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The Cochrane Database of Systematic... Mar 2018Acquired brain injury can cause eye movement disorders which may include: strabismus, gaze deficits and nystagmus, causing visual symptoms of double, blurred or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acquired brain injury can cause eye movement disorders which may include: strabismus, gaze deficits and nystagmus, causing visual symptoms of double, blurred or 'juddery' vision and reading difficulties. A wide range of interventions exist that have potential to alleviate or ameliorate these symptoms. There is a need to evaluate the effectiveness of these interventions and the timing of their implementation.
OBJECTIVES
We aimed to assess the effectiveness of any intervention and determine the effect of timing of intervention in the treatment of strabismus, gaze deficits and nystagmus due to acquired brain injury. We considered restitutive, substitutive, compensatory or pharmacological interventions separately and compared them to control, placebo, alternative treatment or no treatment for improving ocular alignment or motility (or both).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (containing the Cochrane Eyes and Vision Trials Register) (2017, Issue 5), MEDLINE Ovid, Embase Ovid, CINAHL EBSCO, AMED Ovid, PsycINFO Ovid, Dissertations & Theses (PQDT) database, PsycBITE (Psychological Database for Brain Impairment Treatment Efficacy), ISRCTN registry, ClinicalTrials.gov, Health Services Research Projects in Progress (HSRProj), National Eye Institute Clinical Studies Database and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The databases were last searched on 26 June 2017. No date or language restrictions were used in the electronic searches for trials. We manually searched the Australian Orthoptic Journal, British and Irish Orthoptic Journal, and ESA, ISA and IOA conference proceedings. We contacted researchers active in this field for information about further published or unpublished studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of any intervention for ocular alignment or motility deficits (or both) due to acquired brain injury.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies and extracted data. We used standard methods expected by Cochrane. We employed the GRADE approach to interpret findings and assess the quality of the evidence.
MAIN RESULTS
We found five RCTs (116 participants) that were eligible for inclusion. These trials included conditions of acquired nystagmus, sixth cranial nerve palsy and traumatic brain injury-induced ocular motility defects. We did not identify any relevant studies of restitutive interventions.We identified one UK-based trial of a substitutive intervention, in which botulinum toxin was compared with observation in 47 people with acute sixth nerve palsy. At four months after entry into the trial, people given botulinum toxin were more likely to make a full recovery (reduction in angle of deviation within 10 prism dioptres), compared with observation (risk ratio 1.19, 95% CI 0.96 to 1.48; low-certainty evidence). These same participants also achieved binocular single vision. In the injection group only, there were 2 cases of transient ptosis out of 22 participants (9%), and 4 participants out of 22 (18%) with transient vertical deviation; a total complication rate of 24% per injection and 27% per participant. All adverse events recovered. We judged the certainty of evidence as low, downgrading for risk of bias and imprecision. It was not possible to mask investigators or participants to allocation, and the follow-up between groups varied.We identified one USA-based cross-over trial of a compensatory intervention. Oculomotor rehabilitation was compared with sham training in 12 people with mild traumatic brain injury, at least one year after the injury. We judged the evidence from this study to be very low-certainty. The study was small, data for the sham training group were not fully reported, and it was unclear if a cross-over study design was appropriate as this is an intervention with potential to have a permanent effect.We identified three cross-over studies of pharmacological interventions for acquired nystagmus, which took place in Germany and the USA. These studies investigated two classes of pharmacological interventions: GABAergic drugs (gabapentin, baclofen) and aminopyridines (4-aminopyridines (AP), 3,4-diaminopyridine (DAP)). We judged the evidence from all three studies as very low-certainty because of small numbers of participants (which led to imprecision) and risk of bias (they were cross-over studies which did not report data in a way that permitted estimation of effect size).One study compared gabapentin (up to 900 mg/day) with baclofen (up to 30 mg/day) in 21 people with pendular and jerk nystagmus. The follow-up period was two weeks. This study provides very low-certainty evidence that gabapentin may work better than baclofen in improving ocular motility and reducing participant-reported symptoms (oscillopsia). These effects may be different in pendular and jerk nystagmus, but without formal subgroup analysis it is unclear if the difference between the two types of nystagmus was chance finding. Quality of life was not reported. Ten participants with pendular nystagmus chose to continue treatment with gabapentin, and one with baclofen. Two participants with jerk nystagmus chose to continue treatment with gabapentin, and one with baclofen. Drug intolerance was reported in one person receiving gabapentin and in four participants receiving baclofen. Increased ataxia was reported in three participants receiving gabapentin and two participants receiving baclofen.One study compared a single dose of 3,4-DAP (20 mg) with placebo in 17 people with downbeat nystagmus. Assessments were made 30 minutes after taking the drug. This study provides very low-certainty evidence that 3,4-DAP may reduce the mean peak slow-phase velocity, with less oscillopsia, in people with downbeat nystagmus. Three participants reported transient side effects of minor perioral/distal paraesthesia.One study compared a single dose of 4-AP with a single dose of 3,4-DAP (both 10 mg doses) in eight people with downbeat nystagmus. Assessments were made 45 and 90 minutes after drug administration. This study provides very low-certainty evidence that both 3,4-DAP and 4-AP may reduce the mean slow-phase velocity in people with downbeat nystagmus. This effect may be stronger with 4-AP.
