Parkinsonism and Related Disorders 20 (2014) 1035e1036
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Deep brain stimulation for severe secondary stereotypies Keywords: Stereotypies Deep brain stimulation Autism Movement disorders
Deep brain stimulation (DBS) has proven effective to treat several different hyperkinetic movement disorders. However, to date, the effect of DBS on stereotypies has only been investigated in animal models, but not in humans [1]. Stereotypies can be defined as “a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible” [2]. These movements occur frequently and are part of the triad of autism spectrum disorders, as defined by DSM-5 criteria [3]. We present two cases fulfilling the definition of stereotypies in autism spectrum disorders treated with DBS due to the severe and disabling nature of the movements. Patients were evaluated at baseline and at follow-up with the John's Hopkins motor stereotypy rating scale (JHMRS) [4]. Family members gave written informed consent for the procedures and evaluations. Patient 1 is a 19-year-old woman with a long-life history of mental retardation, and autistic behavior was diagnosed with monosomy 2q and trisomy 20p elsewhere. In addition, the patient also has progressive arthritis, multiple nevi, aggressive behavior as well as frequent and severe stereotypies. These consist of hand flapping and ritualistic repetitive self-injuring “picking” movements, which have been present since infancy. In an attempt to reduce the abnormal movement and behavioral problems, she had been treated with risperidone for three years with limited benefit. However, during the course of treatment she developed tardive dyskinesias and dystonia with orolingual dyskinesias, dystonic jaw opening, facial grimacing, and cervical dystonia with prominent retrocollis that resulted in progressive and severe dysphagia leading to 60 lb weight loss. The patient received treatment with botulinum toxin and tetrabenazine up to 25 mg three times a day, with little benefit and prominent daytime somnolence leading to its discontinuation. Of note, her stereotypes derived no benefit with tetrabenazine. At the age of 19, the patient underwent DBS with electrode implantation in both globus pallidus interna (GPi) without complications, in order to treat her severe and self-injurious stereotypies and her tardive dystonia: at this time the patient was no longer on drug therapy for her abnormal movements. During the programming session a remarkable improvement in her motor stereotypies of 91.3% was noted (Table 1). Additionally, there was a marked improvement in her tardive dystonia and dysphagia and she gained 7 lb in the first few months. The improvement in stereotypies and tardive phenomenon was progressive without clear microlesion http://dx.doi.org/10.1016/j.parkreldis.2014.06.019 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
effect, and has been sustained up to 13 months. A bipolar configuration was used in both GPi electrodes, with pulse width (PW) of 120 ms, frequency 80 Hz, and amplitude up to 3.3 V (Table 1). Patient 2 is an 18-year-old man who was referred for evaluation of autism, profound mental retardation, anxiety and aggressive behavior, present most of his life. The patient developed prominent self-injurious stereotypies, consisting in severe body rocking and repetitive punches of his legs and arms; he also pounds his legs on the floor to the point of losing some toenails, together with frequent spitting, severe self-injury behavior and biting his care givers. Diagnostic approach including karyotype analysis and exome sequencing did not reveal any known chromosomal abnormality or gene mutation. He had received behavioral therapy and had tried several combinations of neuroleptics, selective serotonin-reuptake inhibitors and other anxiolytics, tricyclics, tetrabenazine, benzodiazepines, and mood stabilizers with limited or no benefit. At the age of 17 years, he underwent simultaneous bilateral DBS targeting the anterior limb of the internal capsule (ALIC) and the GPi, in an attempt to control his stereotypies and avoid institutionalization. At DBS implantation the patient was no longer on pharmacological therapy. An initial improvement of 71.6% in the JHMRS was gradually noted (67 vs. 19) within 3 months after the surgery with the following DBS settings: bilateral bipolar ALIC at 2.0 V, PW: 210 ms and frequency: 100 Hz, and bilateral bipolar GPi at 2.5 V, PW: 120 ms and frequency: 100 Hz. However, after 6 months, stereotypies slowly returned to baseline, even after trying several combinations of settings, configurations and targets (i.e. GPi þ ALIC, or either target alone) (Table 1). The integrity of the system was verified as well as the correct position of the electrodes with brain MRI. Autism is currently thought as a set of neuro-developmental conditions, collectively defined by difficulties in social communications and interactions, as well as restricted, repetitive behavior, interest and activities, including motor stereotypies [3]. The neural bases of stereotypies are not well understood [2]. In monkeys, lesions induced by microinjections of bicuculline in the limbic part of the external globus pallidus (GPe) induced stereotypies, whereas attention deficit and hyperactivity resulted from lesions in the associative parts of the GPe [1]. Stimulation of the anterior part of the STN suppressed the stereotypies in a similar animal model [1]. However, stimulation of the limbic part of the STN in humans has been associated with neuropsychological side effects that may potentially overcome a theoretical improvement in motor stereotypies. Injection of dopamine D1 receptor agonists in the striatum, nucleus accumbens (NA), bilateral lateral ventricles and ventromedial nucleus of the
