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Buspirona na disfunção respiratória brain development


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Buspirona na disfunção respiratória brain development

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Buspirona na disfunção respiratória brain development

  1. 1. Case report Buspirone in Rett syndrome respiratory dysfunction Daniela K. Andakua,1 , Marcos T. Mercadanteb,2 , Jose´ Saloma˜o Schwartzmanb,* a Santo Amaro University Physical Therapy School, Sa˜o Paulo, Brazil b Pervasive Developmental Disorder Program, Mackenzie Presbyterian University, Sa˜o Paulo, Brazil Received 16 September 2003; received in revised form 16 August 2004; accepted 18 September 2004 Abstract This study details a case of Rett Syndrome where the patient’s respiratory dysfunction was improved after buspirone was administered. Polygraphic studies in the waking state, before and after treatment with 5 mg of buspirone twice a day, were obtained. Breathing movements, oxygen saturation and end-tidal carbon were monitored. Average oxygen saturation increased from 86.9 to 91%, and the period of saturation below 90% was reduced by 42.2%. The oxygen saturation improvement observed in this case suggests that buspirone might be useful in treating respiratory dysfunction associated with Rett Syndrome. Controlled clinical trials are needed to provide more evidence. q 2004 Published by Elsevier B.V. Keywords: Rett syndrome; Respiratory; Dysfunction; Oxygenation; Buspirone 1. Introduction Rett Syndrome (RS) is a severe pervasive development disorder, primarily affecting females and characterized by loss of language and motor skills. The MECP2 gene that encodes the methyl-CpG binding protein 2 and presumably acts as a global transcriptional repressor, has been found to contain a mutation in 80% of classic RS cases [1]. Four distinct clinical stages have been described: Stage I—early onset stagnation period, Stage II—rapid destructive stage, Stage III—pseudostationary stage and Stage IV—late motor deterioration stage. Although still not well studied, the respiratory dysfunctions appear to have a significantly deleterious impact on children suffering from RS as well as on the quality of life of the child’s family [2]. The associated breathing impairment, which occurs only during wakefulness, normally consists of periods of breath holding, shallow breathing, hyperventilation, central apneas, Cheyne–Stokes breathing, Biot’s breathing and other pathological breathing patterns [3]. Studies show that these abnormal breathing patterns may be associated with oxygen saturation variations with values lower than 60% [4,5]. However it is not clear if the continuous exposure to lower levels of oxygen saturation could contribute to the cerebral functional impairment and/or other clinical complications. Julu et al. [3,6] suggest that the multiple respiratory dysrhythmias could be a consequence of the instability of the respiratory oscillator in the medulla oblongata and is probably due to brainstem immaturity. The term ‘immaturity’ in this context is comparable to cardiac vagal tone observed in 2- to 3-day-old neonates. Among the abnormal respiratory patterns, the holding of the breath during inspiration (also called apneusis) has been seen as a malfunction of inhibitory synaptic process into the brain- stem. This region is believed to be responsible for the ending of the cycle of inspiration [3,7]. Buspirone, a serotoninergic type 1A agonist, was successfully used in the treatment of apneusis secondary to the surgical removal of pons and medulla oblonga astrocytoma [8]. It has been suggested that 5-HT1A receptors control the neuronal processes within the brainstem that regulate the termination of the cycle of inspiration. Agonists of these receptors seem to enforce post-synaptic inhibition through the increased gamma- aminobutyric acid receptor activity [3]. At the moment, 0387-7604/$ - see front matter q 2004 Published by Elsevier B.V. doi:10.1016/j.braindev.2004.09.011 Brain & Development 27 (2005) 437–438 * Corresponding author. Address: Rua Franc¸a Pinto, 941 ZIP 04016-034, SP/SP Brazil. Fax: C55 11 5571 7743. E-mail address: (J.S. Schwartzman). 1 Rua Visconde de Inhau´ma 308 (92), ZIP 04145-030, SP/SP, Brazil. 2 Av. BR Campos Gerais, 193 (62), ZIP 05684-000, SP/SP, Brazil.
