Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Electrodiagnostic studies and new diagnostic modalities for evaluation of peripheral nerve disorders.

Electrodiagnostic studies (EDx) are frequently performed in the diagnostic evaluation of peripheral nerve disorders. There is increasing interest in the use of newer, alternative diagnostic modalities, in particular imaging, either to complement or replace established EDx protocols. However, the evidence to support this approach has not been expansively reviewed. In this paper, diagnostic performance data from studies of EDx and other diagnostic modalities in common peripheral nerve disorders have been analyzed and described, with a focus on radiculopathy, plexopathy, compressive neuropathies, and the important neuropathy subtypes of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), vasculitic neuropathy and diabetic neuropathy. Overall EDx retains its place as a primary diagnostic modality in the evaluated peripheral nerve disorders. Magnetic resonance imaging and ultrasound have developed important complementary diagnostic roles in compressive and traumatic neuropathies and atypical CIDP, but their value is more limited in other neuropathy subtypes. Identification of hourglass constriction in nerves of patients with neuralgic amyotrophy may have therapeutic implications. Investigation of radiculopathy is confounded by poor correlation between clinical features and imaging findings and the lack of a diagnostic gold standard. There is a need to enhance the literature on the utility of these newer diagnostic modalities.

Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression. METHODS: Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross-sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS-R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure. RESULTS: Fast-progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS-R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS-R (P = .002) and MRC (P = .002) scores over 40 weeks. Baseline BMI <25 was also associated with faster reduction of ALSFRS-R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression. DISCUSSION: Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials.

Diagnostic Utility of Gold Coast Criteria in Amyotrophic Lateral Sclerosis.

OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with current diagnostic criteria (revised El Escorial [rEEC] and Awaji) being complex and prone to error. Consequently, the diagnostic utility of the recently proposed Gold Coast criteria was determined in ALS. METHODS: We retrospectively reviewed 506 patients (302 males, 204 females) to compare the diagnostic accuracy of the Gold Coast criteria to that of the Awaji and rEEC criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS) in accordance with standards of reporting of diagnostic accuracy criteria. RESULTS: The sensitivity of Gold Coast criteria (92%, 95% confidence interval [CI] = 88.7-94.6%) was comparable to that of Awaji (90.3%, 95% CI = 86.69-93.2%) and rEEC (88.6, 95% CI = 84.8-91.7%) criteria. Additionally, the Gold Coast criteria sensitivity was maintained across different subgroups, defined by site of onset, disease duration, and functional disability. In atypical ALS phenotypes, the Gold Coast criteria exhibited greater sensitivity and specificity. INTERPRETATION: The present study established the diagnostic utility of the Gold Coast criteria in ALS, with benefits evident in bulbar and limb onset disease patients, as well as atypical phenotypes. The Gold Coast criteria should be considered in clinical practice and therapeutic trials. ANN NEUROL 2021;89:979-986.

Factors associated with re-presentation to emergency departments in elderly people with pain.

OBJECTIVES: To identify medical, social and demographic factors associated with increased risk of 30-day re-presentation to the emergency department (ED) in elderly people presenting with pain. METHODS: We undertook a single site, prospective observational study of all patients aged >65 years discharged from the ED with pain. Data were collected on possible medical, social and demographic predictors of ED readmission. Participants were a subset of all elderly patients presenting to the ED with pain, and received follow-up case management as part of the hospital's rapid response, assessment and care planning program for elderly people. RESULTS: Over 8 months, 356 people were eligible for inclusion in the study; of these, 189 consented to case management and to participate in the study. Three factors statistically increased odds of re-presentation to ED within 30 days: (1) prescription of opioids (P=0.003); (2) the presence of Home and Community Care Services (P=0.03); and (3) the absence of a gait aid (P=0.019). Nineteen per cent of eligible patients re-presented to ED within 30 days of initial presentation. CONCLUSION: These findings contribute to current debate about opioid prescription and effective pain management in the elderly. The study highlights the need for routine follow-up care of older people discharged from the ED with pain, particularly those discharged home with opioids or with complex care needs.

Ulnar neuropathy.

Ulnar neuropathy at the elbow is the second most common compressive neuropathy. Less common, although similarly disabling, are ulnar neuropathies above the elbow, at the forearm, and the wrist, which can present with different combinations of intrinsic hand muscle weakness and sensory loss. Electrodiagnostic studies are moderately sensitive in diagnosing ulnar neuropathy, although their ability to localize the site of nerve injury is often limited. Nerve imaging with ultrasound can provide greater localization of ulnar injury and identification of specific anatomical pathology causing nerve entrapment. Specifically, imaging can now reliably distinguish ulnar nerve entrapment under the humero-ulnar arcade (cubital tunnel) from nerve injury at the retro-epicondylar groove. Both these pathologies have historically been diagnosed as either "ulnar neuropathy at the elbow," which is non-specific, or "cubital tunnel syndrome," which is often erroneous. Natural history studies are few and limited, although many cases of mild-moderate ulnar neuropathy at the elbow appear to remit spontaneously. Conservative management, perineural steroid injections, and surgical release have all been studied in treating ulnar neuropathy at the elbow. Despite this, questions remain about the most appropriate management for many patients, which is reflected in the absence of management guidelines.

