Novel Insights from Clinical Practice Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
Received: July 24, 2014 Accepted after revision: November 19, 2014 Published online: April 17, 2015
Intrathecal Morphine Therapy in the Management of Status Dystonicus in Neurodegeneration Brain Iron Accumulation Type 1 William Omar Contreras Lopez Humberto Kluge Schroeder Iuri Santana Neville Manoel Jacobsen Teixeira Danilo Costa Barbosa Bernardo Assumpçao de Mônaco Erich Talamoni Fonoff Division of Functional Neurosurgery, Institute of Psychiatry, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil
Established Facts • Neurodegeneration with brain iron accumulation type 1 is characterized by progressive extrapyramidal dysfunction and dementia. • Status dystonicus treatment is mainly empirical and many cases may be refractory to standard drug therapy requiring the use of continuous infusion of intrathecal baclofen and other neurosurgery procedures. • Continuous intrathecal infusion of baclofen may reduce dystonia up to 20% of the time, nevertheless concerns for baclofen tolerance as well as limited availability in some countries remain an issue.
Novel Insights • A successful intrathecal test of morphine in the case of rapid-onset progressive dystonia is in favor of definitive intrathecal morphine therapy before considering intracranial surgery.
Abstract Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pal-
© 2015 S. Karger AG, Basel 1016–2291/15/0502–0094$39.50/0 E-Mail [email protected] www.karger.com/pne
lidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal
W.O.C.L. and H.K.S. contributed equally as first authors.
Erich Talamoni Fonoff, MD, PhD Division of Neurosurgery, Department of Neurology, School of Medicine University of São Paulo, Rua Dr. Ovídio Pires de Campos, 785 São Paulo 01060-970 (Brazil) E-Mail fonoffet @ usp.br
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/11/2015 3:08:22 AM
Key Words Neurodegeneration with brain iron accumulation type 1 · Status dystonicus · Deep brain stimulation · Intrathecal baclofen therapy · Intrathecal morphine therapy
morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient’s motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1. © 2015 S. Karger AG, Basel
Introduction
Neurodegeneration with brain iron accumulation (NBIA-1) encompasses a group of progressive extrapyramidal disorders characterized by iron accumulation in the brain, mostly in the globus pallidus. The term NBIA1, now widely used in the medical literature, is sufficiently broad to encompass the spectrum of disorders previously called Hallervorden-Spatz syndrome as well as additional disorders of high brain iron [1, 2]. The major form of NBIA-1 is a pantothenate kinase-associated neurodegeneration caused by mutations in the PANK2 gene located on the short arm of chromosome 20 (20p13) [1– 3]. Clinical presentation most commonly begins in the first two decades of life but should be considered in the differential diagnosis of patients at any age with an atypical progressive extrapyramidal disorder and cognitive
impairment [4, 5]. The characteristic hallmark is the symmetric destruction of the globus pallidus and the deposition of ferrocalcium pigment. These changes can also be depicted on T2-weighted magnetic resonance imaging (MRI) as the eye-of-the-tiger sign [6]. Many patients occasionally develop severe episodes of generalized dystonia and muscle contractions with rigidity – status dystonicus (SD) – which is refractory to standard drug therapy. The most severe cases develop bulbar complications and complications of ventilation. Refractory SD cases may benefit from surgical treatment: pallidotomy, deep brain stimulation of the globus pallidus internal segment or intrathecal baclofen (ITB) therapy [7–9]. We describe a patient with intractable dystonia, secondary to NBIA-1, who developed SD and was treated with intrathecal morphine therapy (IMT) after facing a lack of baclofen due to discontinuous commercial availability and a successful intrathecal morphine test.
