Assessment of therapeutic strategies for management of impulse control disorder in Parkinson's disease / Evaluación de las estrategias terapéuticas en trastornos del control de impulsos en enfermedad de Parkinson

ABSTRACT Background: Impulse control disorders (ICD) occur frequently in individuals with Parkinson's disease. So far, prevention is the best treatment. Several strategies for its treatment have been suggested, but their frequency of use and benefit have scarcely been explored. Objective: To investigate which strategy is the most commonly used in a real-life setting and its rate of response. Methods: A longitudinal study was conducted. At the baseline evaluation, data on current treatment and ICD status according to QUIP-RS were collected. The treatment strategies were categorized as "no-change", dopamine agonist (DA) dose lowering, DA removal, DA switch or add-on therapy. At the six-month follow-up visit, the same tools were applied. Results: A total of 132 individuals (58.3% men) were included; 18.2% had at least one ICD at baseline. The therapeutic strategy most used in the ICD group was no-change (37.5%), followed by DA removal (16.7%), DA switch (12.5%) and DA lowering (8.3%). Unexpectedly, in 20.8% of the ICD subjects the DA dose was increased. Overall, nearly 80% of the subjects showed remission of their ICD at follow-up. Conclusions: Regardless of the therapy used, most of the subjects presented remission of their ICD at follow-up Further research with a longer follow-up in a larger sample, with assessment of decision-making processes, is required in order to better understand the efficacy of strategies for ICD treatment.

Resumen Antecedentes: Los trastornos del control de impulsos (TCI) son frecuentes en personas con enfermedad de Parkinson. A la fecha, la prevención es el mejor tratamiento. Existen varias estrategias sugeridas para su tratamiento, pero su frecuencia de uso y beneficio ha sido escasamente explorada. Objetivo: Investigar qué estrategia es la más utilizada en un entorno de la vida real y su tasa de respuesta. Métodos: Se realizó un estudio longitudinal. En la evaluación inicial, se recopiló el tratamiento actual y el estado del TCI de acuerdo con el QUIP-RS. La estrategia de tratamiento se clasificó como "sin cambios", reducción de la dosis de agonista de la dopamina (AD), eliminación de AD, cambio de AD o terapia complementaria. En la visita de seguimiento a los 6 meses, se aplicaron las mismas herramientas. Resultados: Se incluyeron un total de 132 (58.3% hombres) personas. El 18.2% tenía al menos un TCI al inicio del estudio. La estrategia terapéutica más utilizada en el grupo de TCI fue sin cambios (37.5%), seguida de eliminación de DA (16.7%), cambio de AD (12.5%) y reducción de DA (8.3%). En el 20.8% de los sujetos con TCI se aumentó la dosis de AD. Casi el 80% de los sujetos tuvieron una remisión del TCI al seguimiento. Conclusiones: Independientemente de la terapia utilizada, la mayoría de los sujetos tuvieron una remisión del TCI. Se requiere más investigación con un seguimiento y una muestra mayor para evaluar l proceso de toma de decisiones para comprender mejor la eficacia de las estrategias.

Pathological Gambling Due to Aripiprazole: Two Cases

ABSTRACT Aripiprazole is an atypical antipsychotic agent which has a partial agonistic effect on dopamine D2 and D3 receptors. It is effective in the treatment of schizophrenia and bipolar disorder. Owing to its partial agonistic effect, hyperactivity of dopamine may occur in the mesolimbic pathway. In the literature, there are few case reports about pathological gambling due to aripiprazole. In this article, there are two case reports of patients who showed pathological gambling behaviour and alcohol abuse and who were under treatment with aripiprazole. The patient had a history of gambling in the past. With the use of aripiprazole, pathological gambling behaviour occurred quickly and with discontinuation of aripiprazole it ended completely. Aripiprazole causes pathological gambling by forming a hyperdopaminergic condition in the mesolimbic dopaminergic pathway. Aripiprazole should be recommended cautiously and carefully to patients who are impulsive and have a history of alcohol/substance abuse.