Utility of split hand index with different motor unit number estimation techniques in ALS.

OBJECTIVE: Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SICMAP amp). A motor unit number index (MUNIX) based SI method (SIMUNIX) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SIMScanFit-MUNE) methods, in ALS. METHODS: Sixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi. RESULTS: SICMAP amp, SIMUNIX and SIMScanFit-MUNE were significantly reduced in ALS, with SICMAP amp (area under curve (AUC) = 0.801) and SIMScanFit-MUNE (AUC = 0.805) exhibiting greater diagnostic utility than SIMUNIX (AUC = 0.713). SICMAP amp and SIMScanFit-MUNE exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles. CONCLUSIONS: SI differentiated ALS from mimic disorders, with SICMAP amp and SIMScanFit-MUNE exhibiting greater utility. SIGNIFICANCE: The split hand index represents could serve as a potential diagnostic biomarker in ALS.

Rituximab in chronic immune mediated neuropathies: a systematic review.

Chronic immune mediated neuropathy is a heterogenous group of peripheral nerve diseases, encompassing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), autoimmune nodopathy, multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) neuropathy. Rituximab (RTX) is a chimeric monoclonal antibody targeting the CD20 antigen, which has been used in the treatment of autoimmune neuropathies, although the efficacy of RTX remains unclear. A literature search was performed using Medline, Embase and Cochrane Register for studies between 2000 and 2021 using the search terms "Chronic inflammatory demyelinating polyneuropathy" OR "Multifocal motor neuropathy" OR "Myelin associated glycoprotein" OR "Distal acquired demyelinating neuropathy" OR "Multifocal acquired demyelinating sensory and motor neuropathy" OR "demyelinating neuropathy" AND "Rituximab". Twenty-three studies were included, of which two were randomised controlled trials, 6 prospective studies and 15 retrospective studies. RTX was effective in 63% of CIDP patients, 48% of anti-MAG neuropathy, and 96% of patients with autoimmune nodopathy. Neurophysiological improvement was evident in 58% of CIDP and 40% of anti-MAG neuropathy patients. Low rates of serious adverse events (2.6%) were observed. These results indicate that RTX has potential as a treatment in immune mediated polyneuropathy, although the quality of evidence supporting its use it poor. Randomized controlled trials are required to reliably establish the efficacy and safety of RTX. Trial registration number: CRD42020179666.

Muscle ultrasound in hereditary muscle disease.

In this review we summarise the key techniques of muscle ultrasound as they apply to hereditary muscle disease. We review the diagnostic utility of muscle ultrasound including its role in guiding electromyography and muscle biopsy sampling. We summarize the different patterns of sonographic muscle involvement in the major categories of genetic muscle disorders and discuss the limitations of the technique. We hope to encourage others to adopt ultrasound in their care for patients with hereditary muscle diseases.

Review Article "Spotlight on Ultrasonography in the Diagnosis of Peripheral Nerve Disease: The Evidence to Date".

Neuromuscular ultrasound is rapidly becoming incorporated into clinical practice as a standard tool in the assessment of peripheral nerve diseases. Ultrasound complements clinical phenotyping and electrodiagnostic evaluation, providing critical structural anatomical information to enhance diagnosis and identify structural pathology. This review article examines the evidence supporting neuromuscular ultrasound in the diagnosis of compressive mononeuropathies, traumatic nerve injury, generalised peripheral neuropathy and motor neuron disease. Extending the sonographic evaluation of nerves beyond simple morphological measurements has the potential to improve diagnostics in peripheral neuropathy, as well as advancing the understanding of pathological mechanisms, which in turn will promote precise therapies and improve therapeutic outcomes.

Split-hand index: A diagnostic and prognostic marker in amyotrophic lateral sclerosis across varying regions of onset.

OBJECTIVE: The split-hand index (SI), a reliable diagnostic marker of amyotrophic lateral sclerosis (ALS), was prospectively assessed for differences across ALS subtypes and between the onset side of clinical symptoms or the dominant and contralateral sides. In addition, the prognostic utility of the SI was longitudinally assessed. METHODS: Two hundred and forty-five ALS patients underwent measurement of SI on both sides compared with 126 neuromuscular mimic disorders (NMD). A subset of patients (N = 45) underwent longitudinal assessment of SI. RESULTS: The SI was significantly reduced (SI RIGHT ALS 5.47(4.2), SINMD 9.0 (5.0); P < 0.001; SILEFT ALS 5.5 (4.1), SI NMD 9.4 (5.0), P < 0.001) on both sides in all ALS patients with prominent reduction on the onset side in upper limb onset ALS (SI RIGHT P < 0.001; SI LEFT P < 0.05) and in Awaji definite/probable diagnostic category (SI RIGHT P < 0.05; SI LEFT P < 0.05). Longitudinal studies disclosed that the rate of SI decline correlated with the decline in ALSFRS-R (r = 0.21, P < 0.05). CONCLUSION: The SI is reduced in all ALS subtypes most prominently in upper limb onset disease, on the side of clinical onset, and in patients with Awaji definite/probable diagnostic category. SIGNIFICANCE: The split-hand index is a reliable diagnostic and outcome biomarker across ALS subtypes and may have potential utility in a clinical trial setting, although further multicenter studies are required to confirm this.

