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Adverse Events in Children Receiving Intermittent Left Vagal Nerve Stimulation
Adverse Events in Children Receiving Intermittent Left Vagal Nerve Stimulation Jerome V. Murphy, MD*, Gregory W. Hornig, MD†, Gloria S. Schallert, RN*, and Christie L. Tilton, RN* The purpose of this study was to determine the frequency of unexpected events during intermittent vagal nerve stimulation in 24 patients stimulated for a total of 61 patient years. The charts of 24 children undergoing periodic stimulation of the left vagal nerve on research protocols were reviewed to determine the nature and frequency of adverse events and the total length of time they were stimulated. Fifteen adverse events were discovered in 12 patients. Thirteen were likely related to the device, and four other events might have been related. Two of these resulted in voluntary termination of vagal nerve stimulation, and the rest were treatable. Vagal nerve stimulation was tolerated in this series of patients. As opposed to the more standard drug therapies, adverse events during vagal nerve stimulation do not necessitate termination of therapy, but these events frequently lead to unforeseen surgery under general anesthesia. © 1998 by Elsevier Science Inc. All rights reserved. Murphy JV, Hornig GW, Schallert GS, Tilton CL. Adverse events in children receiving intermittent left vagal nerve stimulation. Pediatr Neurol 1998;19:42-44.
Introduction Periodic stimulation of the left vagal nerve as adjunctive therapy in patients with pharmacoresistant partial seizures has been shown in blinded and controlled studies to be effective in reducing the frequency of partial seizures in older children and adults with pharmacoresistant epilepsy [1,2]. Stimulation is performed by an implanted generator with leads to the left vagal nerve. Recently this intervention was approved by the Food and Drug Administration for use in such a population. Observations of the use of vagal nerve stimulation (VNS) in children suggest similar efficacy [3,4].
From the *Sections of Neurology and †Neurosurgery; Children’s Mercy Hospital; Kansas City, Missouri.
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PEDIATRIC NEUROLOGY
Vol. 19 No. 1
Almost all medications useful in the treatment of epilepsy have a risk for adversity, and many times these adversities preclude their further use [5,6]. We have used VNS in 24 children with pharmacoresistant epilepsy and have accumulated a total of 61 patient years of experience with it. Twelve of these patients have maintained more than a 50% reduction in seizure frequency after more than 1 year of stimulation. Several patients encountered adversities during the stimulation, frequently requiring unexpected surgery and general anesthesia. The authors report the frequency and nature of these adverse events herein.
Methods Using a previously described procedure [7] and after obtaining informed consent from the families of these patients, generators were implanted subcutaneously in the anterior chest wall. Twenty patients (aged 4 to 18 years) were followed in a compassionate-use protocol, and four were part of a double-blinded placebo-controlled protocol [8]. One day to 2 weeks after the surgical implantation the generator was activated by a computer-driven wand held against it. Initially the generators were set to deliver about 1 mA of current, depending on tolerance, for 30 seconds, and then were off for 5 minutes, 24 hours a day. Patients were followed monthly for the first year and then biannually. The current was increased over time, depending on tolerance, and several patients were converted to more rapid cycles (e.g., 13 seconds on and 1 minute off) when the initial improvement seemed inadequate to the investigators and/or the family. Generators were removed at the request of the families of the patients or when there was failure to demonstrate benefit either under standard stimulation parameters or with rapid cycling. The helical vagal nerve clips remained attached to the left vagal nerve after generator removal. The number of months of implantation for each patient was combined to calculate the total months of experience. Adverse events were accumulated by reviewing the 24 patient records. Adverse events were defined as clinically significant, unexpected events occurring as a result of implantation and stimulation. A vocal change when the device was delivering current was generally not reported as an adverse event because it was expected in verbal patients.
Communications should be addressed to: Dr. Murphy; Children’s Mercy Hospital; 2401 Gillham Road; Kansas City, MO 64108. Received September 12, 1997; accepted January 20, 1998.
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00013-7 ● 0887-8994/98/$19.00
Table 1.