Diagnostic prediction model for levodopa-induced dyskinesia in Parkinson's disease / Modelo de predição diagnóstica para discinesias induzidas por levodopa na doença de Parkinson

Abstract Background: There are currently no methods to predict the development of levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD) treatment. Clinical predictors and single nucleotide polymorphisms (SNP) have been associated to LID in PD. Objective: To investigate the association of clinical and genetic variables with LID and to develop a diagnostic prediction model for LID in PD. Methods: We studied 430 PD patients using levodopa. The presence of LID was defined as an MDS-UPDRS Part IV score ≥1 on item 4.1. We tested the association between specific clinical variables and seven SNPs and the development of LID, using logistic regression models. Results: Regarding clinical variables, age of PD onset, disease duration, initial motor symptom and use of dopaminergic agonists were associated to LID. Only CC genotype of ADORA2A rs2298383 SNP was associated to LID after adjustment. We developed two diagnostic prediction models with reasonable accuracy, but we suggest that the clinical prediction model be used. This prediction model has an area under the curve of 0.817 (95% confidence interval [95%CI] 0.77‒0.85) and no significant lack of fit (Hosmer-Lemeshow goodness-of-fit test p=0.61). Conclusion: Predicted probability of LID can be estimated with reasonable accuracy using a diagnostic clinical prediction model which combines age of PD onset, disease duration, initial motor symptom and use of dopaminergic agonists.

Resumo Introdução: No momento, não há métodos para se predizer o desenvolvimento de discinesias induzidas por levodopa (DIL), uma frequente complicação do tratamento da doença de Parkinson (DP). Preditores clínicos e polimorfismos de nucleotídeo único (SNP) têm sido associados às DIL na DP. Objetivo: Investigar a associação entre variáveis clínicas e genéticas com as DIL e desenvolver um modelo de predição diagnóstica de DIL na DP. Métodos: Foram avaliados 430 pacientes com DP em uso de levodopa. A presença de DIL foi definida como escore ≥1 no item 4.1 da MDS-UPDRS Parte IV. Nós testamos a associação entre variáveis clínicas específicas e sete SNPs com o desenvolvimento de DIL, usando modelos de regressão logística. Resultados: Em relação às variáveis clínicas, idade de início da doença, duração da doença, sintomas motores iniciais e uso de agonistas dopaminérgicos estiveram associados às DIL. Apenas o genótipo CC do SNP rs2298383 no gene ADORA2A esteve associado com DIL após o ajuste. Nós desenvolvemos dois modelos preditivos diagnósticos com acurácia razoável, mas sugerimos o uso do modelo preditivo clínico. Esse modelo de predição tem uma área sob a curva de 0,817 (intervalo de confiança de 95% [IC95%] 0,77‒0,85) e sem perda significativa de ajuste (teste de qualidade de ajuste de Hosmer-Lemeshow p=0,61). Conclusão: A probabilidade prevista de DIL pode ser estimada, com acurácia razoável, por meio do uso de um modelo preditivo diagnóstico clínico, que combina a idade de início da doença, duração da doença, sintomas motores iniciais e uso de agonistas dopaminérgicos.

O uso do cloridrato de piridoxina para induzir estro em cadelas / The use of pyridoxine chloridrate to induce estrus in female dogs

Os agonistas dopaminérgicos são utilizados para induzir estro em cadelas, pois atuam na síntese e liberação de prolactina. Objetivou-se avaliar o efeito da piridoxina como indutor de estro em cadelas por agir na neurotransmissão dopaminérgica. Foram selecionadas 40 cadelas em anestro, divididas em quatro grupos experimentais, tratadas com 10mg/kg/dia (G1) e 50mg/kg/dia (G2) de cloridrato de piridoxina, 5µg/kg/dia (G3) de cabergolina e grupo controle/placebo (G4) por até 20 dias. Foram realizadas citologias vaginais a cada 24h para acompanhamento do ciclo estral e análises hormonais (FSH, LH e PRL) no dia zero e 120h do início do tratamento. As cadelas do G3 (100%) manifestaram proestro após 12 dias de tratamento aproximadamente, tempo inferior aos demais grupos (P<0,05). Apenas uma cadela do G1 e uma do G2 ficaram gestantes contra oito fêmeas do G3 e nenhuma do G4 (P<0,05). As concentrações plasmáticas de prolactina foram reduzidas nas fêmeas do G2 e G3 (P<0,05). As demais avaliações hormonais não sofreram influência do tratamento (P>0,05). O cloridrato de piridoxina foi ineficiente para induzir estro em cadelas, mas foi capaz de suprimir a prolactina, de forma semelhante à cabergolina, quando utilizado na dose de 50mg/kg/dia.(AU)

