BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011.
OBJECTIVES: To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery.
SEARCH METHODS: On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.
MAIN RESULTS: We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect. Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment.
AUTHORS' CONCLUSIONS: There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.
OBJECTIVES: Half of patients with amyotrophic lateral sclerosis experience sialorrhea due to facial weakness. Although anticholinergic medications are first-line therapy, they often lead to unacceptable side effects. Radiation therapy and botulinum toxin may be considered when medical management fails. In this systematic review, we investigated the effectiveness of these interventions.
METHODS: Eligible studies were retrieved from PubMed and Scopus databases up to March 2017 along with hand-searching of references from primary articles.
RESULTS: Fourteen studies (N = 138) examined the benefits of botulinum toxin. Studies varied in salivary glands treated, dosages used, and the use of botulinum toxin subtype A or B. A majority of studies showed benefit after treatment. Although most studies reported only mild adverse effects, 2 case studies revealed severe complications including recurrent TMJ dislocations and rapid deterioration in bulbar function. Ten studies (N = 171) examined the benefits of radiation. Most studies reported improvement with only mild adverse events reported.
CONCLUSIONS: Both radiation and botulinum toxin are effective treatments for sialorrhea in patients with amyotrophic lateral sclerosis and should be considered when medical management fails. Radiation may offer longer duration of symptom improvement with fewer complications.
OBJETIVO: Hasta el 80% de los pacientes con enfermedad de Parkinson y el 30% de los pacientes con esclerosis lateral amiotrófica (ELA) sufren de la sialorrea. Los pacientes que no responden al tratamiento médico y quirúrgico deben ser considerados para la radioterapia de haz externo (RHE). En este estudio, llevamos a cabo una revisión sistemática para determinar la dosis y técnicas utilizadas que dan como resultado mayor eficacia y menor toxicidad para la administración de radioterapia de haz externo en pacientes con enfermedad de Parkinson o la sialorrea ALS asociada.
MÉTODOS Y MATERIALES: Esta revisión incluyó 216 pacientes de entre cuatro y seis prospectivo estudios retrospectivos publicados desde 1998 hasta 2014, con ELA o enfermedad de Parkinson que fueron tratados con radioterapia de haz externo de electrones o fotones para la sialorrea.
RESULTADOS: Un total de 216 pacientes fueron tratados con radioterapia externa a partir de 10 estudios. La indicación para la radioterapia externa fue el fracaso del tratamiento médico alternativo en todos los pacientes con ELA. Para los pacientes con enfermedad de Parkinson, la radioterapia externa es el principal modo de tratamiento en el 68% de los casos. En general, 176 (81%) de 216 pacientes tratados con radioterapia externa para la sialorrea reportado mejoría sintomática de la línea de base. El objetivo más común era el inferior dos tercios de las glándulas parótidas bilaterales y enteras las glándulas submandibulares bilaterales. El número total de pacientes que experimentaron toxicidad a corto plazo fue de 86 de 216 pacientes (40%). El número total de pacientes que experimentaron toxicidad a largo plazo fue de 24 de 207 (12%).
CONCLUSIONES: radioterapia externa es un tratamiento eficaz para la sialorrea en pacientes que padecen ALS o enfermedad de Parkinson. El tratamiento de las glándulas submandibulares bilaterales y glándulas parótidas caudal es el arreglo de campo más común.
Nivel de evidencia: NA laringoscopio de 2015.
OBJECTIVE: A significant fraction of patients with amyotrophic lateral sclerosis (ALS) are unable to swallow saliva, which may result in the spillage of saliva outside of the oral cavity. Although anticholinergic agents and botulin toxin injections are considered the first line of treatment, they have not been effective for all patients. We performed a literature search on therapeutic salivary gland irradiation in patients with ALS.
METHODS: We searched the PubMed for English language publications up to December 2014 on therapeutic salivary gland irradiation in patients with ALS. The search was performed using the following key words: amyotrophic lateral sclerosis, excessive salivation, sialorrhea, and radiation therapy.
RESULTS: The majority of ALS patients with excessive salivation respond well to salivary gland irradiation. The whole bilateral submandibular, and whole or partial bilateral parotid glands have been the target tissue for radiation therapy in most of the published studies. Various radiation therapy regimens have been utilized. The response to radiation therapy lasts for several months.
CONCLUSIONS: The majority of ALS patients with excessive salivation respond well to salivary gland irradiation. Neurologists should consider this treatment option for select patients with ALS and excessive salivation.