Case Report A 14-year-old male presented to our clinic with the typical clinical features of NBIA-1. There was a family history of consanguinity, his parents were first-degree relatives. Initial psychomotor development was normal. At the age of 6, he started to present frequent falls and difficulty moving the right arm. At the age of 8, dystonic movements were progressively present, primarily in the upper right arm, involving posteriorly all four limbs associated with frequent dystonic spasms of the face and limbs. Difficulty to walk was already severe by this time and MRI imaging revealed bilateral globus pallidus lesions with the classic eye-of-the-tiger sign typical of Hallervorden-Spatz syndrome (fig. 1). Molecular
Fig. 1. MRI showing a typical presentation. a T1-weighted. The characteristic hallmark
Intrathecal Morphine for Status Dystonicus
a
b
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
95
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/11/2015 3:08:22 AM
is the symmetric destruction of the globus pallidus and the deposition of ferrocalcium pigment. b These changes can also be depicted on T2-weighted MRI as the eye-ofthe-tiger sign. This abnormal iron accumulation is seen as a diffuse and bilateral low T2-weighted signal intensity in the globus pallidus (internal and external segments) surrounding a central area of high T2weighted signal intensity in the anteromedial globus pallidus corresponding to neuronal loss and gliosis.
Color version available online
a
b
Fig. 2. a Preoperative state. b Postoperative state after 10 months. The patient’s posture progressively improved
until he was able to sit in a wheelchair for the first time in his life.
96
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
One week after surgery, there was a significant decrease in dystonia with global motor improvement. Less than 1 month later, the patient was able to go home using a wheelchair, and to get back to ambulatory physical and speech therapies. Painful spasms diminished in intensity. He did not recover independent gait, but did not require further hospitalization for the next 6 months, being controlled with medication only. On the Global Dystonia Severity Rating Scale, he achieved 52% improvement, 30% on the Unified Dystonia Rating Scale and 38% after 10 months on the Fahn-Marsden Rating Scale (fig. 2b). At this time, the dose was 1.7 mg/day.
Discussion
NBIA-1 associated with SD represents a treatment challenge. In the pediatric age range, SD has a poor prognosis with the prospect of prolonged ventilation and high morbidity and mortality [10, 11]. SD treatment is mainly empirical, variable and collected from anecdotal reports. Many cases may be refractory to standard drug therapy requiring use of continuous infusion of intrathecal drugs, i.e. baclofen, and other neurosurgery procedures, including pallidotomy or deep brain stimulation of the globus pallidus internus [9–12]. Since the late 1980s, ITB therapy has become the standard treatment for severe generalized spasticity and dysLopez et al.
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/11/2015 3:08:22 AM
genetic analysis did not reveal mutations in the PANK2. He was diagnosed with NBIA-1 and was treated with a combination of anticholinergic agents and benzodiazepines. By the age of 11, symptoms rapidly progressed to a severe generalized dystonia with opisthotonus (fig. 2a). At 12, he was unable to sit and talk. By 14, significant deterioration of dystonic symptoms supervened with severe episodes of generalized dystonia and rigidity (SD), which were refractory to drug therapy, requiring continuous midazolam infusion and mechanical ventilation assistance. He was admitted to the intensive care unit because of risk of respiratory and metabolic complications and was submitted to tracheostomy and gastrostomy. ITB therapy was proposed, however, we faced difficult access to medicines, which is a public health problem throughout our country. These characteristics pose several challenges not only in Brazil but for most developing countries, where access to medicines is a problem as accomplishing the authorization from the public health system for delivering some categories of expensive medications to the users is almost impossible. Approval of public health payment is limited in the case of some specific medicaments, mainly those for chronic use such as baclofen. An intrathecal morphine test was then decided and performed, with a positive response, leading to the implantation of a definitive IMT pump. A SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) was implanted with an intrathecal catheter placed at the mid-thoracic spine level D7. By protocol we implant the tip of the catheter in the thoracic spine due to early complications that occurred with catheters placed at cervical spine level in the case of morphine. Vomiting and respiratory depression were not a rare problem for those patients. Baclofen on the other hand is more suitable for cervical implants. Initial morphine dosage was 1.0 mg/day.
