Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.

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 We contacted known experts in the field to identify further published and unpublished papers.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.

Patent foramen ovale and migraine: what is the relationship between the two?

There is conflicting evidence on the causal relationship of patent foramen ovale (PFO) in migraine. This review will examine the pathophysiological relevance of PFO in migraine, the epidemiological evidence of PFO causing migraine, and the existing evidence on the effectiveness of closure of PFO on the symptomatology of migraine. From the current available evidence, the role of PFO in migraine is debatable, and interventions such as closure of PFO cannot yet be considered routine treatment of migraine.

Statin induced myotoxicity.

Statins are an effective treatment for the prevention of cardiovascular diseases and used extensively worldwide. However, myotoxicity induced by statins is a common adverse event and a major barrier to maximising cardiovascular risk reduction. The clinical spectrum of statin induced myotoxicity includes asymptomatic rise in creatine kinase concentration, myalgia, myositis and rhabdomyolysis. In certain cases, the cessation of statin therapy does not result in the resolution of muscular symptoms or the normalization of creatine kinase, raising the possibility of necrotizing autoimmune myopathy. There is increasing understanding and recognition of the pathophysiology and risk factors of statin induced myotoxicity. Careful history and physical examination in conjunction with selected investigations such as creatine kinase measurement, electromyography and muscle biopsy in appropriate clinical scenario help diagnose the condition. The management of statin induced myotoxicity involves statin cessation, the use of alternative lipid lowering agents or treatment regimes, and in the case of necrotizing autoimmune myopathy, immunosuppression.

Current and emerging treatments for the management of myasthenia gravis.

Myasthenia gravis is an autoimmune neuromuscular disorder. There are several treatment options, including symptomatic treatment (acetylcholinesterase inhibitors), short-term immunosuppression (corticosteroids), long-term immunosuppression (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mycophenolate mofetil, rituximab, tacrolimus), rapid acting short-term immunomodulation (intravenous immunoglobulin, plasma exchange), and long-term immunomodulation (thymectomy). This review explores in detail these different treatment options. Potential future treatments are also discussed.

Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.

BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a progressive, neurodegenerative condition which may cause dysphagia, as well as limb weakness, dysarthria, emotional lability and respiratory failure. Since normal salivary production is 0.5 to 1.5 litres daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to patients. OBJECTIVES: To systematically review evidence on treatment of sialorrhea in MND, including medications, radiotherapy and surgery. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (1 October 2010), the Cochrane Central Register of Controlled Trials )(CENTRAL) (The Cochrane Library issue 3, 2010), MEDLINE (January 1966 to September 2010), EMBASE (January 1980 to September 2010), AMED (1985 to September 2010) and CINAHL Plus (January 1937 September 2010). All bibliographies of the identified randomized trials were reviewed and authors contacted as needed. Known experts in the field were contacted to identify further published and unpublished papers. SELECTION CRITERIA: We included randomized and quasi-randomised controlled studies on any intervention for sialorrhea and related symptoms, in people with MND. DATA COLLECTION AND ANALYSIS: Review authors summarised data independently in a customised data collection form and confirmed data presented in Cochrane Review Manager software. MAIN RESULTS: Only one randomized controlled trial was identified. This was a well designed study of botulinum toxin B injected into parotid and submandibular glands of 20 patients, which showed positive results for four weeks (Jackson 2009). There was low risk of bias in the study and no significant adverse events reported. AUTHORS' CONCLUSIONS: There is some evidence for use of botulinum toxin injections to salivary glands for the treatment of sialorrhea in MND. Further research is required on this important symptom. Data are needed on the problem of sialorrhea in MND and its measurement, both by patient self report measures and objective tests. These will allow the development of better randomized controlled trials.

Managing patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common rapidly progressive adult-onset neurodegenerative disorder. There have been great advances in the management of patients with ALS over the past decade. It starts with the giving of the diagnosis and continues to the terminal phase of the disease. This review will examine the impact of medical and non-medical interventions on improving survival and quality of life in these patients, emphasizing the importance of a multidisciplinary approach.

VEGF and ALS.

In amyotrophic lateral sclerosis (ALS), an adult-onset progressive degeneration of motor neurons occurring as sporadic and familial disease, there is emerging evidence for and against the role of vascular endothelial growth factor (VEGF), an endothelial cell mitogen crucial for angiogenesis, in its etiopathogenesis. Our understanding of the role of VEGF in ALS has come from studies of both experimental models and human cases. In this article, I have examined in detail the in vitro and in vivo evidence for and against VEGF in ALS, concluding that more compelling evidence is required before we can conclusively link VEGF to ALS in humans.