1036
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1035e1036
Table 1 John's Hopkins Motor stereotypy rating scale, DBS settings and configurations. Case 1 Presurgery
Case 1 Postsurgery (13 m)
Case 2 Presurgery
Case 2 Postsurgery (3 m)
Case 2 Postsurgery (6 m)
2 5 4 5 30 46
3 4 5 5 50 67
Left ALIC
e
2 2 3 2 10 19 Monopolar 2.5e5.0 V, 120e210 Monopolar 2.5e4.5 V, 120e210 Bipolar 2.0e5.0 V, 100e210 Bipolar 2.0e5.0 V, 100e210
3 4 5 5 50 67
Right ALIC
1 2 1 0 0 4 Bipolar 3.3 V, 120 ms, 80 Hz Bipolar 3.3 V, 120 ms, 80 Hz e
Number (0e3) Frequency (0e5) Intensity (0e5) Interference (0e5) Global impairment (0e50%) Total Right GPi Left GPi
ms, 40e120 Hza ms, 40e120 Hza ms, 80e200 Hza ms, 80e200 Hza
Number (range from 0-none to 3-more than 5 stereotypies); frequency (range from 0-never to 5-always); intensity (range from 0-absent to 5-severe); interference (range from 0-none to 5-severe); and global impairment (range from 0-none to 50-severe); maximum 68 points. a Range of used settings during programming sessions. M: months.
thalamus induces stereotypies in mice [5]. Stereotypies should be differentiated from compulsive behavior triggered by an obsessive thought. It has been argue that the latter represents a goaldirected and “voluntary” movement, differing conceptually from the non-goal directed movements of stereotypies [2]. The lack of movement-related cortical potential in subjects with primary stereotypies suggests that they are originated by mechanisms different from those involved in voluntary control [5]; however, the exact anatomical dysfunction within the cortico-striato-thalamiccortical pathways is unknown. Case 2 gave us the opportunity to explore the independent and combined effect of neurostimulation in the GPi, ALIC and NA; unfortunately for unknown reasons, the effect was transitory and only observed during simultaneous stimulation of both targets. Stimulation of the GPi, ALIC and NA have been used to treat tics and obsessive-compulsive disorder with variable results [6,7], although the pathophysiology of these disorders differ from that of motor stereotypies, the repetitive nature of the movements gave us the rational to explore the ALIC/NA as therapeutic targets. The GPi has also been used with moderate success in patients with dyskinetic cerebral palsy, tardive dyskinesias and dystonia [8,9]. The reason why only one of our patients had a sustained improvement with DBS is unknown. Several possibilities including different pathogenic mechanisms in both patients, diverse stimulation pathways or the coexistence of tardive dyskinesias in case 1, may explain the differing effects of DBS in these patients. In conclusion, GPi DBS may provide relief for disabling, pharmacologically unresponsive, stereotypies in some patients, although other targets should be explored. To our knowledge, this is the first report of DBS for the treatment of severe stereotypies in patients with autistic spectrum disorders. Conflicts of interest The authors have declared no conflict of interest regarding this study.
Acknowledgment None.
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2014.06.019.
References [1] Baup N, Grabli D, Karachi C, Mounayar S, François C, Yelnik J, et al. High-frequency stimulation of the anterior subthalamic nucleus reduces stereotyped behaviors in primates. J Neurosci 2008;28:8785e8. [2] Edwards MJ, Lang AE, Bhatia KP. Stereotypies: a critical appraisal and suggestion of a clinically useful definition. Mov Disord 2012;27:179e85. [3] Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014;383:896e910. [4] Miller JM, Singer HS, Bridges DD, Waranch HR. Behavioral therapy for treatment of stereotypic movements in nonautistic children. J Child Neurol 2006;21: 119e25. [5] Houdayer E, Walthall J, Belluscio BA, Vorbach S, Singer HS, Hallett M. Absent movement-related cortical potentials in children with primary motor stereotypies. Mov Disord 2013. http://dx.doi.org/10.1002/mds.25753.
Amber Stocco Department of Child Neurology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA Fidel Baizabal-Carvallo* Jose Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, The Smith Tower, Suite 1801, 6550 Fannin, Houston, TX 77030, USA * Corresponding author. Tel.: þ1 713 798 5998. E-mail address: [email protected] (J.F. Baizabal-Carvallo).