In-hospital outcomes and hospital resource utilization of hip replacement procedures.

BACKGROUND: Although the incidence of hip replacement surgery is rapidly increasing, there are few data describing the hospital resource utilization associated with these procedures. We aimed to examine the in-hospital outcomes and resource utilization of primary and revision hip replacement. METHODS: We analysed data from the 2005/2006 Victorian Admitted Episodes Database that included one or more of the International Classification of Diseases procedure codes for hip replacement. Demographic parameters and in-hospital outcomes, including length of stay, duration of intensive/coronary care and discharge destination, were examined. RESULTS: A total of, 7724 separations had a hip replacement. Primary procedures accounted for 86.8% of all separations. Of these, 79.3% were total hip replacements and the remainder were partial hip replacements. Most partial hips were managed (81.6%) and funded (60.0%) within the public system, whereas revisions were largely managed privately (59.0%). Revisions had less satisfactory outcomes than primary total hips, with 22.9% more revisions remaining in hospital for more than a week (P < 0.0001), 14.6% more requiring intensive care (P < 0.0001) and 10.9% less being discharged to a private residence (P < 0.001) (adjusting for confounders). Although primary partial and revision replacements accounted for only 16.8 and 13.2% of all hip replacements, they utilised up to 27.5 and 34.6% of hospital resources, respectively. CONCLUSION: Partial and revision hip replacements are resource intensive for the public and private health-care systems, respectively. It is imperative that strategies to reduce the incidence of these procedures are implemented, as failure to do so will have important implications for the allocation of health-care funding.

Routine follow up of major trauma patients from trauma registries: What are the outcomes?

BACKGROUND: Routine measurement of outcomes other than mortality in trauma is needed to monitor trauma care, benchmark trauma hospitals and systems, and to guide resource provision. Trauma registries are ideally placed to capture morbidity outcomes such as functional loss, disability, and handicap. This study aimed to provide a broad description of the 6-month outcomes of major trauma patients captured by a population-based trauma registry, establish the follow-up rate of registry patients, and determine any biases associated with loss to follow up. METHODS: The Victorian State Trauma Registry (VSTR) is a population-based registry in Victoria, Australia. Major trauma patients captured by the VSTR with a date of injury from October 1, 2003 to September 30, 2004 were followed up at 6 months postinjury by telephone to collect information about their living status, functional levels, and return to work. RESULTS: Of the 1,102 eligible patients, 67% were successfully followed up at 6 months postinjury. Eighteen patients had died since discharge. Patients lost to follow up were less severely injured (p = 0.004) and younger (p = 0.010) at baseline than those followed up. The vast majority of major trauma patients are independent with respect to locomotion (78%), feeding (93%), and expression (93%) by 6 months postinjury. Of those working before injury, 60% had returned to work. CONCLUSIONS: The findings show that follow up of registry patients is feasible, results in few biases in the follow-up population, and reports similar findings to individual studies of trauma populations.

Is the Charlson Comorbidity Index useful for predicting trauma outcomes?

BACKGROUND: Inclusion of a measure of comorbidity in trauma scoring has been suggested due to the potential for preexisting conditions to impact on patient outcomes, but studies have reported varied results. The Charlson Comorbidity Index (CCI) includes 19 diseases weighted on the basis of their association with mortality, and can be extrapolated from International Classification of Diseases, Ninth Revision (ICD-9) codes for administrative databases. OBJECTIVES: To evaluate the CCI as a predictor of trauma outcome. METHODS: Major trauma patient data from the Victorian State Trauma Registry (VSTR) were used to evaluate the CCI (n = 2,819). The CCI was scored from ICD-10 codes through modification of a previous method of mapping ICD-9 codes to the CCI. Logistic regression was used to determine the association between the CCI and mortality, the effect of adding the CCI to the Trauma and Injury Severity Score (TRISS) methodology, and the impact of adding the CCI to a modification of the TRISS methodology. Model performance was assessed through discrimination and calibration. RESULTS: The CCI was associated with death (p < 0.001), but adding the CCI to TRISS [area under the receiver-operating characteristic curve (AUC) 0.86; 95% CI = 0.84 to 0.88] did not result in improved discrimination over TRISS alone (AUC 0.83; 95% CI = 0.81 to 0.86). Modifying TRISS methodology, with age left as a continuous variable, performed better than the original TRISS (AUC 0.91; 95% CI = 0.89 to 0.92), but the addition of the CCI did not further improve this model (AUC 0.91; 95% CI = 0.89 to 0.92). CONCLUSIONS: While the CCI can be extrapolated from ICD codes and provides a measure of comorbid condition severity and was associated with mortality, addition of the CCI to prediction models did not result in a substantial improvement in performance.