Dopaminergic agonists are used to induce estrus in female dogs as they act in the synthesis and release of prolactin. The objective of this study was to evaluate the effect of pyridoxine as an inducer of estrus by acting on dopaminergic neurotransmission. A total of 40 female dogs in anestrous were divided into four experimental groups treated with 10mg/kg/day (G1) and 50mg/kg/day (G2) of pyridoxine hydrochloride, 5µg/kg/day (G3) of cabergoline and control group/placebo (G4) for up to 20 days. Vaginal cytologies were performed every 24h for follow-up of the estrous cycle and hormonal analyzes (FSH, LH and PRL) on day zero and 120 hours after the start of treatment. The female dogs from G3 (100%) showed proestrus after 12 days of treatment, less time than the other groups (P< 0.05). Only one female from G1 and one from G2 were pregnant against eight from G3 and none from G4 (P< 0.05). Plasma concentrations of prolactin were reduced by treatment in females from G2 and G3 (P< 0.05). The other hormonal evaluations were not influenced by the treatment (P> 0.05). Pyridoxine chloridrate was inefficient to induce estrus in female dogs but was able to suppress prolactin when used at a dose of 50mg/kg/day.(AU)

Body self-image disturbances in women with prolactinoma

Objective: To evaluate body dissatisfaction and distorted body self-image in women with prolactinoma. Methods: Body dissatisfaction and distorted body self-image were evaluated in 80 women with prolactinoma. All patients were in menacme, 34% had normal body mass index (BMI), and 66% were overweight. Most patients (56.2%) had normal prolactin (PRL) levels and no hyperprolactinemia symptoms (52.5%). The Body Shape Questionnaire (BSQ) was used to assess the patients' dissatisfaction with and concern about their physical form, and the Stunkard Figure Rating Scale (FRS) was used to assess body dissatisfaction and distorted body self-image. The patients were divided according to PRL level (normal vs. elevated) and the presence or absence of prolactinoma symptoms. Results: The normal and elevated PRL groups had similar incidences of body dissatisfaction and distorted body self-image. However, symptomatic patients reported a higher incidence of dissatisfaction than asymptomatic patients. Distorted body self-image was less common among symptomatic patients. Conclusion: Symptomatic patients showed higher body dissatisfaction, but lower body self-image distortion. The presence of symptoms may have been responsible for increased body awareness. The perception of body shape could have triggered feelings of dissatisfaction compared to an ideal lean body. Therefore, a distorted body self-image might not necessarily result in body dissatisfaction in women with prolactinomas.

Resolution of headache after reduction of prolactin levels in hyperprolactinemic patients / Resolução de cefaleia após redução dos níveis de prolactina em pacientes com hiperprolactinemia

Abstract Prolactin (PRL) secreting adenomas are associated with high incidence of headache. The role of hyperprolactinemia in the headache context is not clear, nor is the effect of its treatment on headache. Methods: The present longitudinal study evaluated hyperprolactinemic patients (69), in terms of presence and characteristics of headache before and after hyperprolactinemia treatment. Results: Headache was reported by 45 (65.2%) patients, independent of the etiology of hyperprolactinemia. The migraine phenotype was the most prevalent (66.6%). Medications used in the treatment of headache not changed during the study. The first line of treatment of hyperprolactinemia was dopaminergic agonists. In the last reevaluation, PRL level under treatment was within the reference range in 54.7% of the cases, and it was observed complete or partial resolution of the headache in 75% of the cases. The median PRL at this time in patients with complete headache resolution was 17 ng/mL, in those who reported partial recovery was 21 ng/mL, and in those in whom the headache did not change was 66 ng/mL, with a significant difference between the group with complete headache resolution vs. the group with unchanged headache (p=0.022). In the cases with complete headache resolution, the median fall on PRL levels was 89% and in those cases with partial headache resolution 86%, both significantly different (p<0.001) from the fall in the cases with an unchanged headache. Conclusion: Data allow us to conclude that, in this series, in the majority of cases the reduction in the level of PRL was followe3d by cessation or relief of the pain.

