. Moore AP, Behan PO, Jacobson W, et al: Biopterin in Parkinson's disease. J Neurol Neurosurg Psychiatry 50: 85-87, 1987 10. Nayernouri T: Posttraumatic parkinsonism. Surg Neurol 24:263-264, 1985 11. Obbens EAMT, Leavens ME, Beal JW, et al: Ommaya reservoirs in 387 cancer patients: a 15-year experience.
776
Neurology 35:1274-1278, 1985 12. Ommaya AK: Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet 2: 983-984, 1963 13. Rubin JM, Dohrmann GJ: Use of ultrasonically guided probes and catheters in neurosurgery. Surg Neurol 18: 143-148, 1982 14. Siegal T, Pfeffer MR, Steiner I: Antibiotic therapy fol infected Ommaya reservoir systems. Neurosurgery 22: 97-100, 1988 15. Silverstein FS, Johnston MV: A model of methotrexate encephalopathy: neurotransmitter and pathologic abnormalities. J Child Neurol 1:351-357, 1986 16. Slevin JT, Sparks DL, Dempsey R J, et al: Altered striata] dopaminergic metabolism 36 hours after unilateral trauma to the human mesencephalon. Neurology 37: 322-325, 1987 17. Smith I, Howells DW, Hyland K: Pteridines and mono. amines: relevance to neurological damage. Postgrad Me~ J 62:113-123, 1986 18. Steinherz P, Jereb B, Galicich J: Therapy of CNS leuke. mia with intraventricular chemotherapy and low-dos~ neuraxis radiotherapy. J Clin Oncol 3:1217-1226, 1985 19. Ward AA Jr, McCulloch WS, Magoun HW: Productior of an alternating tremor at rest in monkeys. J Neurophy. siol 11:317-330, 1948
Manuscript received November 7, 1989. Accepted in final form April 19, 1990. Address reprint requests to: William P. Cheshire, M.D. Department of Neurology, 751 Clinical Sciences Building University of North Carolina, Chapel Hill, North Carolin', 27599-7025.
J. Neurosurg. / Volume 73/November, 199
Hemiparkinsonism as a complication of an Ommaya reservoir Case report WILLIAM P. CHESHIRE, M.D., AND ALBERT L. EHLE, M . D .
Department of Neurology, University of North Carolina, Chapel Hill, North Carolina ~" The authors describe the case of a 28-year-old woman who developed the following symptoms in her right hand: a lasting resting tremor, transient focal rigidity, and paresthesia. These deficits occurred following treatment with intrathecal methotrexate via an Ommaya reservoir which was placed too deeply, resulting in trauma to the contralateral mesencephalon. KEY WORDS methotrexate
9 O m m a y a reservoir
T
HE intraventricular Ommaya reservoir 12 is a preferred method for delivery of intrathecal chemotherapy in terms of therapeutic efficacy and patient comfort. The most common complication is infection, estimated to occur in 3% to 15% of patients t4 or once in every 153 reservoir-months. 3 Less frequent problems include reservoir malfunction, hemorrhage, and focal seizuresJ l Pericatheter necrosis and leukoencephalopathy have been reported in patients who received intrathecal methotrexate, particularly when combined with irradiation. T M 1,15,18To our knowledge, parkinsonism has not been described as an outcome of intraventricular reservoir placement or the drugs injected by this means. Case Report
This 28-year-old woman with acute lymphoblastic leukemia underwent placement of an Ommaya reservoir via a nondominant right frontal approach as a route for intrathecal methotrexate delivery. Its position was not confirmed radiographically. Upon aspiration, resistance was consistently encountered, but periodic injection of methotrexate met no resistance until 16 months later when fluid could not be withdrawn and the reservoir, if depressed, took many hours to refill. Computerized tomography (CT) at that time demonstrated the path of the catheter from the Ommaya reservoir at Kocher's point 7 traversing the third ventricle to its tip lodged in the left mesencephalon (Fig. 1).