tonia in children. ITB decreases generalized secondary dystonia and has been associated with improved comfort and ease of care in approximately 85% and with improved function in about 33% of patients. Continued effectiveness of ITB in treating spasticity has been observed for up to 17 years, and its effectiveness in treating dystonia has been observed for up to 10 years. ITB therapy is associated with complications such as infections, catheter malfunction, and cerebrospinal fluid leaks; however, benefits outweigh the risks [13]. The use of intraventricular baclofen as an alternative to ITB has been reported by Rocque et al. [14] in 2012 in a case series of 2 patients, in the first one of whom placement of an intrathecal catheter was deemed too technically difficult due to a short and lordotic neck and existence of a previous spinal fusion. The second case was a patient with severe dystonia who had not responded to ITB. The first patient responded well while the second had minimal response. Baclofen is an agonist of γ-aminobutyric acid-B (GABA-B) receptors. It is believed that it acts primarily at the level of the spinal cord by binding to GABA receptors which are located in the superficial layer of the dorsal gray matter in the spinal cord [15, 16]. Nevertheless, concern for baclofen tolerance remains a problem [15], demanding the progressive escalation of the doses to obtain the same effective outcome. The availability and costs of the medicament may also play a role in choosing such a treatment in some countries and poor geographic areas. Morphine, on the other hand, has a greater availability, lower costs and less tolerance when compared to bac-
lofen. Continuous intrathecal morphine has been traditionally successful when used intrathecally for the treatment of untreatable chronic benign pain. IMT has also been reported to be useful for the treatment of spinal cord injury spasticity [17]. Erickson et al. [18], Penn and Kroin [19], and Soni [20] have reported the use of morphine sulfate given intrathecally to reduce spasticity, raising the possibility of switching medicines to intrathecal morphine in the case of facing a significant tolerance to baclofen. The primary site of action of intrathecal morphine is in the neuron pool of the dorsal horn [18]. Morphine is receptor-specific and primarily influences the multisynaptic reflexes associated with A delta or C fiber stimulation with little or no effect on the monosynaptic segmental reflex [18]. Therefore in addition to blocking afferent pain transmission, the reflex arc contributing to spasticity might also be inhibited by morphine [18]. The rationale behind IMT is that it may substantially reduce the intensity of painful spasms, lowering the need for oral medication. It is postulated to diminish spasticity by acting as an inhibitory GABA agonist at the level of the spinal cord [11]. We report a favorable response in a child with SD due to NBIA-1 treated with IMT. IMT seems to be a good alternative in the case of an untreatable rapidly progressive form of dystonia and may be considered in resistant SD cases before intracranial surgery. However, trials with larger a population on a long-term basis are required.
References
Intrathecal Morphine for Status Dystonicus
6
7
8
9
going deep brain stimulation. Dev Med Child Neurol 2011;53:275–279. Baumeister FAM, Auer DP, Hörtnagel K, Freisinger P, Meitinger T: The eye-of-the-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome. Neuropediatrics 2005;36:221–222. Mikati MA, Yehya A, Darwish H, Karam P, Comair Y: Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration. Eur J Paediatr Neurol 2009;13:61–64. Umemura A, Jaggi JL, Dolinskas CA, Stern MB, Baltuch GH: Pallidal deep brain stimulation for longstanding severe generalized dystonia in Hallervorden-Spatz syndrome. Case report. J Neurosurg 2004;100:706–709. Justesen CR, Penn RD, Kroin JS, Egel RT: Stereotactic pallidotomy in a child with Haller-
10
11
12
13
vorden-Spatz disease. Case report. J Neurosurg 1999;90:551–554. Manji H, Howard RS, Miller DH, Hirsch NP, Carr L, Bhatia K, et al: Status dystonicus: the syndrome and its management. Brain 1998; 121:243–252. Kyriagis M, Grattan-Smith P, Scheinberg A, Teo C, Nakaji N, Waugh M: Status dystonicus and Hallervorden-Spatz disease: treatment with intrathecal baclofen and pallidotomy. J Paediatr Child Health 2004; 40: 322– 325. Teive HAG, Munhoz RP, Souza MM, Antoniuk SA, Santos MLSF, Teixeira MJ, et al: Status dystonicus: study of five cases. Arq Neuropsiquiatr 2005;63:26–29. Albright AL, Ferson SS: Intrathecal baclofen therapy in children. Neurosurg Focus 2006; 21:e3.
