Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis

Vucic, Steve; Krishnan, Arun V.; Kiernan, Matthew C.

doi:10.1136/jnnp.2006.112078

Cited by 54 publications

(37 citation statements)

References 53 publications

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“…IVIg has both direct adverse effects as reported here, as well as indirect adverse effects such as the often considerable time burden associated with the infusions, prolongation of the period of diagnostic uncertainty for the patient, delay of institution of other appropriate treatments, and the lingering fatigue that often accompanies IVIg treatment 22 that may compound this common symptom in ALS. 23,24 Hence, based on the findings of the present study, IVIg treatment is recommended for those patients in whom there is a possibility of a positive response, specifically those patients with a normal CK, EMG abnormalities confined to the areas of weakness, and distal, asymmetric limb weakness.…”

Section: Methodology and Treatmentmentioning

confidence: 84%

Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block?

2013

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Objective: To evaluate the likelihood of response to IV immunoglobulin (IVIg) by studying consecutive patients presenting with progressive, asymmetric, pure lower motor neuron (LMN) limb weakness, and to determine the clinical phenotype of those who respond.Methods: Thirty-one consecutive patients with progressive, focal-onset LMN limb weakness, without evidence of clinical upper motor neuron signs; sensory, respiratory, or bulbar involvement; or evidence of motor nerve conduction block on electrodiagnostic studies, were prospectively included in this study. Each patient underwent treatment with IVIg (2 g/kg) for a minimum of 3 months. Electrodiagnostic studies, a neuromuscular symptom score, and expanded Medical Research Council sum score were documented before and after IVIg treatment. The final diagnosis was determined after prolonged clinical follow-up.Results: Only 3 of 31 patients (10%) responded to IVIg. All responders demonstrated distal upper limb-onset weakness, EMG abnormalities confined to the clinically weak muscles, and a normal creatine kinase. This set of features was also identified in 31% of nonresponders presenting with distal upper limb weakness. Sex, age at onset, number of involved limb regions, and the duration of symptoms before treatment were not significantly different between groups. Conclusion:The findings of the present study do not support uniform use of IVIg in patients presenting with progressive asymmetric LMN limb weakness. It is suggested that IVIg treatment be limited to patients who demonstrate clinical and laboratory features suggestive of multifocal motor neuropathy. Classification of evidence:This study provides Class IV evidence that IVIg will not improve muscle function in 90% of patients with progressive, asymmetric, pure LMN weakness. Neurology ® 2013;81:2116-2120 GLOSSARY ALS 5 amyotrophic lateral sclerosis; CB 5 conduction block; CK 5 creatine kinase; CMAP 5 compound muscle action potential; EMRCSS 5 expanded Medical Research Council sum score; GM1 5 ganglioside M1; HRUS 5 high-resolution ultrasonography; IVIg 5 IV immunoglobulin; LMN 5 lower motor neuron; MMN 5 multifocal motor neuropathy; NCS 5 nerve conduction studies; NSS 5 neuromuscular symptom score; PLMNS 5 progressive lower motor neuron syndrome; PMA 5 progressive muscular atrophy; UL 5 upper limb; UMN 5 upper motor neuron.

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Section: Methodology and Treatmentmentioning

confidence: 84%

Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block?

2013

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“…Ensemble neuronal activity recorded from ALS patients (Vucic et al, 2007;de Carvalho et al, 2012), mouse models (e.g., SOD1-G93A; van Zundert et al, 2012), or single unit recordings from cultured motor neurons (Kuo et al, 2004;Le Masson et al, 2014) reveal chronic and persistent hyperexcitability in motor neurons in ALS. In addition, the s-1R KO/SOD1-G93A mouse shows enhanced neuronal activity when compared with the SOD1-G93A mouse alone (Mavlyutov et al, 2015b), suggesting that the s-1R may modulate neuronal excitability.…”

Section: Disrupted Subcellular Dynamics Of S-1r Mutantsmentioning

confidence: 99%

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

et al. 2016

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The sigma-1 receptor (s-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two s-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (D31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The s-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K 1 channel K ir 2.1, compared with the wild-type s-1R. Thus, these s-1R mutants have different functional properties that could contribute to their disease phenotypes.

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“…In addition, motoneuron hyperexcitability is also a pathological feature late in ALS disease progression (Kanai et al 2006;Tamura et al 2006;Kiernan 2006a, 2006b;Vucic et al 2007Vucic et al , 2008. We therefore hypothesized that further increasing motoneuron excitability at any age would be detrimental to SOD1 G93A mice because it would enhance these pathological features, increasing metabolic demands and exacerbating any excitotoxic effects.…”

Section: Discussionmentioning

confidence: 99%

“…In these patients motoneuron hyperexcitability is a pathological feature (Kanai et al 2006;Tamura et al 2006;Kiernan 2006a, 2006b;Vucic et al 2007Vucic et al , 2008, and at therapeutic doses riluzole, still the only FDA-approved drug to treat ALS, is known to decrease motoneuron excitability through inhibition of persistent inward currents (PICs) and glutamate release (Coderre et al 2007;Del Negro et al 2005;Harvey et al 2006c;Lamanauskas and Nistri 2008;Mantz et al 1992;Martin et al 1993;Miles et al 2005;Theiss et al 2007;Zona et al 2002).…”

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confidence: 99%

Effect of fluoxetine on disease progression in a mouse model of ALS

Koschnitzky

Quinlan

Lukas

et al. 2014

Journal of Neurophysiology

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Koschnitzky JE, Quinlan KA, Lukas TJ, Kajtaz E, Kocevar EJ, Mayers WF, Siddique T, Heckman CJ. Effect of fluoxetine on disease progression in a mouse model of ALS. J Neurophysiol 111: 2164-2176, 2014. First published March 5, 2014 doi:10.1152/jn.00425.2013.-Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1 G93A and control: nontransgenic and SOD1 WT ) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1 G93A mice reached end stage ϳ8 days (ϳ6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. amyotrophic lateral sclerosis; motoneuron excitability; fluoxetine; Prozac; antidepressant

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Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis

Abstract: Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.

Cited by 54 publications

References 53 publications

Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block?

Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block?

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Effect of fluoxetine on disease progression in a mouse model of ALS

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