Clinical applications of surface electromyography in neuromuscular disorders

From Neurophysiologie Clinique/Clinical Neurophysiology, Volume 35, Issues 2-3, July 2005, Pages 59-71

Surface electromyography (SEMG) is still rarely used in clinical settings for the detection and analysis of myoelectric signals. The electromyographic signal detected on the skin surface includes information from a greater proportion of the muscle of interest than conventional clinical EMG, acquired using needle electrodes. SEMG is therefore more representative than the localised, and thus very selective needle EMG signals currently used. However, both reliability and interpretation of surface EMG need to be questioned. This review looks at the studies concerned with the characterisation of neuromuscular pathologies using EMG parameters. After introducing principles and limitations of surface EMG, an overview of the main results obtained in clinical settings is presented and discussed. There is a particular focus on high spatial resolution surface EMG as it is currently the best compromise between the selectivity of needle EMG and the representative nature of classical SEMG. Several perspectives are proposed that underline the fact that surface EMG is an evolving discipline and should be worthy of a place in routine clinical examinations.

A new frontier for molecular medicine: Noncoding RNAs

From Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Article in Press, Corrected Proof

It is now becoming evident that the variety of noncoding RNA (ncRNA) molecules play important roles in many cellular processes and they are not just mere intermediates in transfer of genetic information from DNA to proteins. Recent data, from the analyses of transcriptional activity of human genome, suggest that it may contain roughly equal numbers of protein- and RNA-encoding transcription units. Many of the ncRNAs described in humans as well as in other mammals have been linked, through specific chromosomal localization or expression patterns, with certain diseases including complex congenital syndromes, neurobehavioral and developmental disorders and cancer. These findings clearly indicate that an expression of genes of which end-products are RNA molecules is crucial for development, differentiation and normal functioning of the cells. The ncRNAs expression patterns can therefore be used as molecular markers for specific diagnostic methods.

Prevalence and patterns of cognitive impairment in sporadic ALS

From NEUROLOGY 2005;65:586-590

Objective: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study.

Methods: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes.

Results: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance.

Conclusions: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Frequency of a tau genotype in amyotrophic lateral sclerosis

From Journal of the Neurological Sciences Volume 236, Issues 1-2 , 15 September 2005, Pages 13-16

We investigated the susceptibility of the dinucleotide polymorphism A0 in the tau gene to amyotrophic lateral sclerosis (ALS). In 416 unrelated patients with ALS and 242 control subjects the A0/A0 genotype was not associated with the pooled sample of ALS cases. Subgroup analysis revealed that in sporadic ALS the A0 polymorphism was significantly overrepresented. There was no association of the A0/A0 genotype with the age and site of disease onset or the presence of dementia. The studied tau genotype may contribute to the multifactorial genetic background of ALS.

Analgesic Therapy in Postherpetic Neuralgia: A Quantitative Systematic Review

From PloS Medicine Vol 2(7); 2005

Background
Postherpetic neuralgia (PHN) is a complication of acute herpes zoster, which is emerging as a preferred clinical trial model for chronic neuropathic pain. Although there are published meta-analyses of analgesic therapy in PHN, and neuropathic pain in general, the evidence base has been substantially enhanced by the recent publication of several major trials. Therefore, we have conducted a systematic review and meta-analysis for both efficacy and adverse events of analgesic therapy for PHN.

Methods and Findings
We systematically searched databases (MEDLINE 1966–2004, EMBASE 1988–2004, CINAHL 1982–2002, and PubMed [29 October 2004]) for trials of PHN. We also searched references of retrieved studies and review articles for further trials. We included trials that examined adult patients with PHN of greater duration than 3 mo, that were blinded, randomised, and had at least one measure of pain outcome. Dichotomous pain outcome data were extracted for 50% decrease in baseline pain using a hierarchy of pain/pain-relief measurement tools. Where available, dichotomous data were also collected for adverse events. Calculated estimates of efficacy included relative benefit and number needed to treat.