  2. 2. there is a single RS case described by Kerr et al. [9] where an improvement in the apneusis was reported. 2. Case report The patient in this case study was a 15-year-old girl with classic RS (Stage IV, late motor deterioration stage) who received 5 mg of buspirone twice daily. Her parents first observed her breathing impairment when she was 4 years old and, as they described the symptoms, it was clearly a case of apnea associated with cyanosis. The mother stated that the respiratory dysfunction became worse after menarche. Before starting medication, the patient’s parents received a written and verbal explanation of the procedures. They subsequently provided written consent for the procedure as well as for publication of the results. Before starting medication, a polygraphic study was administered during the waking state for a period of 75 min. Breathing movements with thoracic and abdominal strain gauges were monitored, oxygen saturation was measured by pulse oxymetry, and end-tidal carbon was measured through a nasal catheter. The results demonstrated an average oxygen saturation of 86.9% and the patient stayed 67.7 min (90.2% of the total time) with oxygen saturation values lower than 90% (Fig. 1). After 10 days on buspirone, a dramatic improvement in patient breathing pattern was observed by the caretakers. After 5 months of treatment the patient was reassessed using the same polygraphic methods. The reassessment showed an improvement in oxygen saturation with average oxygen saturation of 91%. Values below 90% saturation were observed for 39.1 min (52% of total time) and a total reduction of 42.2% of the time compared to the baseline (Fig. 1). Due to oral breathing no end-tidal carbon data was obtained. 3. Discussion This study reports significant improvements with buspir- one in the breathing pattern and in the saturation values in a RS adolescent. While it is worth noting that the patient’s parents and the clinical neurologist also observed a significant improvement in the social contact and alertness of the patient, it is not clear if this improvement is related to the increased level of oxygen saturation or to the improved function of the other brain regions by the action of the 5HT1A agonist. Controlled clinical trials are recommended to evaluate the efficacy of buspirone in children with RS. Outcomes should focus on behavior aspects as well as breathing patterns. Acknowledgements The authors thank Gerar Sono-Centro de Diagno´sticos do Sono Co. for the research’s technical support and Mark VanMeter for the manuscript’s review. Supported in part by a grant from MackPesquisa, grant: 1014 to Dr Schwartzman. References [1] Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, et al. Mice with truncated MECP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 2002;35:243–54. [2] Schwartzman JS. Sindrome de Rett. Rev Bra Psiq 2003;25:110–3. [3] Julu POO, Kerr AM, Apartopoulos F, Al-Rawas S, Witt-Engerstro¨m I, Engerstro¨m L, et al. Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder. Arch Dis Child 2001;85:29–37. [4] Southall DP, Kerr AM, Tirosh E, Amos P, Lang MH, Stephenson JBP. Hyperventilation in the awake state: potentially treatable component of Rett syndrome. Arch Dis Child 1988;63:1039–48. [5] Marcus CL, Carroll JL, McColley SA, Loughlin GM, Curtis S, Pyzik P, et al. Polysomnographic characteristics of patients with Rett syndrome. J Pediatr 1994;125:218–24. [6] Julu POO, Kerr AM, Hansen S, Apartopoulos F, Jamal GA. Functional evidence of brainstem immaturity in Rett syndrome. Eur Child Adolesc Psychiatry 1997;6(S1):47–54. [7] Kerr AM, Julu POO. Recent insights into hyperventilation from the study of Rett syndrome. Arch Dis Child 1999;80:384–7. [8] Wilken B, Lalley P, Bischoff AM, Christen HJ, Behnke J, Hanefeld F, et al. Treatment of apneustic respiratory disturbance with a serotonin- receptor agonist. J Pediatr 1997;130:89–94. [9] Kerr AM, Julu POO, Hansen S, Apartopoulus F. Serotonin and breathing dysrhythmia in Rett syndrome. In: Perat MV, editor. New developments in child neurology. Bologna: Monduzzi Editore; 1998. p. 191–5. Fig. 1. Improvement of oxygen saturation noted by the time (in min) the patient remained in specific oxygen saturation (SO2) levels before (pre-tx) and after (tx) treatment with buspirone. D.K. Andaku et al. / Brain & Development 27 (2005) 437–438438