18 February 2014
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Deep brain stimulation for severe secondary stereotypies Keywords: Stereotypies Deep brain stimulation Autism Movement disorders
Deep brain stimulation (DBS) has proven effective to treat several different hyperkinetic movement disorders. However, to date, the effect of DBS on stereotypies has only been investigated in animal models, but not in humans [1]. Stereotypies can be defined as “a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible” [2]. These movements occur frequently and are part of the triad of autism spectrum disorders, as defined by DSM-5 criteria [3]. We present two cases fulfilling the definition of stereotypies in autism spectrum disorders treated with DBS due to the severe and disabling nature of the movements. Patients were evaluated at baseline and at follow-up with the John's Hopkins motor stereotypy rating scale (JHMRS) [4]. Family members gave written informed consent for the procedures and evaluations. Patient 1 is a 19-year-old woman with a long-life history of mental retardation, and autistic behavior was diagnosed with monosomy 2q and trisomy 20p elsewhere. In addition, the patient also has progressive arthritis, multiple nevi, aggressive behavior as well as frequent and severe stereotypies. These consist of hand flapping and ritualistic repetitive self-injuring “picking” movements, which have been present since infancy. In an attempt to reduce the abnormal movement and behavioral problems, she had been treated with risperidone for three years with limited benefit. However, during the course of treatment she developed tardive dyskinesias and dystonia with orolingual dyskinesias, dystonic jaw opening, facial grimacing, and cervical dystonia with prominent retrocollis that resulted in progressive and severe dysphagia leading to 60 lb weight loss. The patient received treatment with botulinum toxin and tetrabenazine up to 25 mg three times a day, with little benefit and prominent daytime somnolence leading to its discontinuation. Of note, her stereotypes derived no benefit with tetrabenazine. At the age of 19, the patient underwent DBS with electrode implantation in both globus pallidus interna (GPi) without complications, in order to treat her severe and self-injurious stereotypies and her tardive dystonia: at this time the patient was no longer on drug therapy for her abnormal movements. During the programming session a remarkable improvement in her motor stereotypies of 91.3% was noted (Table 1). Additionally, there was a marked improvement in her tardive dystonia and dysphagia and she gained 7 lb in the first few months. The improvement in stereotypies and tardive phenomenon was progressive without clear microlesion http://dx.doi.org/10.1016/j.parkreldis.2014.06.019 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
effect, and has been sustained up to 13 months. A bipolar configuration was used in both GPi electrodes, with pulse width (PW) of 120 ms, frequency 80 Hz, and amplitude up to 3.3 V (Table 1). Patient 2 is an 18-year-old man who was referred for evaluation of autism, profound mental retardation, anxiety and aggressive behavior, present most of his life. The patient developed prominent self-injurious stereotypies, consisting in severe body rocking and repetitive punches of his legs and arms; he also pounds his legs on the floor to the point of losing some toenails, together with frequent spitting, severe self-injury behavior and biting his care givers. Diagnostic approach including karyotype analysis and exome sequencing did not reveal any known chromosomal abnormality or gene mutation. He had received behavioral therapy and had tried several combinations of neuroleptics, selective serotonin-reuptake inhibitors and other anxiolytics, tricyclics, tetrabenazine, benzodiazepines, and mood stabilizers with limited or no benefit. At the age of 17 years, he underwent simultaneous bilateral DBS targeting the anterior limb of the internal capsule (ALIC) and the GPi, in an attempt to control his stereotypies and avoid institutionalization. At DBS implantation the patient was no longer on pharmacological therapy. An initial improvement of 71.6% in the JHMRS was gradually noted (67 vs. 19) within 3 months after the surgery with the following DBS settings: bilateral bipolar ALIC at 2.0 V, PW: 210 ms and frequency: 100 Hz, and bilateral bipolar GPi at 2.5 V, PW: 120 ms and frequency: 100 Hz. However, after 6 months, stereotypies slowly returned to baseline, even after trying several combinations of settings, configurations and targets (i.e. GPi þ ALIC, or either target alone) (Table 1). The integrity of the system was verified as well as the correct position of the electrodes with brain MRI. Autism is currently thought as a set of neuro-developmental conditions, collectively defined by difficulties in social communications and interactions, as well as restricted, repetitive behavior, interest and activities, including motor stereotypies [3]. The neural bases of stereotypies are not well understood [2]. In monkeys, lesions induced by microinjections of bicuculline in the limbic part of the external globus pallidus (GPe) induced stereotypies, whereas attention deficit and hyperactivity resulted from lesions in the associative parts of the GPe [1]. Stimulation of the anterior part of the STN suppressed the stereotypies in a similar animal model [1]. However, stimulation of the limbic part of the STN in humans has been associated with neuropsychological side effects that may potentially overcome a theoretical improvement in motor stereotypies. Injection of dopamine D1 receptor agonists in the striatum, nucleus accumbens (NA), bilateral lateral ventricles and ventromedial nucleus of the