Resumo Os adenomas secretores de prolactina (PRL) estão associados à alta incidência de cefaleia. O papel da hiperprolactinemia no contexto da dor de cabeça não está claro, nem o efeito da redução dos níveis da PRL na cefaleia. Métodos: O presente estudo longitudinal avaliou pacientes hiperprolactinêmicos (69), quanto à presença e às características da cefaleia antes e após o tratamento da hiperprolactinemia. Resultados: Cefaleia foi relatada por 45 (65,2%) pacientes, independente da etiologia da hiperprolactinemia. O fenótipo de enxaqueca foi mais prevalente (66,6%). Os medicamentos usados ​​no tratamento da cefaleia não foram alterados durante o estudo. A primeira linha de tratamento da hiperprolactinemia foram os agonistas dopaminérgicos. Na última reavaliação, o nível de PRL sob tratamento estava dentro da faixa de referência em 54,7% dos casos, observando-se resolução completa ou parcial da cefaleia em 75% dos casos. A mediana de PRL neste momento em pacientes com resolução completa da cefaleia foi de 17 ng/mL, nos que relataram recuperação parcial foi de 21 ng/mL, e naqueles em que a cefaleia não se alterou foi de 66 ng/mL, com uma diferença significativa entre o grupo com resolução completa da cefaleia versus o grupo com cefaleia inalterada (p=0,022). Nos casos com resolução completa da cefaleia, a queda mediana nos níveis de PRL foi de 89% e nos casos com resolução parcial de cefaleia de 86%, ambos significativamente diferentes (p<0,001) da queda nos casos com cefaleia inalterada. Conclusão: Os dados permitem concluir que, nesta série, na maioria dos casos, a redução do nível de PRL foi seguida pela cessação ou alívio da dor.

Adenoma hipofisario ectópico del seno esfenoidal persistente tras cirugía manejado con tratamiento conservador / Ectopic pituitary adenoma in the sphenoid sinus persistent after surgery managed with conservative treatment

Los adenomas hipofisarios ectópicos (EPA) constituyen un reto diagnóstico, dada su escasa prevalencia y variada presentación en la que puede incluirse un síndrome de hipersecreción de hormonas hipofisarias. La clínica suele ser larvada e inespecífica, no presentan ninguna característica radiológica diferencial y el diagnóstico habitualmente es anatomopatológico. Sin embargo, a pesar de ser tumores benignos, pueden presentar un comportamiento agresivo, con invasión ósea y difícil resección completa, por lo que un diagnóstico de sospecha precoz podría resultar en un tratamiento más eficaz y con un menor número de complicaciones. Presentamos el caso de una paciente con un adenoma hipofisario ectópico silente en el seno esfenoidal con inmunohistoquímica positiva para Hormona de crecimiento (GH) y prolactina que presentaba restos tumorales tras la intervención quirúrgica y ha sido manejada con tratamiento médico conservado, con buenos resultados.

Ectopic pituitary adenomas constitute a diagnostic challenge, given their low prevalence and varied presentation in which a pituitary hormone hypersecretion syndrome may be included. Clinical symptoms are usually latent and nonspecific, they have no differential radiological characteristics and the diagnosis is usually anatomopathological. However, despite being benign tumors, they can exhibit aggressive behavior, with bone invasion and difficult complete resection, so a diagnosis of early suspicion could result in more effective treatment and fewer complications. We present the case of a patient with a silent ectopic pituitary adenoma in the sphenoid sinus with positive immunohistochemistry for Growth Hormone (GH) and prolactin who had tumor remnants after surgery and was managed with conservative medical treatment, with good results.