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
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1 Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KHL, et al: Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003 2;348:33–40. 2 Gregory A, Polster BJ, Hayflick SJ: Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46:73–80. 3 Sachin S, Goyal V, Singh S, Shukla G, Sharma MC, Gaikwed S, et al: Clinical spectrum of Hallervorden-Spatz syndrome in India. J Clin Neurosci 2009;16:253–258. 4 Diaz N: Late onset atypical pantothenate-kinase-associated neurodegeneration. Case Rep Neurol Med 2013;2013:860201. 5 Mahoney R, Selway R, Lin J-P: Cognitive functioning in children with pantothenatekinase-associated neurodegeneration under-
98
16 Ankman MN, et al: Intrathecal baclofen: does tolerance occur. Paraplegia 1993;31:516–520. 17 Soni BM, Mani RM, Oo T, Vaidyanathan S: Treatment of spasticity in a spinal cord-injured patient with intrathecal morphine due to intrathecal baclofen tolerance – a case report and review of literature. Spinal Cord 2003;41:586–589. 18 Erickson DL, et al: Control of spasticity by implantable continuous flow morphine pump. Neurosurgery 1985;16:215–217.
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
19 Penn RD, Kroin JS: Long-term intrathecal baclofen infusion for treatment of spasticity. J Neurosurg 1987;66:181–185. 20 Soni BM: Management of spasticity – Southport experience; in Pedotti A, Ferrarin M, Quintern J, Riener R (eds): Neuroprosthetics from Basic Research to Clinical Applications. Berlin, Springer, 1996, pp 469–479.
Lopez et al.
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14 Rocque BG, Leland Albright A: Intraventricular vs intrathecal baclofen for secondary dystonia: a comparison of complications. Neurosurgery 2012;70(2 suppl Operative):321–325; discussion 325–326. 15 Chabal C, Jacobson L, Terman G: Intrathecal fentanyl alleviates spasticity in the presence of tolerance to intrathecal baclofen. Anesthesiology 1992;76:312–314.
Received: July 24, 2014 Accepted after revision: November 19, 2014 Published online: April 17, 2015
Intrathecal Morphine Therapy in the Management of Status Dystonicus in Neurodegeneration Brain Iron Accumulation Type 1 William Omar Contreras Lopez Humberto Kluge Schroeder Iuri Santana Neville Manoel Jacobsen Teixeira Danilo Costa Barbosa Bernardo Assumpçao de Mônaco Erich Talamoni Fonoff Division of Functional Neurosurgery, Institute of Psychiatry, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil
Established Facts • Neurodegeneration with brain iron accumulation type 1 is characterized by progressive extrapyramidal dysfunction and dementia. • Status dystonicus treatment is mainly empirical and many cases may be refractory to standard drug therapy requiring the use of continuous infusion of intrathecal baclofen and other neurosurgery procedures. • Continuous intrathecal infusion of baclofen may reduce dystonia up to 20% of the time, nevertheless concerns for baclofen tolerance as well as limited availability in some countries remain an issue.
Novel Insights • A successful intrathecal test of morphine in the case of rapid-onset progressive dystonia is in favor of definitive intrathecal morphine therapy before considering intracranial surgery.