1036
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1035e1036
Table 1 John's Hopkins Motor stereotypy rating scale, DBS settings and configurations. Case 1 Presurgery
Case 1 Postsurgery (13 m)
Case 2 Presurgery
Case 2 Postsurgery (3 m)
Case 2 Postsurgery (6 m)
2 5 4 5 30 46
3 4 5 5 50 67
Left ALIC
e
2 2 3 2 10 19 Monopolar 2.5e5.0 V, 120e210 Monopolar 2.5e4.5 V, 120e210 Bipolar 2.0e5.0 V, 100e210 Bipolar 2.0e5.0 V, 100e210
3 4 5 5 50 67
Right ALIC
1 2 1 0 0 4 Bipolar 3.3 V, 120 ms, 80 Hz Bipolar 3.3 V, 120 ms, 80 Hz e
Number (0e3) Frequency (0e5) Intensity (0e5) Interference (0e5) Global impairment (0e50%) Total Right GPi Left GPi
ms, 40e120 Hza ms, 40e120 Hza ms, 80e200 Hza ms, 80e200 Hza
Number (range from 0-none to 3-more than 5 stereotypies); frequency (range from 0-never to 5-always); intensity (range from 0-absent to 5-severe); interference (range from 0-none to 5-severe); and global impairment (range from 0-none to 50-severe); maximum 68 points. a Range of used settings during programming sessions. M: months.
thalamus induces stereotypies in mice [5]. Stereotypies should be differentiated from compulsive behavior triggered by an obsessive thought. It has been argue that the latter represents a goaldirected and “voluntary” movement, differing conceptually from the non-goal directed movements of stereotypies [2]. The lack of movement-related cortical potential in subjects with primary stereotypies suggests that they are originated by mechanisms different from those involved in voluntary control [5]; however, the exact anatomical dysfunction within the cortico-striato-thalamiccortical pathways is unknown. Case 2 gave us the opportunity to explore the independent and combined effect of neurostimulation in the GPi, ALIC and NA; unfortunately for unknown reasons, the effect was transitory and only observed during simultaneous stimulation of both targets. Stimulation of the GPi, ALIC and NA have been used to treat tics and obsessive-compulsive disorder with variable results [6,7], although the pathophysiology of these disorders differ from that of motor stereotypies, the repetitive nature of the movements gave us the rational to explore the ALIC/NA as therapeutic targets. The GPi has also been used with moderate success in patients with dyskinetic cerebral palsy, tardive dyskinesias and dystonia [8,9]. The reason why only one of our patients had a sustained improvement with DBS is unknown. Several possibilities including different pathogenic mechanisms in both patients, diverse stimulation pathways or the coexistence of tardive dyskinesias in case 1, may explain the differing effects of DBS in these patients. In conclusion, GPi DBS may provide relief for disabling, pharmacologically unresponsive, stereotypies in some patients, although other targets should be explored. To our knowledge, this is the first report of DBS for the treatment of severe stereotypies in patients with autistic spectrum disorders. Conflicts of interest The authors have declared no conflict of interest regarding this study.
Acknowledgment None.
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2014.06.019.
References [1] Baup N, Grabli D, Karachi C, Mounayar S, François C, Yelnik J, et al. High-frequency stimulation of the anterior subthalamic nucleus reduces stereotyped behaviors in primates. J Neurosci 2008;28:8785e8. [2] Edwards MJ, Lang AE, Bhatia KP. Stereotypies: a critical appraisal and suggestion of a clinically useful definition. Mov Disord 2012;27:179e85. [3] Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014;383:896e910. [4] Miller JM, Singer HS, Bridges DD, Waranch HR. Behavioral therapy for treatment of stereotypic movements in nonautistic children. J Child Neurol 2006;21: 119e25. [5] Houdayer E, Walthall J, Belluscio BA, Vorbach S, Singer HS, Hallett M. Absent movement-related cortical potentials in children with primary motor stereotypies. Mov Disord 2013. http://dx.doi.org/10.1002/mds.25753.
Amber Stocco Department of Child Neurology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA Fidel Baizabal-Carvallo* Jose Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, The Smith Tower, Suite 1801, 6550 Fannin, Houston, TX 77030, USA * Corresponding author. Tel.: þ1 713 798 5998. E-mail address: [email protected] (J.F. Baizabal-Carvallo).
18 February 2014