Of 62 studies identified, 35 were randomised controlled trials. Of these, 31 were placebo controlled and suitable for meta-analysis, from which it was possible to extract dichotomous efficacy outcome data from 25.
This meta-analysis revealed that there is evidence to support the use of the following orally administered therapies: tricyclic antidepressants, “strong” opioids, gabapentin, tramadol, and pregabalin. Topical therapies associated with efficacy were lidocaine 5% patch and capsaicin. Finally, a single study of spinal intrathecal administration of lidocaine and methyl prednisolone demonstrated efficacy, although this has yet to be replicated.
Data suggest that the following therapies are not associated with efficacy in PHN: certain NMDA receptor antagonists (e.g., oral memantine, oral dextromethorphan, intravenous ketamine), codeine, ibuprofen, lorazepam, certain 5HT1 receptor agonists, and acyclovir. Topical administration of benzydamine, diclofenac/diethyl ether, and vincristine (iontophoresis) are similarly not associated with efficacy, nor are intrathecal administration of lidocaine alone or epidural administration of lidocaine and methylprednisolone, intravenous therapy with lidocaine, subcutaneous injection of Cronassial, or acupuncture. However, many of the trials that demonstrated a lack of efficacy represented comparatively low numbers of patient episodes or were single-dose studies, so it may be appropriate to regard such interventions as “not yet adequately tested” rather than demonstrating “no evidence of efficacy.” Topical aspirin/diethyl ether has not been adequately tested.

Conclusion
The evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids in PHN. Topical therapy with lidocaine patches and capsaicin is similarly supported. Intrathecal administration of methylprednisolone appears to be associated with high efficacy, but its safety requires further evaluation.

Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

From BMJ 2005;331:321-327.

Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.

Data sources The terms "donepezil", "rivastigmine", and "galantamine", limited by "randomized-controlled-trials" were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language.

Study selection All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality.

Results 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale—cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws—for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation.

Conclusion Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.

Is carotid endarterectomy safe in patients over 80 years old?

From Nature Clinical Practice Cardiovascular Medicine (2005) 2, 382-383

Background
The most effective treatment for carotid artery stenosis is carotid endarterectomy (CEA). To date, randomized trials of this procedure versus best medical care have excluded patients aged 80 years or more, and consequently elderly individuals with this condition have been labeled 'high risk' for CEA, and are often treated with medical therapy or angioplasty and stenting.

Objective
To identify whether age of 80 years or more increases morbidity, mortality and length of hospital stay after CEA.

Design and intervention
This retrospective review of the Jobst Vascular Registry, a prospective record of vascular procedures carried out at the Toledo Hospital, Ohio, USA, analyzed all patients undergoing CEA between January 1993 and August 2004. The pretreatment characteristics, postoperative complications, surgical outcomes and length of hospitalization of patients were reviewed. Before CEA, patients underwent duplex ultrasonography and four-vessel cerebral arteriography. Most CEAs were performed under general anesthesia with intraoperative shunting; an autologous vein or synthetic patch was used to close the arteriotomy. Patients were monitored in intensive care for 24 h after CEA and followed up at day 7−10 postsurgery if no adverse events occurred.

Outcome measures
The main outcomes were procedure-related stroke and death. Length of hospital stay, destination after leaving hospital or in-hospital mortality, and complications were secondary outcomes. Operative mortality was defined as all deaths attributable to the procedure regardless of the time of occurrence, and included all deaths occurring within 30 days postoperatively, regardless of cause.

Results
In 1,961 patients in the registry, 2,217 CEAs were carried out: 334 patients aged 80 years or more underwent 360 procedures, and the remaining 1,627 patients under 80 years old underwent 1,857 CEAs. The occurrence of postoperative stroke did not differ significantly between the two age groups: 14 (0.8%) strokes occurred in patients under 80 years versus 4 (1.1%) in patients 80 years old or more. Operative mortality was slightly lower in the younger group, compared with the older group (0.8% versus 1.9%, respectively, P = 0.053). Mortality was similar in all asymptomatic patients, but was higher in older symptomatic than older asymptomatic patients (P = 0.007). The combined rate of stroke, death or both was higher in the older group than in the younger group (3.1% versus 1.5%, respectively, P = 0.041), the difference arising from the significantly higher rate seen in the older symptomatic patients compared with older asymptomatic patients. The average postoperative and total length of hospitalization was shorter in the younger than older group (P = 0.001). The groups had similar adverse event rates. Survival curve analysis demonstrated higher mortality in the older age group, however, this was similar to mortality in the normal, age-adjusted population.

Conclusion
Although increased, the combined stroke and death rate in patients aged 80 years or more falls within acceptable levels in national guidelines and compares favorably with best medical care. Miller et al. stress that patients over 80 years old should not be arbitrarily deemed 'high risk' for CEA.