Clinical features of patients encountering adverse events during vagal nerve stimulation
Patient No.
Age (Years) at Implantation
MR
Seizure Type
Etiology
Months of Stimulation to Event (Total)
1 2 3 4 5 6 7 8
7 10 5 15 9 15 19 15
No Yes Yes No No No Yes Yes
SP CP GTC CP CP Abs, GTC PC CP
Malformation Idiopathic Postimmunization Malformation Idiopathic Idiopathic Idiopathic Encephalitis
31 (40) 22 (47) 35 (58) 38 (60) 36 (53) 1 (14) 2 (31) 3 (24)
Lead fracture Lead fracture Lead fracture Lead fracture Lead fracture Wound erythema Wound erythema Abscess
Yes Yes Yes Yes Yes Yes Yes Yes
9 6 4 10 4 11 12
5 15 15 14 15 16 15
No No No Yes No No No
GTC Abs, GTC CP GTC CP CP CP
Idiopathic Idiopathic Malformation Idiopathic Malformation Idiopathic Idiopathic
21 (21) 24 (24) 15 (60) 10 (39) 42 (60) 5 (20) 21 (27)
Removal requested Removal requested Generator malfunction Gastrostomy Pregnancy Recurrent psychosis Inaudible during stimulation
Yes Yes Yes Possibly Possibly Possibly Yes
Abbreviations: Abs 5 Absence CP 5 Complex partial GTC 5 Generalized tonic-clonic
Related to VNS
Adverse Event
Outcome Replace leads Replace leads Replace leads Replace leads Replace leads Oral antibiotics Oral antibiotics Device removal Intravenous antibiotics Device replacement Device removal Device removal Replacement Continuation Termination Psychiatric therapy Magnet inactivation during calls
MR 5 Mental retardation PC 5 Partial complex SP 5 Simple partial
Results Twenty-four patients were stimulated for a total of 61 years up to the time of chart reviews. The 15 adverse events, occurring in 11 patients, are summarized in Table 1. Patient 4 had three adversities, and Patients 6 and 9 each had two. Five patients (4 male, 1 female) had lead fractures not associated with any known trauma. Four of these had an older, more fragile lead, and one had a newer, hardier lead. These were discovered on x-ray taken when the device started to fail. All were replaced under general anesthesia without adversity. Two patients had postoperative wound erythema that resolved with oral antibiotic use. One patient (No. 8) developed an abscess around the generator and leads that did not resolve with parenteral antibiotics. She underwent device removal, another 4 weeks of parenteral antibiotics, and reimplantation 10 days later. During this month seizure frequency increased, but the intensity did not revert to that noted before implantation. Two patients and/or their families requested removal of the generator despite demonstrated reduction in seizure frequency, resulting in unexpected surgery. One was a thin 5-year-old girl (No. 9) in whom the device created a cosmetic defect on the chest wall (according to the parents), and the other was a frequently noncompliant teenager (No. 6) who desired more control over her therapy. One generator unexplicably failed to function after 1
year and was replaced (No. 4). One severely impaired child underwent placement of a feeding gastrostomy during VNS. Further studies (i.e., barium-contrast swallow studies) are being done to see if this is a device-related adversity. One 16-year-old patient (No. 4) became pregnant during VNS. The pregnancy may have been indirectly related to VNS because it became possible only with improved seizure control and subsequent social acceptance by her peers. Acute psychosis occurred in a teenager with a positive history of psychosis after an incredible 2-week seizure-free period. Possibly the daily convulsions were therapeutic for his psychosis. Therefore, VNS provided seizure control and led to expression of his psychosis. Patient 11 is a soft-spoken teenager whose speech volume was further diminished when the stimulation occurred. The device was turned off, and frequent seizures and status epilepticus occurred. Resumption of stimulation provided excellent seizure control. We advised temporary inactivation with an overlying magnet when necessary (e.g., when on the telephone).
