Levodopa-Induced Dyskinesia Is Associated with Increased Thyrotropin Releasing Hormone in the Dorsal Striatum of Hemi-Parkinsonian Rats

Background Dyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) therapy for Parkinson's disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition. Methodology/Principal Findings Quantitative real-time polymerase chain reaction (PCR) was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson's disease. With this technique, we determined that thyrotropin releasing hormone (TRH) was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes. Conclusions/Significance TRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson's disease.Morris K. Udall Center for Excellence in Parkinson’s Research at MGH/MITNational Institutes of Health (U.S.) (NIH NS38372)American Parkinson Disease Association, Inc.University of Alabama at BirminghamMassachusetts General HospitalNational Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIDDK/NIH grant R01 DK58148)National Institute of Neurological Disorders and Stroke (U.S.) (R01 NINDS/NIH grant NS045231)Stanley H. and Sheila G. Sydney FundMichael J. Fox Foundation for Parkinson's Researc

Tratamiento con agonistas dopaminérgicos en la enfermedad de Parkinson: consenso de expertos españoles sobre su uso en diferentes situaciones clínicas

Background: Different types of therapies were proven effective for the medical management of motor and non-motor symptoms in Parkinson's disease (PD). We aimed to gain consensus on the dopamine agonist (DA) therapy use in different clinical scenarios of Parkinson's disease (PD) patients. Methods: This consensus study was based on the nominal group technique. Initially, a consensus group comprising 12 expert neurologists in the PD field identified the topics to be addressed and elaborated different evidence-based preliminary statements. Next, a panel of 48 Spanish neurologists expressed their opinion on an internet-based systematic voting program. Finally, initial ideas were reviewed and rewritten according to panel contribution and were ranked by the consensus group using a Likert-type scale. The analysis of data was carried out by using a combination of both qualitative and quantitative methods. The consensus was achieved if the statement reached ≥ 3.5 points in the voting process. Results: The consensus group produced 76 real-world recommendations. The topics addressed included 12 statements related to DA therapy in early PD, 20 statements concerning DA treatment strategy in patients with motor complications, 11 statements associated with DA drugs and their side effects, and 33 statements regarding DA therapy in specific clinical scenarios. The consensus group did not reach a consensus on 15 statements. Conclusion: The findings from this consensus method represent an exploratory step to help clinicians and patients in the appropriate use of DA in different stages and clinical situations of PD.Antecedentes: Se demostró la efectividad de diferentes tipos de terapias para el tratamiento médico de los síntomas motores y no motores en la enfermedad de Parkinson (EP). Nos propusimos lograr un consenso sobre el uso de la terapia con agonistas dopaminérgicos (DA) en diferentes escenarios clínicos de pacientes con enfermedad de Parkinson (EP). Métodos: Este estudio de consenso se basó en la técnica de grupo nominal. Inicialmente, un Grupo de Consenso formado por 12 neurólogos expertos en el campo de la EP identificó los temas a tratar y elaboró diferentes declaraciones preliminares basadas en la evidencia. A continuación, un panel de 48 neurólogos españoles ? expresó su opinión en un programa de votación sistemática a través de Internet. Finalmente, las ideas iniciales fueron revisadas y reescritas de acuerdo con la contribución del panel y fueron clasificadas por el grupo de Consenso utilizando una escala tipo Likert. El análisis de los datos se llevó a cabo mediante una combinación de métodos cualitativos y cuantitativos. El consenso se alcanzaba si la afirmación alcanzaba ≥3,5 puntos en el proceso de votación. Resultados: El Grupo de Consenso elaboró 76 recomendaciones para el mundo real. Los temas abordados incluyeron 12 afirmaciones relacionadas con la terapia con DA en la EP temprana, 20 afirmaciones relativas a la estrategia de tratamiento con DA en pacientes con complicaciones motoras, 11 afirmaciones asociadas con los fármacos DA y sus efectos secundarios, y 33 afirmaciones relativas a la terapia con DA en escenarios clínicos específicos. El Grupo de Consenso no llegó a un consenso en 15 afirmaciones. Conclusiones: Los resultados de este método de consenso representan un paso exploratorio para ayudar a clínicos y pacientes en el uso apropiado de la DA en diferentes estadios y situaciones clínicas de la EP.Funding: This study was funded by the Chair of Epilepsy and Movement Disorders UFV-UCB. Acknowledgement: We thank the neurologists who participated in phase 1 for their disinterested collaboration. We thank the Epilepsy and Movement Disorders UFV-UCB Chair for supporting this initiative. We thank Irene Santamaría of the Francisco de Vitoria University for the technical coordination work of this study

Spreading of complex regional pain syndrome: not a random process

Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process. One hundred and eighty-five CRPS patients were retrospectively evaluated. Cox’s proportional hazards model was used to evaluate factors that influenced spread of CRPS symptoms. Eighty-nine patients exhibited CRPS in multiple limbs. In 72 patients spread from a first to a second limb occurred showing a contralateral pattern in 49%, ipsilateral pattern in 30% and diagonal pattern in 14%. A trauma preceded the onset in the second limb in 37, 44 and 91%, respectively. The hazard of spread of CRPS increased with the number of limbs affected. Compared to patients with CRPS in one limb, patients with CRPS in multiple limbs were on average 7 years younger and more often had movement disorders. In patients with CRPS in multiple limbs, spontaneous spread of symptoms generally follows a contralateral or ipsilateral pattern whereas diagonal spread is rare and generally preceded by a new trauma. Spread is associated with a younger age at onset and a more severely affected phenotype. We argue that processes in the spinal cord as well as supraspinal changes are responsible for spontaneous spread in CRPS