774
9 ventricular catheter
9 parkinsonism
9
Function of the catheter was restored after it was withdrawn 3.5 cm; during this maneuver unusual resistance was encountered. Methotrexate injections were resumed 2 months later. Postoperatively, the patient noticed paresthesia and stiffness of the right hand and right perioral area; these resolved over 6 weeks but were succeeded 4 months later by a persistent 3 to 5 cycle/ sec resting tremor of the right hand, chiefly of the thumb and index finger, involving at times the forearm and right foot, and disappearing with intention. Magnetic resonance imaging revealed a small signal-void focus in the former path of the catheter tip (Fig. 2) and showed no signs of leukoencephalopathy. Physical examination, which took place after anticholinergic therapy had been initiated, did not disclose other features of parkinsonism such as bradykinesia, rigidity, abnormality of gait, loss of postural reflexes, or autonomic dysfunction. No ballismus, chorea, or ataxia was present. No deficits were detected in language, attention, memory, strength, sensation, or ocular motility. There was no family history of parkinsonism, and serum ceruloplasmin was normal. The patient had undergone no irradiation. Parenteral and oral medications had included Adriamycin (doxorubicin hydrochloride), vincristine, prednisone, cyclophosphamide, actinomycin D, 6-mercaptopurine, and carmustine. The tremor failed to improve after cessation of the antiemetic drugs metoclopramide and thiethylperazine. Three years later, the patient's leukemia is in remission.
J. Neurosurg. / Volume 73/November, 1990
Hemiparkinsonism after Ommaya reservoir placement
FIG. 1. Diagnostic studies performed prior to catheter withdrawal. A: Lateral skull roentgenogram showing the 11cm extent of the intraventricular catheter from the Ommaya reservoir at Kocher's point to its tip in the contralateral mesencephalon. B: Computerized tomography scan demonstrating the position of the catheter tip. The tremor has not progressed but has reduced in intensity with trihexyphenidyl. Discussion
Posttraumatic parkinsonism has been described following penetrating injury to nigrostriatal tracts, but such cases are rare because midbrain injury is often fatal. 4J~ In our patient the trauma was exceptionally limited and, aside from transient paresthesia, was confined to the motor system. It is of interest that no symptoms were noted for more than a year following insertion of the catheter but occurred after it was withdrawn from the midbrain. This may be attributed to disruption of tissue ingrowth in catheter fenestrations or to increased methotrexate exposure to tissue within the hollow catheter track which ordinarily would not have been brought into contact with intrathecally injected agents. The site of injury resembles the electrolytic lesions induced in monkeys by Ward, et al., w in 1948, particularly those of their monkeys TM1 and BR12 which developed Parkinson-like tremors immediately following focal ablation within the mesencephalic tegmentum in locations that approximate the signal void area seen in Fig. 2A. More extensive than our patient's lesion, theirs extended into the pontine tegmentum. Monkeys TM6 and BR14 probably failed to develop tremor because the lesions were more medially placed and insufficiently destroyed the substantia nigra or its outflow to the striatum. The small artificial mesencephalic cavity left in the wake of the catheter tip would have allowed methotrexate to pool in direct proximity to the substantia nigra. Unlike the immediate tremor produced experimentally in monkeys by Ward, et al., ~9 our patient did not experience tremor until several months after catheter withdrawal and after intrathecal methotrexate was reJ. Neurosurg. / Volume 73 / November, 1990
FIG. 2. Magnetic resonance studies following catheter withdrawal. Consecutive horizontal T~-weighted images through rostral (A) and more caudal (B) portions of the mesencephalon demonstrating the former path of the catheter passing through the plane of the substantia nigra and terminating in the lateral tegmentum of the mesencephalon. (Apparent blurring is due to enlargement of these 1.0-tesla images.)