Abstract Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pal-
© 2015 S. Karger AG, Basel 1016–2291/15/0502–0094$39.50/0 E-Mail [email protected] www.karger.com/pne
lidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal
W.O.C.L. and H.K.S. contributed equally as first authors.
Erich Talamoni Fonoff, MD, PhD Division of Neurosurgery, Department of Neurology, School of Medicine University of São Paulo, Rua Dr. Ovídio Pires de Campos, 785 São Paulo 01060-970 (Brazil) E-Mail fonoffet @ usp.br
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/11/2015 3:08:22 AM
Key Words Neurodegeneration with brain iron accumulation type 1 · Status dystonicus · Deep brain stimulation · Intrathecal baclofen therapy · Intrathecal morphine therapy
morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient’s motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1. © 2015 S. Karger AG, Basel
Introduction
Neurodegeneration with brain iron accumulation (NBIA-1) encompasses a group of progressive extrapyramidal disorders characterized by iron accumulation in the brain, mostly in the globus pallidus. The term NBIA1, now widely used in the medical literature, is sufficiently broad to encompass the spectrum of disorders previously called Hallervorden-Spatz syndrome as well as additional disorders of high brain iron [1, 2]. The major form of NBIA-1 is a pantothenate kinase-associated neurodegeneration caused by mutations in the PANK2 gene located on the short arm of chromosome 20 (20p13) [1– 3]. Clinical presentation most commonly begins in the first two decades of life but should be considered in the differential diagnosis of patients at any age with an atypical progressive extrapyramidal disorder and cognitive
impairment [4, 5]. The characteristic hallmark is the symmetric destruction of the globus pallidus and the deposition of ferrocalcium pigment. These changes can also be depicted on T2-weighted magnetic resonance imaging (MRI) as the eye-of-the-tiger sign [6]. Many patients occasionally develop severe episodes of generalized dystonia and muscle contractions with rigidity – status dystonicus (SD) – which is refractory to standard drug therapy. The most severe cases develop bulbar complications and complications of ventilation. Refractory SD cases may benefit from surgical treatment: pallidotomy, deep brain stimulation of the globus pallidus internal segment or intrathecal baclofen (ITB) therapy [7–9]. We describe a patient with intractable dystonia, secondary to NBIA-1, who developed SD and was treated with intrathecal morphine therapy (IMT) after facing a lack of baclofen due to discontinuous commercial availability and a successful intrathecal morphine test.
Case Report A 14-year-old male presented to our clinic with the typical clinical features of NBIA-1. There was a family history of consanguinity, his parents were first-degree relatives. Initial psychomotor development was normal. At the age of 6, he started to present frequent falls and difficulty moving the right arm. At the age of 8, dystonic movements were progressively present, primarily in the upper right arm, involving posteriorly all four limbs associated with frequent dystonic spasms of the face and limbs. Difficulty to walk was already severe by this time and MRI imaging revealed bilateral globus pallidus lesions with the classic eye-of-the-tiger sign typical of Hallervorden-Spatz syndrome (fig. 1). Molecular
Fig. 1. MRI showing a typical presentation. a T1-weighted. The characteristic hallmark
Intrathecal Morphine for Status Dystonicus
a
b
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
95
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/11/2015 3:08:22 AM
is the symmetric destruction of the globus pallidus and the deposition of ferrocalcium pigment. b These changes can also be depicted on T2-weighted MRI as the eye-ofthe-tiger sign. This abnormal iron accumulation is seen as a diffuse and bilateral low T2-weighted signal intensity in the globus pallidus (internal and external segments) surrounding a central area of high T2weighted signal intensity in the anteromedial globus pallidus corresponding to neuronal loss and gliosis.
Color version available online
a
b
Fig. 2. a Preoperative state. b Postoperative state after 10 months. The patient’s posture progressively improved
until he was able to sit in a wheelchair for the first time in his life.