Updates on the Diagnosis and Treatment of Restless Legs Syndrome / 신경정신의학

Restless legs syndrome (RLS) is a neurological sleep disorder characterized by an urge to move the legs or arms and is associated with discomfort and paresthesia in the legs. RLS is diagnosed based on the clinical symptoms, and polysomnography is performed to quantify the periodic limb movements during sleep or in patients who undergo the suggested immobilization test. Determining the cause of RLS is important for accurately diagnosing and evaluating this condition. The treatment of RLS varies according to the etiology, severity, and frequency of the patients' symptoms. Accurate identification and treatment of the cause of RLS are important in patients with secondary RLS. Iron supplementation could be useful in patients with uremia, iron deficiency, and for RLS during pregnancy. Dopamine agonists have been used as the first-line treatment for primary RLS. On the other hand, augmentation is a known adverse effect associated with the long-term use of dopamine agonists. Therefore, recent treatment guidelines recommend the administration of anticonvulsants, such as pregabalin and gabapentin, to treat RLS. Iron, opioids, or benzodiazepines may be useful in patients refractory to anticonvulsants or dopamine agonists. RLS is a chronic condition. Therefore, it is essential to establish a long-term treatment plan, considering both the efficacy and adverse effects of therapeutic agents used in patients.

Therapeutic Effect of a Novel Chimeric Molecule Targeting Both Somatostatin and Dopamine Receptors on Growth Hormone-Secreting Pituitary Adenomas

BACKGROUND: Acromegaly is a rare disease primarily caused by growth hormone (GH)-secreting pituitary adenomas, and its treatment is costly. Moreover, some patients are unresponsive to treatment. Hence, there are increasing efforts to develop new drugs with improved effectiveness for this disease. BIM23B065 is a novel chimeric molecule that acts on both somatostatin and dopamine receptors. This study aimed to investigate the effects of BIM23B065 compared with those of a somatostatin receptor analog and a dopamine agonist.METHODS: The effects of BIM23B065 on the proliferation, GH and insulin-like growth factor-1 (IGF-1) levels, and extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element binding (CREB) phosphorylation of GH3 cells were investigated with MTS assay, enzyme-linked immunosorbent assay, and Western blotting, respectively. The dosage and treatment duration of BIM23B065 were tested in animal models of GH-secreting pituitary adenoma. The effect of BIM23B065 (3 mg/kg/day) on changes in IGF-1 levels before and after treatment was further investigated.RESULTS: In vitro, BIM23B065 treatment decreased GH release in the culture media and downregulated ERK 1/2 and CREB phosphorylation to 22% and 26%, respectively. In vivo, IGF-1 expression decreased to 50 % after 4 weeks of treatment with BIM23B065 using an osmotic pump implant. Moreover, magnetic resonance imaging results showed that the tumor size decreased significantly following treatment with BIM23B065 for 4 weeks.CONCLUSION: The novel chimeric molecule was effective in decreasing IGF-1 and GH levels and may serve as an effective therapeutic agent for acromegaly.

Chromosomal Deletion in 7q31.2-31.32 Involving Ca2⁺-Dependent Activator Protein for Secretion Gene in a Patient with Cerebellar Ataxia: a Case Report

We present a 33-year-old male patient with cerebellar ataxia. He was first considered to have a psychiatric conversion disorder but finally found to have chromosomal deletion in 7q31.2-31.32 involving Ca2⁺-dependent activator protein for secretion (CADPS) gene. When a targeted gene sequencing using next-generation sequencing panel and chromosomal microarray analysis were performed, an 8.6 Mb deletion within chromosome 7q31.2-31.32 was discovered. Deletion of CADPS gene in the 7q31.2-31.32 was suggested as the causative factor of cerebellar ataxia. Functional levels evaluated by Berg balance scale and modified Barthel index were improved via comprehensive rehabilitation including balance training and a dopamine agonist medication. To the best of our knowledge, this is the first report of chromosomal deletion in 7q31.2-31.32 including CADPS gene detected in patients with cerebellar ataxia.

The position of combined medical treatment in acromegaly

ABSTRACT Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52

Pegvisomant in acromegaly: a multicenter real-life study in Argentina

ABSTRACT Objective To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. Subjects and methods We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. Results Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). Conclusion this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7

The elevated gradient of aversion: a new apparatus to study the rat behavior dimensions of anxiety, fear, and impulsivity

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.