Steroids and immunosuppressant drugs in myasthenia gravis.

In chronic autoimmune conditions such as myasthenia gravis (MG), immunosuppression--usually long-term--is often necessary. The mechanisms of action of immunosuppressant drugs in MG fall into three main categories: inhibition of the cell cycle (azathioprine, cyclophosphamide, methotrexate and mycophenolate mofetil), immunosuppression of T cells (steroids, ciclosporin and tacrolimus), and B-cell depletion (rituximab). Data on immunosuppressant drugs in MG derive mainly from clinical experience, observational studies and expert opinion. The main drawbacks of the randomized evidence are the small size of most drug trials, variations in study design, and a lack of head-to-head studies. It is therefore difficult to determine the relative efficacy of each immunosuppressant. Oral prednisolone, usually started at a low dose on an alternate-day regimen, and gradually increased, is the recommended first-choice short-term immunosuppressant. Long-term immunosuppression regimens vary between different countries and physicians. Azathioprine is often the first-choice drug for long-term immunosuppression, and it is usually started together with steroids to allow tapering of steroids to the lowest dose possible. Methotrexate, mycophenolate mofetil or tacrolimus should be considered in patients who are intolerant of or unresponsive to azathioprine. Ciclosporin and cyclophosphamide should only be considered as a last resort, as these drugs can cause serious adverse events. Data on rituximab use in MG are sparse, but the initial results are promising.

Brown-Vialetto-Van Laere syndrome.

The Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurological disorder characterized by progressive pontobulbar palsy associated with sensorineural deafness. Fifty-eight cases have been reported in just over 100 years. The female to male ratio is approximately 3:1. The age of onset of the initial symptom varies from infancy to the third decade. The syndrome most frequently presents with sensorineural deafness, which is usually progressive and severe. Lower cranial nerve involvement and lower and upper motor neuron limb signs are common neurological features. Other features include respiratory compromise (the most frequent non-neurological finding), limb weakness, slurring of speech, facial weakness, and neck and shoulder weakness. Optic atrophy, retinitis pigmentosa, macular hyperpigmentation, autonomic dysfunction, epilepsy may occur. The etiopathogenesis of the condition remains elusive. Approximately 50% of cases are familial, of which autosomal recessive is suggested. The remaining cases are sporadic. The diagnosis is usually based on the clinical presentation. Investigations (neurophysiological studies, magnetic resonance imaging of the brain, muscle biopsy, cerebrospinal fluid examination) are done to exclude other causes or to confirm the clinical findings. The differential diagnoses include the Fazio-Londe syndrome, amyotrophic lateral sclerosis, Nathalie syndrome, Boltshauser syndrome and Madras motor neuron disease. Treatment with steroids or intravenous immunoglobulin may result in temporary stabilization of the syndrome. However, the mainstays of management are supportive and symptomatic treatment, in particular assisted ventilation and maintenance of nutrition via gastrostomy. The clinical course of BVVL is variable and includes gradual deterioration (almost half of cases), gradual deterioration with stable periods in between (a third of cases) and deterioration with abrupt periods of worsening (just under a fifth of cases). After the initial presentation, one third of patients survive for ten years or longer.

Susac syndrome in a patient with hepatitis C.

A 38-year-old woman seropositive for hepatitis C developed headache, sensorineural hearing loss, encephalopathy, and retinal arteriolar occlusions. Brain MRI showed signal abnormalities in the basal ganglia and corpus callosum. These features are consistent with Susac syndrome, a multifocal central nervous system disorder of uncertain etiology. This is the first reported case of Susac syndrome in a patient with hepatitis C.

Apoptosis in amyotrophic lateral sclerosis--what is the evidence?

There is increasing evidence that a programmed mechanism of cell death resembling apoptosis is responsible for motor-neuron degeneration in amyotrophic lateral sclerosis. Our understanding of the cell-death pathway has come from studies of both experimental models and human tissue. Here we examine in detail the in vitro and in vivo evidence for and against apoptosis in amyotrophic lateral sclerosis, looking at morphological changes, caspase activation, alterations in Bcl-2 oncoproteins, involvement of death receptors, expression of apoptosis-related molecules, and the role of the p53 pathway. Finally, we present evidence of potential therapeutic agents that could modulate the apoptotic pathway in amyotrophic lateral sclerosis and slow disease progression.