AUTHORS' CONCLUSIONS
The included studies provide insufficient evidence to inform decisions about treatments specifically for eye movement disorders that occur following acquired brain injury. No information was obtained on the cost of treatment or measures of participant satisfaction relating to treatment options and effectiveness. It was possible to describe the outcome of treatment in each trial and ascertain the occurrence of adverse events.
Topics: 4-Aminopyridine; Abducens Nerve Diseases; Amifampridine; Amines; Baclofen; Botulinum Toxins; Brain Injuries; Cyclohexanecarboxylic Acids; Gabapentin; Humans; Neuromuscular Agents; Nystagmus, Pathologic; Ocular Motility Disorders; Randomized Controlled Trials as Topic; Vision, Binocular; Watchful Waiting; gamma-Aminobutyric Acid
PubMed: 29505103
DOI: 10.1002/14651858.CD011290.pub2 -
Neurology and Therapy Dec 2015Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting the neuromuscular junction, clinically characterized by proximal muscle weakness and...
INTRODUCTION
Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting the neuromuscular junction, clinically characterized by proximal muscle weakness and autonomic changes. LEMS is often associated with an underlying tumor (paraneoplastic form) but also occurs in the absence of cancer (idiopathic form). Treatment consists of immunomodulation (immunosuppression), anticancer treatment when carcinoma is present, and symptomatic treatment [acetylcholinesterase inhibitors and potassium channel blockers, e.g., amifampridine (3,4-diaminopyridine, i.e., 3,4-DAP), to improve neurotransmission]. Although there has long been information from case reports, several randomized controlled trials, and treatment guidelines, population data are still scarce.
METHODS
The LEMS patient registry was launched in the European community in mid-2010 as a voluntary, multinational, observational, non-interventional program to collect structured empirical data on clinical course, treatment utilization, and safety and efficacy from the use of LEMS-specific treatments.
RESULTS
Sixty-nine patients have been enrolled [36 males, 32 females, 1 gender not reported; mean age 61.5 (27-84) years]. Eighteen patients (26%) were diagnosed with an associated carcinoma. At the time of enrollment, the majority of patients (65%) were receiving amifampridine [either compounded 3,4-DAP (22%) or 3,4-DAP phosphate, Firdapse(®) (43%)]. At enrollment, most patients demonstrate a profile of mild-to-moderate deficits in daily functioning but generally have good muscle strength, albeit with reduced deep tendon reflexes, frequent ataxia during walking, and signs of autonomic dysfunction including dry mouth, bladder dysfunction, and constipation.
CONCLUSION
The LEMS European Union registry will continue to enroll patients and periodically report the accrued longitudinal data obtained on clinical assessments and laboratory findings, treatment practices, the safety and efficacy of treatment approaches, and long-term clinical outcomes.
FUNDING
BioMarin Pharmaceutical Inc., Novato, CA, USA.
PubMed: 26525537
DOI: 10.1007/s40120-015-0034-0 -
Neurology and Therapy Sep 2022Lambert-Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal...
INTRODUCTION
Lambert-Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal muscle weakness, decreased tendon reflexes, and autonomic changes. The European LEMS registry aimed to collate observational safety data for 3,4-diaminopyridine phosphate (3,4-DAPP) and examine long-term outcomes for patients with LEMS.
METHODS
Thirty centers across four countries participated in the non-interventional European LEMS registry. Any patients diagnosed with LEMS by means of clinical assessment and abnormal neurophysiological testing, or clinical assessment and positive for VGCC antibodies were eligible to participate. Patients were monitored using standard assessments for LEMS-related clinical manifestations.