Pharmacological Treatment in Parkinson's Disease

Parkinson's disease is one of the most common neurodegenerative disorders world widely. Although curable therapies are practically not available yet, symptomatic managements using anti-Parkinson medications have shown to be quite effective to improve patients' quality of life. The discovery of dopaminergic deficits in Parkinson's disease in 1960s have brought about the human clinical trials of levodopa, which opened an “Era of Dopamine” in treatment history of the Parkinson's disease. Levodopa still remains gold standard. Dopamine agonists have proved their efficacies and delayed the development of long-term complications of levodopa use. Inhibitors of respective enzyme monoamine oxidase-B and catechol-O-methyltransferase, anticholinergics, and amantadine strengthen the therapeutic effects via either monotherapy or adjunctive way. Strategy of continuous dopaminergic stimulation and disease modification are weighing in current advances. This article is providing evidence-based review of pharmacological treatment of Parkinson's disease from early to advanced stages as well as management its unavoidable adverse reactions.

Limonene Inhibits Methamphetamine-Induced Sensitizations via the Regulation of Dopamine Receptor Supersensitivity

Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine-induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated the effects of limonene on the psychological dependence induced by drug abuse. The development of sensitization, dopamine receptor supersensitivity, and conditioned place preferences in rats was measured following administration of limonene (10 or 20 mg/kg) and methamphetamine (1 mg/kg) for 4 days. Limonene inhibits methamphetamine-induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonene-pretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between the limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity.

Apomorphine in the treatment of Parkinson's disease: a review / O uso da apomorfina no tratamento da doença de Parkinson: revisão da literatura

ABSTRACT Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.

RESUMO A optimização do tratamento da doença de Parkinson idiopática se faz um desafio, pois tem impacto direto na qualidade de vida do paciente. O melhor esquema terapêutico é o que permite o melhor controle motor com os menores efeitos adversos, através de terapêutica individualizada. A apomorfina é o único medicamento antiparkinsoniano que pode ser comparável à potência da levodopa no controle dos sintomas motores. Trata-se de um agonista dopaminérgico empregado na terapia de resgate em pacientes com flutuações motoras e também contribui para a melhora de muitos sintomas não motores. A via subcutânea, com injeções intermitentes, ou com infusão contínua, parece ser a melhor opção pela eficácia e tolerabilidade. Essa revisão resume aspectos históricos, estrutura da molécula, mecanismo de ação, indicação, contra-indicação e efeitos colaterais, compara a terapia de infusão com apomorfina com outros tratamentos, como a terapia oral, estimulação cerebral profunda e infusão enteral contínua de levodopa/carbidopa gel, e fornece instruções práticas de como iniciar o tratamento.

Síndrome de piernas inquietas/Willis Ekbom desde la mirada del psiquiatra / Restless legs syndrome from the perspective of psychiatry

Restless Legs Syndrome (RLS) or Willis-Ekbom Disease is an under-diagnosed chronic and progressive primary sensory-motor disorder. It can lead to severe sleep disturbances, a usual cause of consultation. It is characterized by an urgent need to move the legs in resting situations, a cardinal symptom that is usually accompanied by an unpleasant sensation in legs. These symptoms appear or aggravate at the end of the day and in resting situations and are alleviated with movement. Based on these clinical characteristics, it has been defined as a quiescegenic focal akathisia. The diagnosis is essentially clinical. As a guide, there are five cardinal diagnostic criteria. The treatment consists of non-pharmacological measures and the use of medications such as dopamine agonists. Despite the treatment, the symptoms persist in 40% of patients. Psychiatrists should be aware of the syndrome since many drugs used by them such as antipsychotics, antidepressants and anxiolytics can worsen the symptoms. Moreover, the syndrome may be associated with depressive and anxiety diseases.

Motor and non-motor wearing-off and its impact in the quality of life of patients with Parkinson's disease / Flutuações motoras e não-motoras e seu impacto na qualidade de vida de pacientes com doença de Parkinson

ABSTRACT The wearing-off phenomenon is common in patients with Parkinson's disease. Motor and non-motor symptoms can fluctuate in relation to the "on/off" periods. Objective: To assess the impact of motor and non-motor wearing-off on activities of daily living and quality of life of patients with PD. Methods: A cross-sectional study was carried out. All patients were evaluated using the Movement Disorders Society Unified Parkinson's Disease Rating Scale. Wearing-off was assessed using the Wearing-Off Questionnaire-19, and quality of life was assessed using the Parkinson's Disease Questionnaire-8. Results: A total of 271 patients were included; 73.4% had wearing-off; 46.8% had both motor and non-motor fluctuations. Patients with both motor and non-motor wearing-off had a worst quality of life compared with those with only motor fluctuations (p = 0.047). Conclusions: Motor and non-motor fluctuations have an impact on activities of daily living and quality of life. Non-motor wearing-off may have a higher impact.