Cerebrospinal fluid biomarkers in Creutzfeldt–Jakob disease

From Clinical Neurology and Neurosurgery Volume 107, Issue 5 , August 2005, Pages 355-360 [Review]

Abstract
Creutzfeldt–Jakob disease (CJD) is a rare neurodegenerative disorder. Since the emergence of variant CJD (vCJD) vigilance concerning the disease's incidence has increased and the interest in accurate in vivo diagnosis has augmented. So far, a large number of biomarkers has been investigated as aid in the differential diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) and vCJD. These include, among others, neuron-specific enolase (NSE), microtubuli associated protein Tau, S-100β, amyloid-beta (Aβ1–42) and the 14-3-3 protein. Multiple studies have confirmed that CSF detection of 14-3-3 protein by Western blot was the best single biomarker for sCJD with an average sensitivity and specificity of 92%. Also, in genetic and iatrogenic CJD (iCJD) patients with an average disease duration of less than 1 year, 14-3-3 is the best differential biomarker. Unfortunately, the 14-3-3 protein has a lower sensitivity if the disease duration exceeds beyond 1 year in both sporadic CJD and other CJD types (vCJD, and specific genetic or iatrogenic CJD types).

Middle cerebral artery dissections: Differences between isolated and extended dissections of internal carotid artery

From Journal of the Neurological Sciences Volume 235, Issues 1-2 , 15 August 2005, Pages 37-44

Abstract
Isolated middle cerebral artery dissection (MCAD) has rarely been encountered clinically and few have reviewed it systemically. The etiologies, clinical manifestations, natural clinical course and prognosis of MCAD remain poorly understood. From 1995 to 2004, there were 5 cases diagnosed clinically and angiographically to have MCAD (isolated MCAD in 1, ICAD-MCAD in 4) from a medical center in Taiwan. MEDLINE (1966–2003) was searched for published articles in English that concerned the diagnosis of MCAD. Clinical presentations, stroke types, angiographic findings, etiologies, treatment strategies and outcomes were compared between cases with isolated MCAD or ICAD-MCAD. There were 23 cases (male, 46%; mean age, 22.9 ± 19.5 years) with 24 events of isolated MCAD and 31 cases (male, 47%; mean age, 22.2 ± 12.9 years) with 35 events of ICAD-MCAD. The types of stroke in isolated MCAD group included subarachnoid hemorrhage (12%) and cerebral infarction (88%); and in ICAD-MCAD group were subarachnoid hemorrhage (6%) and cerebral infarction (94%). The presenting symptoms were similar between both groups. Fluctuating course was more often in isolated MCAD than in ICAD-MCAD (17% vs. 3%, p = 0.061). Recurrence of dissection events in both groups was infrequent (4% vs. 9%, p = 0.56). Both groups had high case-fatality rates (MCAD, 48%; ICAD-MCAD, 58%). The cause of dissection in both groups was idiopathic in the majority. Congenital vessel wall defects were found in 26% of ICAD-MCAD, but in only 4% of isolated MCAD (p = 0.066). In contrast, preceded trauma was more often found in isolated MCAD than ICAD-MCAD (35% vs. 19%, p = 0.085). Arteritis was noted in 16% of ICAD-MCAD patients, but none in isolated MCAD. Angiography revealed segmental stenosis in 72% of isolated MCAD and 96% of ICAD-MCAD. Aneurysmal dilatation of the involved cerebral arteries was noted in 28% of isolated MCAD, but none in MCAD-ICAD. Both isolated MCAD and ICAD-MCAD can cause vascular events with high mortality rates. Several aspects differed between 2 groups, including clinical course, underlying etiologies and angiographic findings.

Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of ALS

From Journal of the Neurological Sciences Volume 235, Issues 1-2 , 15 August 2005, Pages 61-68

Abstract
Insulin-like growth factor (IGF)-1 has been shown to have a protective effect on motor neurons both in vitro and in vivo, but has limited efficacy in patients with amyotrophic lateral sclerosis (ALS) when given subcutaneously. To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) with a G93A mutation were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Furthermore, it increased the expression of phosphorylated Akt and ERK in spinal motor neurons, and partially prevented motor neuron loss in these mice. Taken together, the results suggest that direct administration of IGF-1 into the intrathecal space may have a therapeutic benefit for ALS.

CSF from ALS patients preferentially elevates intracellular calcium and toxicity in motor neurons via AMPA/k receptor

From Journal of the Neurological Sciences Volume 235, Issues 1-2 , 15 August 2005, Pages 45-54