RESULTS
Among 96 evaluable participants, 50 (52.1%) were being treated with 3,4-DAPP, 21 (21.9%) with 3,4-diaminopyridine (3,4-DAP), and 25 (26.0%) with other treatments (e.g., pyridostigmine, corticosteroids, immunoglobulins, and azathioprine); 74 participants (77.1%) were exposed to 3,4-DAPP at any time. Quantitative myasthenia gravis scores were similar across treatment groups. Muscle strength was generally good and maintained during follow-up. Cerebellar ataxia, defined as a negative Romberg's test and at least one other positive ataxia test, was observed in 30 (56.6%) patients. Most participants had reduced reflex tone and limited functioning. Sustained or improved functioning was observed in participants administered 3,4-DAPP. Inconsistent and sporadic functional improvement and regression was observed with 3,4-DAP and other treatments. Fifty-five treatment-related adverse events (AEs) were reported by 32 (33.3%) participants. Eight (8.3%) participants reported nine treatment-related serious AEs. No new safety signals were identified.
CONCLUSION
No new safety signals were observed following long-term management of LEMS with 3,4-DAPP.
PubMed: 35511347
DOI: 10.1007/s40120-022-00354-8 -
Acta Pharmacologica Sinica Jun 2004Botulinum neurotoxins (BoNTs), a group of bacterial proteins that comprise a light chain disulfide linked a heavy chain, are the most lethal biotoxins known to mankind.... (Review)
Review
Botulinum neurotoxins (BoNTs), a group of bacterial proteins that comprise a light chain disulfide linked a heavy chain, are the most lethal biotoxins known to mankind. By inhibiting neurotransmitter release, BoNTs cause severe neuroparalytic disease, botulism. A series of important findings in the past 10 years which displayed the molecular targets of BoNTs and hence proposed a four-step action mechanism to explain BoNT intoxication greatly advanced the study of antibotulismic drug. In this article, we reviewed these progresses and anti-botulismic compounds found in recent years. These compounds function due to their facilitation on neurotransmitter release or to their interference on the binding, internalization, translocation, and endopeptidase activity of the toxins. Toosendanin is a triterpenoid derivative extracted from a digestive tract-parasiticide in Chinese traditional medicine. Chinese scientists have found that the compound is a selective prejunctional blocker. In spite of sharing some similar action with BoNT, toosendanin can protect botulism animals that have been administrated with lethal doses of BoNT/A or BoNT/B for several hours from death and make them restore normal activity. The neuromuscular junction preparations isolated from the rats that have been injected with toosendanin tolerate BoNT/A challenge. Toosendanin seems to have no effect on endopeptidase activity of BoNT, but blocks the toxin approach to its enzymatic substrate.
Topics: 4-Aminopyridine; Amifampridine; Animals; Botulinum Toxins; Botulism; Drugs, Chinese Herbal; Melia; Neurotransmitter Agents; Plants, Medicinal; Potassium Channel Blockers
PubMed: 15169642
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... May 20213,4-Diaminopyridine (3,4-DAP) and its phosphate form, 3,4-DAPP have been used efficiently in the past years to treat muscular weakness in myasthenic syndromes with...
3,4-Diaminopyridine (3,4-DAP) and its phosphate form, 3,4-DAPP have been used efficiently in the past years to treat muscular weakness in myasthenic syndromes with neuromuscular junctions (NMJs) impairment. Pompe disease (PD), an autosomal recessive metabolic disorder due to a defect of the lysosomal enzyme α-glucosidase (GAA), presents some secondary symptoms that are related to neuromuscular transmission dysfunction, resulting in endurance and strength failure. In order to evaluate whether 3,4-DAPP could have a beneficial effect on this pathology, we took advantage of a transient zebrafish PD model that we previously generated and characterized. We investigated presynaptic and postsynaptic structures, NMJs at the electron microscopy level, and zebrafish behavior, before and after treatment with 3,4-DAPP. After drug administration, we observed an increase in the number of acetylcholine receptors an increment in the percentage of NMJs with normal structure and amelioration in embryo behavior, with recovery of typical movements that were lost in the embryo PD model. Our results revealed early NMJ impairment in Pompe zebrafish model with improvement after administration of 3,4-DAPP, suggesting its potential use as symptomatic drug in patients with Pompe disease.
Topics: Amifampridine; Animals; Behavior, Animal; Embryo, Nonmammalian; Glycogen Storage Disease Type II; Motor Activity; Muscle Fibers, Skeletal; Neuromuscular Junction; Receptors, Cholinergic; Zebrafish; alpha-Glucosidases
PubMed: 33724918
DOI: 10.1016/j.biopha.2021.111357 -
Neurology Dec 2015To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and...
OBJECTIVES
To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release.
METHODS
We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine.
RESULTS
Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission.
CONCLUSION
SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.