RESUMO O fenômeno de encurtamento do fim de dose é comum em pacientes com doença de Parkinson. Tanto os sintomas motores quanto os não motores podem flutuar em relação aos períodos de "on/off". Objetivo: Avaliar o impacto das flutuações motoras e não-motoras nas atividades da vida diária e qualidade de vida em pacientes com doença de Parkinson. Métodos: Um estudo transversal foi realizado. Todos os sujeitos foram avaliados utilizando a escala unificada para a doença de Parkinson da Sociedade de Distúrbios do Movimento. O encurtamento do fim de dose foi avaliado através do questionário WOQ-19 e a qualidade de vida foi avaliada através do PDQ-8. Resultados: Um total de 271 pacientes foram incluídos, 73,4% tiveram deterioração de fim de dose. A maioria dos pacientes tiveram tanto flutuações motoras quanto não-motoras (46,8%). Os pacientes com ambos os tipos de flutuações motoras e não-motoras tiveram pior qualidade de vida do que pacientes apenas com flutuações motoras (p = 0.047). Conclusões: Pacientes com flutuações motoras e não-motoras tiveram impacto significativo nas atividades da vida diária e na qualidade de vida. As flutuações não-motoras parecem ter um impacto maior que as flutuações motoras sobre a qualidade de vida.

Pegvisomanto para acromegalia / Pegvisomanto for acromegaly

CONTEXTO: A acromegalia é uma doença crônica, rara e debilitante, causada pela hipersecreção do hormônio do crescimento (GH), que leva a uma produção excessiva do fator de crescimento similar a insulina I (IGF-I), produzido pelo fígado. Resulta numa doença multissistêmica caracterizada por crescimento somático exagerado, comorbidades múltiplas, desfiguramento físico e redução de expectativa de vida. Os objetivos do tratamento são atenuar os sintomas da hipersecreção de GH, reduzir as comorbidades e o risco de mortalidade, preservando as funções normais da hipófise e melhorando a qualidade de vida destes pacientes, através da normalização dos níveis de GH e IGF-I. A adenoidectomia transesfenoidal permanece o tratamento primário da acromegalia e controla estes níveis em 50 a 75% dos pacientes, dependendo da morfologia do adenoma e da experiência do cirurgião. Para aqueles que permanecem com doença ativa após o tratamento cirúrgico, existe tratamento de segunda linha, com medicamentos e radioterapia. Os medicamentos disponíveis são os agonistas da dopamina, os análogos da somatostatina e o pegvisomanto. O pegvisomanto não é disponibilizado atualmente pelo SUS. TECNOLOGIA: Pegvisomanto (PEG-V). INDICAÇÃO: A acromegalia é uma doença crônica, rara e debilitante, causada pela hipersecreção do hormônio do crescimento (GH), que leva a uma produção excessiva do fator de crescimento similar a insulina I (IGF-I), produzido pelo fígado. Resulta numa doença multissistêmica caracterizada por crescimento somático exagerado, comorbidades múltiplas, desfiguramento físico e redução de expectativa de vida. PERGUNTA: O pegvisomanto é eficaz, seguro e custo-efetivo em pacientes com acromegalia refratária ao tratamento convencional? EVIDÊNCIAS CIENTÍFICAS: Os estudos disponíveis que avaliam o pegvisomanto são, em sua maioria, de baixa qualidade metodológica. Os principais desfechos localizados nos artigos foram os níveis de IGF-I e os desfechos clínicos apareceram nos estudos de forma secundária. O pegvisomanto foi eficaz nos estudos controlados quando se avaliaram como desfechos a redução dos níveis sanguíneos de IGF-I e o controle de alguns dos sinais e sintomas característicos da doença. Mesmo existindo estudos de longo prazo e com grande tamanho da amostra, as limitações metodológicas dos estudos trazem incertezas quanto aos benefícios do pegvisomanto na redução dos sinais e sintomas da doença. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A estimativa de impacto orçamentário anual resultante da incorporação de pegvisomanto no SUS variou de aproximadamente 23 a 206 milhões, dependendo da dose de pegvisomanto utilizada. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros da CONITEC recomendaram por unanimidade a não incorporação no SUS do pegvisomanto para tratamento da acromegalia refratária ao tratamento convencional. CONSULTA PÚBLICA: O Relatório da CONITEC foi disponibilizado por meio da Consulta Pública nº 67/2017 entre os dias 29/11/2017 e 18/12/2017. Foram recebidas 14 contribuições, sendo 5 técnico-científicas e 9 de experiência ou opinião, das quais 7 foram excluídas por não tratar do tema em questão. Das 7 contribuições consideradas, 6 foram totalmente contra a recomendação da CONITEC e 1 foi totalmente a favor. Nas contribuições que foram contra a recomendação da CONITEC, os participantes argumentaram que o pegvisomanto é eficaz e seguro no tratamento de pacientes com acromegalia refratária ao tratamento convencional e fizeram críticas em relação ao impacto orçamentário, considerando-o superestimado. DELIBERAÇÃO FINAL: Os membros da CONITEC consideraram que não houve nenhuma informação nova sobre o tema que motivasse a mudança nas recomendações de não incorporação do pegvisomanto feitas em suas análises anteriores sobre o medicamento. Dessa forma, deliberaram por recomendar a não incorporação do pegvisomanto para acromegalia refratária ao tratamento estabelecido. DECISÃO: Não incorporar o pegvisomanto para acromegalia refratária ao tratamento estabelecido, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria nº 14, publicada no DOU nº 61, do dia 29 de março de 2018, seção 1, pág. 240.(AU)