sumed. The reason for this is uncertain but could have been the addition of chemical to mechanical injury. Exposure of methotrexate to divided tissue might have been capable of inducing parkinsonism, interrupting dopaminergic projection to the striatum by inhibition of the biosynthesis of tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase. The susceptibility of this biopterin pathway to degeneration has been postulated to explain idiopathic parkinsonism, although administration of exogenous tetrahydrobiopterin has been therapeutically disappointingfl '9'17 Fortunately, leukovorin rescue was not part of our patient's protocol, since intrathecal injections of folic acid in rats have resulted in excessive stimulation and eventual injury of nigral gamma-aminobutyric acid (GABA)ergic and dopaminergic neurons. 8 Asymmetric tremor, this patient's major symptomatic feature, is not typical of juvenile onset Parkinson's disease. Its course did not correlate with administration of metoclopramide or thiethylperazine, drugs which are known to reversibly precipitate or unmask evolving parkinsonism. We conclude that our patient's tremor was a complication of trauma combined with metabolic insult to the substantia nigra. Paresthesia may be explained by trauma to the medial and ventral trigeminal lemnisci, which also lie in the catheter's path. The fascination of this unusual case lies in its anatomically discrete lesion and definable clinical correlate. It also emphasizes the importance of routine postoperative CT verification of intraventricular catheter placement prior to injection of cytotoxic agents. In cases such as this, ultrasonic guidance represents a potential method of observing catheter position intraoperatively, when immediate recognition of unforeseen difficulties would allow prompt correction to be made. 1'13 References
1. Chandler WF, Knake JE, McGillicuddy JE, et al: Intraoperative use of real-time ultrasonography in neurosurgery. J Neurosurg 57:157-163, 1982 775
W. P. Cheshire and A. L. Ehle 2. Curtius HC, Niederwieser A, Levine R, et al: Therapeutic efficacy of tetrahydrobiopterin in Parkinson's disease, in Hassler RG, Christ JF (eds): Advances in Neurology. Vol
40: Parkinson-Specific Motor and Mental Disorders, Role of Pallidum: Pathophysiological, Biochemical, and Therapeutic Aspects. New York: Raven Press, 1984, pp
463-466 3. Dinndorf PA, Bleyer WA: Management of infectious complications of intraventricular reservoirs in cancer patients: low incidence and successful treatment without reservoir removal. Cancer Drug Deliv 4:105-117, 1987 4. Factor SA, Sanchez-Ramos J, Weiner WJ: Trauma as an etiology of Parkinsonism: an historical review of the concept. Move Dis 3:30-36, 1988 5. Glass JP, Lee YY, Bruner J, et al: Treatment-related leukoencephalopathy. A study of three cases and literature review. Medicine 65:154-162, 1986 6. Lemann W, Wiley RG, Posner JB: Leukoencephalopathy complicating intraventricular catheters: clinical, radiographic and pathologic study of 10 cases. J Neurooncol 6: 67-74, 1988 7. Mapstone TB, Ratcheson RA: Techniques of ventricular puncture, in Wilkins RH, Rengachary SS (eds): Neurosurgery. New York: McGraw-Hill, 1985, Vol 1, pp 151-155 8. McGeer EG, McGeer PL: Substantia nigra cell death from kainic acid or folic acid injections into the pontine tegmentum. Brain Res 298:339-342, 1984 9. Moore AP, Behan PO, Jacobson W, et al: Biopterin in Parkinson's disease. J Neurol Neurosurg Psychiatry 50: 85-87, 1987 10. Nayernouri T: Posttraumatic parkinsonism. Surg Neurol 24:263-264, 1985 11. Obbens EAMT, Leavens ME, Beal JW, et al: Ommaya reservoirs in 387 cancer patients: a 15-year experience.
776
Neurology 35:1274-1278, 1985 12. Ommaya AK: Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet 2: 983-984, 1963 13. Rubin JM, Dohrmann GJ: Use of ultrasonically guided probes and catheters in neurosurgery. Surg Neurol 18: 143-148, 1982 14. Siegal T, Pfeffer MR, Steiner I: Antibiotic therapy fol infected Ommaya reservoir systems. Neurosurgery 22: 97-100, 1988 15. Silverstein FS, Johnston MV: A model of methotrexate encephalopathy: neurotransmitter and pathologic abnormalities. J Child Neurol 1:351-357, 1986 16. Slevin JT, Sparks DL, Dempsey R J, et al: Altered striata] dopaminergic metabolism 36 hours after unilateral trauma to the human mesencephalon. Neurology 37: 322-325, 1987 17. Smith I, Howells DW, Hyland K: Pteridines and mono. amines: relevance to neurological damage. Postgrad Me~ J 62:113-123, 1986 18. Steinherz P, Jereb B, Galicich J: Therapy of CNS leuke. mia with intraventricular chemotherapy and low-dos~ neuraxis radiotherapy. J Clin Oncol 3:1217-1226, 1985 19. Ward AA Jr, McCulloch WS, Magoun HW: Productior of an alternating tremor at rest in monkeys. J Neurophy. siol 11:317-330, 1948
Manuscript received November 7, 1989. Accepted in final form April 19, 1990. Address reprint requests to: William P. Cheshire, M.D. Department of Neurology, 751 Clinical Sciences Building University of North Carolina, Chapel Hill, North Carolin', 27599-7025.
J. Neurosurg. / Volume 73/November, 199