Topics: 4-Aminopyridine; Adolescent; Adult; Aged; Amifampridine; Child; Electrophysiological Phenomena; Female; Humans; Male; Middle Aged; Mutation; Myasthenic Syndromes, Congenital; Potassium Channel Blockers; Pyridostigmine Bromide; Reflex; Synaptic Transmission; Synaptotagmin II; Young Adult
PubMed: 26519543
DOI: 10.1212/WNL.0000000000002185 -
JCI Insight Jan 2020Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning...
Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning is infusion of antitoxin immunoglobulins. However, antitoxins have poor therapeutic efficacy in symptomatic patients; thus, there is an urgent need for treatments that reduce the need for artificial ventilation. We report that the US Food and Drug Administration-approved potassium channel blocker 3,4-diaminopyridine (3,4-DAP) reverses respiratory depression and neuromuscular weakness in murine models of acute and chronic botulism. In ex vivo studies, 3,4-DAP restored end-plate potentials and twitch contractions of diaphragms isolated from mice at terminal stages of BoNT serotype A (BoNT/A) botulism. In vivo, human-equivalent doses of 3,4-DAP reversed signs of severe respiratory depression and restored mobility in BoNT/A-intoxicated mice at terminal stages of respiratory collapse. Multiple-dosing administration of 3,4-DAP improved respiration and extended survival at up to 5 LD50 BoNT/A. Finally, 3,4-DAP reduced gastrocnemius muscle paralysis and reversed respiratory depression in sublethal models of serotype A-, B-, and E-induced botulism. These findings make a compelling argument for repurposing 3,4-DAP to symptomatically treat symptoms of muscle paralysis caused by botulism, independent of serotype. Furthermore, they suggest that 3,4-DAP is effective for a range of botulism symptoms at clinically relevant time points.
Topics: Amifampridine; Animals; Antitoxins; Botulinum Toxins; Botulinum Toxins, Type A; Botulism; Disease Models, Animal; Female; Lethal Dose 50; Mice; Muscle, Skeletal; Paralysis; Potassium Channel Blockers; Serogroup; United States; United States Food and Drug Administration
PubMed: 31996484
DOI: 10.1172/jci.insight.132891 -
Journal of Neuropathology and... Jul 2014Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that primarily involves...
Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that primarily involves motor dysfunction and is usually associated with neuromyotonia (i.e. prolonged muscle contraction resulting from hyperexcitability of peripheral nerves). Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 appeared normal and yielded normal behavioral test results or motor performance, although they moved more slowly and for a smaller fraction of time in an open-field arena than wild-type mice. Muscles, neuromuscular junctions, and nodes of Ranvier were anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at ages 4 and 13 months. Axons were slightly smaller than those in wild-type mice at age 4 months, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. With electromyography, we were unable to detect neuromyotonia even after using supraphysiologic stimuli and stressors such as reduced temperature or 3,4-diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia.
Topics: 4-Aminopyridine; Amifampridine; Animals; Anxiety; Axons; Behavior, Animal; Electromyography; Immunohistochemistry; Isaacs Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Muscle, Skeletal; Mutation; Nerve Tissue Proteins; Peripheral Nervous System Diseases; Phenotype; Postural Balance; Potassium Channel Blockers; Psychomotor Performance
PubMed: 24918641
DOI: 10.1097/NEN.0000000000000085 -
Zhongguo Yao Li Xue Bao = Acta... Jan 1991We used 3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP) as stimuli for evoking [3H]norepinephrine ([3H]NE) release in rabbit hippocampal slices to investigate...
We used 3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP) as stimuli for evoking [3H]norepinephrine ([3H]NE) release in rabbit hippocampal slices to investigate the mechanism underlying the aminopyridines evoked [3H]NE release and the effect of protein kinase C activator phorbol ester PDB. 3,4-DAP and 4-AP evoked [3H]NE release were concentration dependent and enhanced by phorbol ester PDB. 4-AP (300 mumol.L-1) evoked [3H]NE release and enhancement of this evoked release by PDB were antagonized by protein kinase C inhibitor polymyxin B and almost abolished by tetrodotoxin. N-ethylmaleimide inhibited the facilitatory effect of PDB on 3,4-DAP evoked [3H]NE release implicating that G-protein is involved in the modulation of evoked [3H]NE release. 3,4-DAP evoked also dopamine release in caudate nucleus, and acetylcholine release in hippocampus suggesting that the mechanism by which 3,4-DAP evoked transmitters release is similar to that of electrical stimulation.
Topics: 4-Aminopyridine; Amifampridine; Animals; Female; Hippocampus; Male; Norepinephrine; Phorbol 12,13-Dibutyrate; Polymyxin B; Rabbits
PubMed: 1950580
DOI: No ID Found