Neurotoxina botulínica (BoNT) se puede inyectar para lograr un beneficio terapéutico a través de una amplia gama de condiciones clínicas. Para evaluar la eficacia y seguridad de inyecciones de NTBo para el tratamiento de ciertos trastornos de hipersecreción, incluyendo la hiperhidrosis, sialorrea, y rinorrea crónica, un panel de expertos revisado la evidencia de la literatura publicada. Las fuentes de datos incluyen estudios de Inglés-idioma identificados a través de MEDLINE, EMBASE, CINAHL, Current Contents y el Registro Central Cochrane de Ensayos Controlados. Tablas de evidencia que se generan en el Informe de la Subcomisión de las Tecnologías Terapéutica y Evaluación de la Academia Americana de Neurología (AAN) revisión del uso de la NTBo para los trastornos autonómicos de 2008 también fueron revisadas y actualizadas. El panel evaluó pruebas en varios niveles, el apoyo de BoNT como una clase, los serotipos de BoNT-A y BoNT-B, así como las cuatro formulaciones individuales disponibles comercialmente: abobotulinumtoxinA (A / Abo), toxina botulínica tipo A (A / Ona), incobotulinumtoxinA ( A / Inco) y rimabotulinumtoxinB (B / Rima). El grupo finalmente hizo recomendaciones para cada indicación terapéutica, basada en la fuerza de la evidencia clínica y siguiendo el modelo de clasificación AAN. Para el tratamiento del hiperhidrosis axilar en un total de 923 pacientes, la evidencia apoya el Nivel A recomendación de la NTBo-A, con una recomendación de nivel B para A / Abo y A / Ona y una recomendación U Nivel (datos insuficientes) para A / Inco y B / Rima. Cinco ensayos en 82 pacientes apoyaron el uso de la NTBo en la hiperhidrosis palmar, con una recomendación de nivel B de la NTBo-A y una recomendación C Nivel de NTBo-B, formulaciones individuales recibieron una calificación de U Nivel por falta de datos. BoNT (y todas las formulaciones individuales) recibió una recomendación U de nivel para el tratamiento de la sudoración gustativa. Soporte para el uso de la NTBo en sialorrea se deriva de ocho ensayos en un total de 222 adultos y niños. La evidencia apoya una recomendación de nivel B para A / Abo, A / Ona y B / Rima y una recomendación U Nivel de A / Inco. La evidencia apoya una recomendación Nivel B para A / Ona para el tratamiento de la rinitis alérgica, sobre la base de dos estudios clase II en 73 pacientes. A falta de estudios publicados para A / Abo, A / Inco, o B / Rima apoya la recomendación U Nivel de las formulaciones. Más claridad sobre el modo óptimo de administración y estudios adicionales usando otras formulaciones de NTBo se necesitan para llenar los huecos vacíos actuales.
OBJETIVOS: La toxina botulínica se ha convertido en un método eficaz para el tratamiento de la sialorrea. Este estudio presenta una revisión de la literatura crítica y meta-análisis para determinar el impacto de la toxina botulínica en el babeo severidad en pacientes con sialorrea.
FUENTES DE INFORMACIÓN: Ovid MEDLINE y las bases de datos Cochrane.
REVISAR LOS MÉTODOS: Las fuentes antes mencionadas se realizaron búsquedas para identificar los estudios que examinan la toxina botulínica para el tratamiento de la sialorrea. Los estudios incluidos fueron ensayos aleatorios, controlados con placebo. Estudios excluidos no informaron medidas de resultados cuantificables de babeo severidad a las 4 semanas después de la intervención.
RESULTADOS: Ocho estudios con 181 pacientes (83 con placebo; 98 activo) se incluyeron en el análisis. Se encontró toxina botulínica para reducir significativamente la severidad de babeo en los pacientes con sialorrea (diferencia de medias estandarizada [DME] -1,54; intervalo de confianza del 95% [IC]: -2,05 a -1,04, p = 0,06; I (2) = 48%) en comparación con el control de placebo utilizando modelos de efectos aleatorios. El efecto fue significativo tanto para adultos (SMD -1.29, IC del 95%: -1,88 a -0,71) y pediátricos (SMD -1.84, IC del 95%: -2,67 a -1,00) poblaciones. Tanto la toxina botulínica A (SMD -1.53, IC del 95%: -2,27 a -0,79) y B (SMD -1.56, IC del 95%: -2,32 a -0,79) produjeron efectos similares. Dosis de toxina botulínica más de 50 U (SMD -3.81, IC del 95%: -6,19 a -1,43) producen un efecto mucho mayor en comparación con la dosis menor o igual a 50 U (SMD -1.32, IC 95%, -2,28 a -0.36).
CONCLUSIÓN: La toxina botulínica es un tratamiento clínicamente eficaz que mejora babeo severidad en pacientes con sialorrea. Los estudios futuros deberán evaluar más a fondo la técnica y examinar las dosis necesarias para lograr resultados óptimos.
Fifty percent of patients with amyotrophic lateral sclerosis (ALS) experience problems handling serous saliva and 20% fail to achieve adequate control of sialorrhea with anticholinergic medications, or experience intolerable adverse effects from these drugs. Both botulinum and radiotherapy have been suggested in the literature as treatments for intractable sialorrhea. In this review, we assess the evidence for the effectiveness and toxicity of botulinum toxin and radiotherapy for sialorrhea in patients with ALS. Relevant studies were retrieved from Medline, Embase and Cochrane Databases. Handsearching of Neurology, Journal of Pain and Symptom Management, and Palliative Medicine and of reference lists, was carried out. Five studies (28 patients) were included in the analysis of botulinum. Of the four studies using an intraglandular method of injection, no adverse effects occurred. Two of these had positive findings of the effect of botulinum in salivary secretion rate and quality of life. In contrast, significant adverse effects were experienced by two patients in a study of retrograde injections into the salivary ducts. Two studies were included in the analysis of radiotherapy (27 patients). Both demonstrated a positive effect of radiotherapy on salivary secretion rate. Some patients experienced mild acute side effects. Because of the small numbers of studies, small sample sizes, and poor quality of reporting, it is not possible to draw firm conclusions. There is some evidence indicating that both botulinum and radiotherapy are well tolerated, effective treatments for persistent sialorrhea in patients with ALS and that the duration of action is up to three months with botulinum and six months with radiotherapy.
Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011.
OBJECTIVES:
To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery.
SEARCH METHODS:
On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers.
SELECTION CRITERIA:
We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND.
DATA COLLECTION AND ANALYSIS:
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS:
We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect. Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment.
AUTHORS' CONCLUSIONS:
There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.