96
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
One week after surgery, there was a significant decrease in dystonia with global motor improvement. Less than 1 month later, the patient was able to go home using a wheelchair, and to get back to ambulatory physical and speech therapies. Painful spasms diminished in intensity. He did not recover independent gait, but did not require further hospitalization for the next 6 months, being controlled with medication only. On the Global Dystonia Severity Rating Scale, he achieved 52% improvement, 30% on the Unified Dystonia Rating Scale and 38% after 10 months on the Fahn-Marsden Rating Scale (fig. 2b). At this time, the dose was 1.7 mg/day.
Discussion
NBIA-1 associated with SD represents a treatment challenge. In the pediatric age range, SD has a poor prognosis with the prospect of prolonged ventilation and high morbidity and mortality [10, 11]. SD treatment is mainly empirical, variable and collected from anecdotal reports. Many cases may be refractory to standard drug therapy requiring use of continuous infusion of intrathecal drugs, i.e. baclofen, and other neurosurgery procedures, including pallidotomy or deep brain stimulation of the globus pallidus internus [9–12]. Since the late 1980s, ITB therapy has become the standard treatment for severe generalized spasticity and dysLopez et al.
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/11/2015 3:08:22 AM
genetic analysis did not reveal mutations in the PANK2. He was diagnosed with NBIA-1 and was treated with a combination of anticholinergic agents and benzodiazepines. By the age of 11, symptoms rapidly progressed to a severe generalized dystonia with opisthotonus (fig. 2a). At 12, he was unable to sit and talk. By 14, significant deterioration of dystonic symptoms supervened with severe episodes of generalized dystonia and rigidity (SD), which were refractory to drug therapy, requiring continuous midazolam infusion and mechanical ventilation assistance. He was admitted to the intensive care unit because of risk of respiratory and metabolic complications and was submitted to tracheostomy and gastrostomy. ITB therapy was proposed, however, we faced difficult access to medicines, which is a public health problem throughout our country. These characteristics pose several challenges not only in Brazil but for most developing countries, where access to medicines is a problem as accomplishing the authorization from the public health system for delivering some categories of expensive medications to the users is almost impossible. Approval of public health payment is limited in the case of some specific medicaments, mainly those for chronic use such as baclofen. An intrathecal morphine test was then decided and performed, with a positive response, leading to the implantation of a definitive IMT pump. A SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) was implanted with an intrathecal catheter placed at the mid-thoracic spine level D7. By protocol we implant the tip of the catheter in the thoracic spine due to early complications that occurred with catheters placed at cervical spine level in the case of morphine. Vomiting and respiratory depression were not a rare problem for those patients. Baclofen on the other hand is more suitable for cervical implants. Initial morphine dosage was 1.0 mg/day.
tonia in children. ITB decreases generalized secondary dystonia and has been associated with improved comfort and ease of care in approximately 85% and with improved function in about 33% of patients. Continued effectiveness of ITB in treating spasticity has been observed for up to 17 years, and its effectiveness in treating dystonia has been observed for up to 10 years. ITB therapy is associated with complications such as infections, catheter malfunction, and cerebrospinal fluid leaks; however, benefits outweigh the risks [13]. The use of intraventricular baclofen as an alternative to ITB has been reported by Rocque et al. [14] in 2012 in a case series of 2 patients, in the first one of whom placement of an intrathecal catheter was deemed too technically difficult due to a short and lordotic neck and existence of a previous spinal fusion. The second case was a patient with severe dystonia who had not responded to ITB. The first patient responded well while the second had minimal response. Baclofen is an agonist of γ-aminobutyric acid-B (GABA-B) receptors. It is believed that it acts primarily at the level of the spinal cord by binding to GABA receptors which are located in the superficial layer of the dorsal gray matter in the spinal cord [15, 16]. Nevertheless, concern for baclofen tolerance remains a problem [15], demanding the progressive escalation of the doses to obtain the same effective outcome. The availability and costs of the medicament may also play a role in choosing such a treatment in some countries and poor geographic areas. Morphine, on the other hand, has a greater availability, lower costs and less tolerance when compared to bac-