Prolactinoma en una adolescente como causa de alteraciones visuales / Prolactinoma as the cause of visual alterations in a female adolescent

Introducción: los prolactinomas corresponden a la mitad de las causas etiológicas de los adenomas de presentación en la población pediátrica, lo cual les proporciona una gran importancia para tenerlos como diagnóstico diferencial ante el estudio de un tumor hipofisario. Las alteraciones visuales no corresponden al síntoma más común, sin embargo, es necesario tenerlo presente, especialmente ante la identificación de un macroadenoma. Presentación del caso: paciente femenina, de 16 años de edad, con un macroadenoma en estudio, que fue identificado como un macroprolactinoma. La sintomatología principal de consulta correspondió a alteraciones visuales y cefalea. Recibió tratamiento médico por Endocrinología Pediátrica con cabergolina, con estabilidad en el tamaño y características de la masa tumoral, y disminución de los niveles de prolactina sérica. Conclusiones: en la población pediátrica los prolactinomas que producen afectaciones visuales son más frecuentes en el sexo masculino, sin embargo, también puede ocurrir en el femenino; su diagnóstico implica la realización de estudios de laboratorio especializados y neuroimágenes, así como la participación activa de Endocrinología Pediátrica. Se resalta la importancia del tratamiento médico con agonistas dopaminérgicos, como la primera opción en esta entidad antes de plantear decisión quirúrgica, y es necesario un seguimiento médico cuidadoso al respecto(AU)

Introduction: prolactinomas account for half of the etiological causes of presentation adenomas in the pediatric population, hence their important role as differential diagnosis in the study of a pituitary tumor. Visual alterations are not their most common symptom, but they should be borne in mind, particularly in the identification of a macroadenoma. Case presentation: female 16-year-old patient with a macroadenoma under study which was identified as a macroprolactinoma. The main symptoms at presentation were visual alterations and headaches. She received medical treatment with cabergoline at the Pediatric Endocrinology service, achieving stability in the size and characteristics of the tumor mass, and a reduction in serum prolactin levels. Conclusions: in the pediatric population, prolactinomas causing visual alterations are more common in males, but they can also occur among females. Their diagnosis includes specialized laboratory tests and neuroimaging, as well as the active involvement of the Pediatric Endocrinology service. Mention must be made of the medical treatment with dopaminergic agonists as the first choice for this condition before indicating surgery, and careful medical follow-up is required in this respect(AU)