Discussion In summary, during these 46 months of observation, 15 possible adverse events occurred. The emergence of psychotic behavior in one patient and pregnancy in another may have been indirectly related to VNS because the prior frequent seizures prevented the occurrence of these behav-
Murphy et al: Vagal Nerve Stimulation 43
iors. The placement of feeding gastrostomies in one patient could have caused interruption of the normal vagal influence on swallowing or may have been a coincidental event. Barium cineswallow studies are being done to answer this question. The remaining adverse events appear directly related to VNS. Therefore, of the 15 possible adverse events, two are indirectly related, two are possibly related, and 13 are definitely related. Regarding the severity of these adverse events, 11 surgical procedures under general anesthesia were required for their resolution. These included one gastrostomy, five lead replacements, two requested generator removals, one replacement of a faulty generator, and one device removal and placement of an indwelling venous line and (5 weeks later) generator replacement. The single pregnancy was voluntarily terminated, and the psychotic patient is under psychiatric care. Most adverse events during drug therapy require either drug withdrawal or tolerance of the adverse events [5,6]. In this series, in only 2 of 16 adverse events (i.e., the requested device removal) was VNS terminated. Thirteen adverse events were resolved surgically, resulting in continued use of VNS. Although surgically correctable, this does add to the expense of this therapy, and the unforeseen general anesthesia carries the risk of further complications. Based on the results of this small series, VNS appears tolerable in children. Clinically related adverse events
44
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were correctable, but many required general anesthesia and surgical intervention.
References [1] Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. First International Vagus Nerve Study Group. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. Epilepsia 1994;35:616-26. [2] Ramsay RE, Uthman BM, Augustinsson LE, et al. First International Vagus Nerve Stimulation Study Group. Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects and tolerability. Epilepsia 1994;35;627-36. [3] Murphy JV, Hornig G, Schallert G. Left vagal nerve stimulation in children with refractory epilepsy: Preliminary observations. Arch Neurol 1995;52;886-9. [4] Hornig G, Murphy JV, Schallert G. Left vagal nerve stimulation in children with refractory epilepsy: An update. South Med J 1997;90; 484-8. [5] Pellock JM, Pippenger CE. Adverse effects of antiepileptic drugs. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy diagnosis and therapy. New York: Demos Publications, 1993:253-64. [6] Dooley J, Camfield P, Gordon K, Camfield C, Wirrell E, Smith E. Lamotrigine-induced rash in children. Neurology 1996;46;240-2. [7] Reid SA. Surgical technique for implantation of the neurocybernetic prosthesis. Epilepsia 1990;31(suppl 2):S38-9. [8] Degiorgio C, Heck C, Smith T, Duffel W. Randomised doubleblind study of vagus nerve stimulation in intractable partial seizures: The USC experience and the EUS study group (abstract). Epilepsia 1997; 38(suppl 3):245.
Introduction Periodic stimulation of the left vagal nerve as adjunctive therapy in patients with pharmacoresistant partial seizures has been shown in blinded and controlled studies to be effective in reducing the frequency of partial seizures in older children and adults with pharmacoresistant epilepsy [1,2]. Stimulation is performed by an implanted generator with leads to the left vagal nerve. Recently this intervention was approved by the Food and Drug Administration for use in such a population. Observations of the use of vagal nerve stimulation (VNS) in children suggest similar efficacy [3,4].
From the *Sections of Neurology and †Neurosurgery; Children’s Mercy Hospital; Kansas City, Missouri.
42
PEDIATRIC NEUROLOGY
Vol. 19 No. 1
Almost all medications useful in the treatment of epilepsy have a risk for adversity, and many times these adversities preclude their further use [5,6]. We have used VNS in 24 children with pharmacoresistant epilepsy and have accumulated a total of 61 patient years of experience with it. Twelve of these patients have maintained more than a 50% reduction in seizure frequency after more than 1 year of stimulation. Several patients encountered adversities during the stimulation, frequently requiring unexpected surgery and general anesthesia. The authors report the frequency and nature of these adverse events herein.