Abstract
Several lines of evidence in the literature purport the contribution of glutamate mediated excitotoxicity in the etiology of amyotrophic lateral sclerosis (ALS) but the cellular mechanisms responsible for selective loss of motor neurons are still obscure. Elevation of intracellular Ca2+ is considered as the early event in glutamate mediated cell injury. We have studied the changes in [Ca2+]i and cytotoxicity in motor neurons and other spinal neurons in culture upon exposure to cerebrospinal fluid (CSF) from ALS patients. CSFs from 20 ALS patients and 20 disease control patients were examined. Eighteen out of twenty (90%) ALS–CSF samples induced a transient but pronounced elevation of [Ca2+]i in neurons, whereas only 1/20 (5%) sample from disease control patients induced a marginal elevation of [Ca2+]i. Strikingly the [Ca2+]i rise was 2–3-fold higher and longer lasting in motor neurons in comparison to the other spinal neurons. Exposure of cells to ALS–CSF drastically decreased the survival rate of motor neurons to 32.26 ± 2.06% whereas a moderate decrease was observed in case of other spinal neurons (67.90 ± 2.04%). In cultures treated with disease control CSF, a small decrease was observed in the survival rate with 80.14 ± 2.00% and 90.07 ± 1.37% survival of motor neuron and other spinal neurons respectively. The AMPA/kainate receptor antagonist NBQX rendered significant protection against the ALS–CSF induced Ca2+ influx and neurotoxicity while the NMDA receptor antagonist APV showed a mild effect. Our data demonstrate that the exposure of spinal cord neurons to ALS–CSF differentially elevates [Ca2+]i and neurotoxicity in motor neurons by activation of glutamate receptors, the AMPA/kainate receptor playing the major role.

Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis

Permphan Dharmasaroja, Faculty of Science, Department of Anatomy, Mahidol University, 272 Rama VI Road, Rajthevi, Bangkok 10400, Thailand

From Journal of the Neurological Sciences Volume 206, Issue 1 , 15 January 2003, Pages 7-16

Abstract
An autoimmune response to one or more myelin-protein components is thought to be part of the pathogenesis of multiple sclerosis (MS). The immunodominant-autoantibody epitope may be localized on a linear peptide segment, on a conformation-sensitive epitope, or on an epitope resulting from post-translational modifications. Primary, secondary, and tertiary structures of myelin proteins may determine the specific site for binding of autoantibodies. A myelin protein-specific autoantibody can bind to either a linear or conformational epitope, whereas all of the T cell epitopes are linear. At present, the conformational epitopes of myelin proteins have not been identified; most of the methods used to identify the myelin-protein epitopes corresponding to the pathogenesis of multiple sclerosis are involved in the linear epitope mapping. Polymorphism or mutations may cause inappropriate expression of the myelin proteins with alterations to their linear and/or conformational epitopes, and make them susceptible to autoantibody binding, especially if these changes occur at the surface of the protein. This review focuses on the specificity of autoantibodies to the epitopes of myelin proteins and correlates this to the structures of proteins. Factors that influence the expression of myelin-protein epitopes such as the α-helical or β-sheet structure of the protein, the tri-proline site, and the post-translational modifications as well as physicochemical properties of amino acid changed are included.

Author Keywords: Multiple sclerosis; Myelin basic protein; Myelin proteolipid protein; Myelin oligodendrocyte glycoprotein; Immunoglobulins; Epitope mapping; Epitope specificity; Myelin proteins

Cited by
1. The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis • Journal of Neuroimmunology, In Press, Corrected Proof, Available online 26 July 2005, Francesco Lolli, Benedetta Mazzanti, Marta Pazzagli, Elisa Peroni, Maria Claudia Alcaro, Giuseppina Sabatino, Roberta Lanzillo, Vincenzo Brescia Morra, Lucio Santoro, Claudio Gasperini et al. SummaryPlus Full Text + Links PDF (177 K)

2. A possible link between multiple sclerosis and Creutzfeldt–Jakob disease based on clinical, genetic, pathological and immunological evidence involving Acinetobacter bacteria • Medical Hypotheses, Volume 64, Issue 3, 2005, Pages 487-494 Alan Ebringer, Taha Rashid, Clyde Wilson, Richard Boden and Edward Thompson SummaryPlus Full Text + Links PDF (353 K)

3. Myelin basic protein—diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis • Micron, Volume 35, Issue 7, October 2004, Pages 503-542 George Harauz, Noboru Ishiyama, Christopher M. D. Hill, Ian R. Bates, David S. Libich and Christophe Farès SummaryPlus Full Text + Links PDF (2095 K)

4. Linear epitopes of two different autoantigens-La/SSB and myelin basic protein—with a high degree of molecular similarity, cause different humoral immune responses • Journal of Autoimmunity, Volume 21, Issue 1, August 2003, Pages 47-57 Apostolos G. Terzoglou, John G. Routsias, Constantinos Sakarellos, Maria Sakarellos-Daitsiotis, Haralampos M. Moutsopoulos and Athanasios G. Tzioufas SummaryPlus Full Text + Links PDF (312 K)

Early-onset parkinsonism associated with PINK1 mutations

From: NEUROLOGY 2005;65:87-95

Objective: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50>

Methods: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.

Results: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.

Conclusions: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.