lofen. Continuous intrathecal morphine has been traditionally successful when used intrathecally for the treatment of untreatable chronic benign pain. IMT has also been reported to be useful for the treatment of spinal cord injury spasticity [17]. Erickson et al. [18], Penn and Kroin [19], and Soni [20] have reported the use of morphine sulfate given intrathecally to reduce spasticity, raising the possibility of switching medicines to intrathecal morphine in the case of facing a significant tolerance to baclofen. The primary site of action of intrathecal morphine is in the neuron pool of the dorsal horn [18]. Morphine is receptor-specific and primarily influences the multisynaptic reflexes associated with A delta or C fiber stimulation with little or no effect on the monosynaptic segmental reflex [18]. Therefore in addition to blocking afferent pain transmission, the reflex arc contributing to spasticity might also be inhibited by morphine [18]. The rationale behind IMT is that it may substantially reduce the intensity of painful spasms, lowering the need for oral medication. It is postulated to diminish spasticity by acting as an inhibitory GABA agonist at the level of the spinal cord [11]. We report a favorable response in a child with SD due to NBIA-1 treated with IMT. IMT seems to be a good alternative in the case of an untreatable rapidly progressive form of dystonia and may be considered in resistant SD cases before intracranial surgery. However, trials with larger a population on a long-term basis are required.
References
Intrathecal Morphine for Status Dystonicus
6
7
8
9
going deep brain stimulation. Dev Med Child Neurol 2011;53:275–279. Baumeister FAM, Auer DP, Hörtnagel K, Freisinger P, Meitinger T: The eye-of-the-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome. Neuropediatrics 2005;36:221–222. Mikati MA, Yehya A, Darwish H, Karam P, Comair Y: Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration. Eur J Paediatr Neurol 2009;13:61–64. Umemura A, Jaggi JL, Dolinskas CA, Stern MB, Baltuch GH: Pallidal deep brain stimulation for longstanding severe generalized dystonia in Hallervorden-Spatz syndrome. Case report. J Neurosurg 2004;100:706–709. Justesen CR, Penn RD, Kroin JS, Egel RT: Stereotactic pallidotomy in a child with Haller-
10
11
12
13
vorden-Spatz disease. Case report. J Neurosurg 1999;90:551–554. Manji H, Howard RS, Miller DH, Hirsch NP, Carr L, Bhatia K, et al: Status dystonicus: the syndrome and its management. Brain 1998; 121:243–252. Kyriagis M, Grattan-Smith P, Scheinberg A, Teo C, Nakaji N, Waugh M: Status dystonicus and Hallervorden-Spatz disease: treatment with intrathecal baclofen and pallidotomy. J Paediatr Child Health 2004; 40: 322– 325. Teive HAG, Munhoz RP, Souza MM, Antoniuk SA, Santos MLSF, Teixeira MJ, et al: Status dystonicus: study of five cases. Arq Neuropsiquiatr 2005;63:26–29. Albright AL, Ferson SS: Intrathecal baclofen therapy in children. Neurosurg Focus 2006; 21:e3.
Pediatr Neurosurg 2014–15;50:94–98 DOI: 10.1159/000370005
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1 Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KHL, et al: Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003 2;348:33–40. 2 Gregory A, Polster BJ, Hayflick SJ: Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46:73–80. 3 Sachin S, Goyal V, Singh S, Shukla G, Sharma MC, Gaikwed S, et al: Clinical spectrum of Hallervorden-Spatz syndrome in India. J Clin Neurosci 2009;16:253–258. 4 Diaz N: Late onset atypical pantothenate-kinase-associated neurodegeneration. Case Rep Neurol Med 2013;2013:860201. 5 Mahoney R, Selway R, Lin J-P: Cognitive functioning in children with pantothenatekinase-associated neurodegeneration under-
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