Methods Using a previously described procedure [7] and after obtaining informed consent from the families of these patients, generators were implanted subcutaneously in the anterior chest wall. Twenty patients (aged 4 to 18 years) were followed in a compassionate-use protocol, and four were part of a double-blinded placebo-controlled protocol [8]. One day to 2 weeks after the surgical implantation the generator was activated by a computer-driven wand held against it. Initially the generators were set to deliver about 1 mA of current, depending on tolerance, for 30 seconds, and then were off for 5 minutes, 24 hours a day. Patients were followed monthly for the first year and then biannually. The current was increased over time, depending on tolerance, and several patients were converted to more rapid cycles (e.g., 13 seconds on and 1 minute off) when the initial improvement seemed inadequate to the investigators and/or the family. Generators were removed at the request of the families of the patients or when there was failure to demonstrate benefit either under standard stimulation parameters or with rapid cycling. The helical vagal nerve clips remained attached to the left vagal nerve after generator removal. The number of months of implantation for each patient was combined to calculate the total months of experience. Adverse events were accumulated by reviewing the 24 patient records. Adverse events were defined as clinically significant, unexpected events occurring as a result of implantation and stimulation. A vocal change when the device was delivering current was generally not reported as an adverse event because it was expected in verbal patients.
Communications should be addressed to: Dr. Murphy; Children’s Mercy Hospital; 2401 Gillham Road; Kansas City, MO 64108. Received September 12, 1997; accepted January 20, 1998.
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00013-7 ● 0887-8994/98/$19.00
Table 1.
Clinical features of patients encountering adverse events during vagal nerve stimulation
Patient No.
Age (Years) at Implantation
MR
Seizure Type
Etiology
Months of Stimulation to Event (Total)
1 2 3 4 5 6 7 8
7 10 5 15 9 15 19 15
No Yes Yes No No No Yes Yes
SP CP GTC CP CP Abs, GTC PC CP
Malformation Idiopathic Postimmunization Malformation Idiopathic Idiopathic Idiopathic Encephalitis
31 (40) 22 (47) 35 (58) 38 (60) 36 (53) 1 (14) 2 (31) 3 (24)
Lead fracture Lead fracture Lead fracture Lead fracture Lead fracture Wound erythema Wound erythema Abscess
Yes Yes Yes Yes Yes Yes Yes Yes
9 6 4 10 4 11 12
5 15 15 14 15 16 15
No No No Yes No No No
GTC Abs, GTC CP GTC CP CP CP
Idiopathic Idiopathic Malformation Idiopathic Malformation Idiopathic Idiopathic
21 (21) 24 (24) 15 (60) 10 (39) 42 (60) 5 (20) 21 (27)
Removal requested Removal requested Generator malfunction Gastrostomy Pregnancy Recurrent psychosis Inaudible during stimulation
Yes Yes Yes Possibly Possibly Possibly Yes
Abbreviations: Abs 5 Absence CP 5 Complex partial GTC 5 Generalized tonic-clonic
Related to VNS
Adverse Event
Outcome Replace leads Replace leads Replace leads Replace leads Replace leads Oral antibiotics Oral antibiotics Device removal Intravenous antibiotics Device replacement Device removal Device removal Replacement Continuation Termination Psychiatric therapy Magnet inactivation during calls
MR 5 Mental retardation PC 5 Partial complex SP 5 Simple partial
Results Twenty-four patients were stimulated for a total of 61 years up to the time of chart reviews. The 15 adverse events, occurring in 11 patients, are summarized in Table 1. Patient 4 had three adversities, and Patients 6 and 9 each had two. Five patients (4 male, 1 female) had lead fractures not associated with any known trauma. Four of these had an older, more fragile lead, and one had a newer, hardier lead. These were discovered on x-ray taken when the device started to fail. All were replaced under general anesthesia without adversity. Two patients had postoperative wound erythema that resolved with oral antibiotic use. One patient (No. 8) developed an abscess around the generator and leads that did not resolve with parenteral antibiotics. She underwent device removal, another 4 weeks of parenteral antibiotics, and reimplantation 10 days later. During this month seizure frequency increased, but the intensity did not revert to that noted before implantation. Two patients and/or their families requested removal of the generator despite demonstrated reduction in seizure frequency, resulting in unexpected surgery. One was a thin 5-year-old girl (No. 9) in whom the device created a cosmetic defect on the chest wall (according to the parents), and the other was a frequently noncompliant teenager (No. 6) who desired more control over her therapy. One generator unexplicably failed to function after 1
year and was replaced (No. 4). One severely impaired child underwent placement of a feeding gastrostomy during VNS. Further studies (i.e., barium-contrast swallow studies) are being done to see if this is a device-related adversity. One 16-year-old patient (No. 4) became pregnant during VNS. The pregnancy may have been indirectly related to VNS because it became possible only with improved seizure control and subsequent social acceptance by her peers. Acute psychosis occurred in a teenager with a positive history of psychosis after an incredible 2-week seizure-free period. Possibly the daily convulsions were therapeutic for his psychosis. Therefore, VNS provided seizure control and led to expression of his psychosis. Patient 11 is a soft-spoken teenager whose speech volume was further diminished when the stimulation occurred. The device was turned off, and frequent seizures and status epilepticus occurred. Resumption of stimulation provided excellent seizure control. We advised temporary inactivation with an overlying magnet when necessary (e.g., when on the telephone).
Discussion In summary, during these 46 months of observation, 15 possible adverse events occurred. The emergence of psychotic behavior in one patient and pregnancy in another may have been indirectly related to VNS because the prior frequent seizures prevented the occurrence of these behav-
Murphy et al: Vagal Nerve Stimulation 43
iors. The placement of feeding gastrostomies in one patient could have caused interruption of the normal vagal influence on swallowing or may have been a coincidental event. Barium cineswallow studies are being done to answer this question. The remaining adverse events appear directly related to VNS. Therefore, of the 15 possible adverse events, two are indirectly related, two are possibly related, and 13 are definitely related. Regarding the severity of these adverse events, 11 surgical procedures under general anesthesia were required for their resolution. These included one gastrostomy, five lead replacements, two requested generator removals, one replacement of a faulty generator, and one device removal and placement of an indwelling venous line and (5 weeks later) generator replacement. The single pregnancy was voluntarily terminated, and the psychotic patient is under psychiatric care. Most adverse events during drug therapy require either drug withdrawal or tolerance of the adverse events [5,6]. In this series, in only 2 of 16 adverse events (i.e., the requested device removal) was VNS terminated. Thirteen adverse events were resolved surgically, resulting in continued use of VNS. Although surgically correctable, this does add to the expense of this therapy, and the unforeseen general anesthesia carries the risk of further complications. Based on the results of this small series, VNS appears tolerable in children. Clinically related adverse events
44
PEDIATRIC NEUROLOGY
Vol. 19 No. 1
were correctable, but many required general anesthesia and surgical intervention.
References [1] Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. First International Vagus Nerve Study Group. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. Epilepsia 1994;35:616-26. [2] Ramsay RE, Uthman BM, Augustinsson LE, et al. First International Vagus Nerve Stimulation Study Group. Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects and tolerability. Epilepsia 1994;35;627-36. [3] Murphy JV, Hornig G, Schallert G. Left vagal nerve stimulation in children with refractory epilepsy: Preliminary observations. Arch Neurol 1995;52;886-9. [4] Hornig G, Murphy JV, Schallert G. Left vagal nerve stimulation in children with refractory epilepsy: An update. South Med J 1997;90; 484-8. [5] Pellock JM, Pippenger CE. Adverse effects of antiepileptic drugs. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy diagnosis and therapy. New York: Demos Publications, 1993:253-64. [6] Dooley J, Camfield P, Gordon K, Camfield C, Wirrell E, Smith E. Lamotrigine-induced rash in children. Neurology 1996;46;240-2. [7] Reid SA. Surgical technique for implantation of the neurocybernetic prosthesis. Epilepsia 1990;31(suppl 2):S38-9. [8] Degiorgio C, Heck C, Smith T, Duffel W. Randomised doubleblind study of vagus nerve stimulation in intractable partial seizures: The USC experience and the EUS study group (abstract). Epilepsia 1997; 38(suppl 3):245.