What Is in the Literature.

ABSTRACT: This issue of What is in the Literature focuses on the Guillain-Barré syndrome. Guillain-Barré syndrome is a monophasic illness, and there is new information about precipitating factors, changes in nerve conduction studies over time, potential biomarkers, optimal treatment, and features in uncommon patient populations.

Quantitative electrodiagnosis of the motor unit.

Electromyography (EMG) focuses on assessment of the motor unit (MU), and a given muscle has several hundred MUs, each innervating hundreds of muscle fibers. Assessment is limited by the recording radius of electrodes, 1-2 fibers with single-fiber electrodes and 7-15 fibers with concentric or monopolar electrodes. Routine qualitative EMG studies rely on observing MUs in free-run mode and qualitatively estimating common metrics. In contrast, quantitative EMG (QEMG) applied to routine studies includes assessment of individual MUs by software available in modern EMG machines with extraction of discrete values for common metrics, and also derived metrics. This results in greater precision and statistical interpretation. Other QEMG techniques assess muscle fiber density within the MU and time variability at the neuromuscular junction. The interference pattern can also be assessed. The number of MUs innervating a muscle can be estimated. Advanced signal processing, called near-fiber EMG, allows for extraction of underlying muscle fiber contributions to MU waveforms. It is also possible to use QEMG to make statistical probabilities of the state of a muscle as to whether normal, myopathic, or neuropathic. Time to acquire QEMG data is minimal. QEMG is most useful in situations where pathology is uncertain.

ALSUntangled #63: ketogenic diets.

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

What Is in the Literature.

ABSTRACT: What is in the Literature focuses on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a neuropathy with challenges in diagnosis and treatment. A recent revision of diagnostic criteria (EFN/PNS criteria) has helped define clinical features of typical and atypical variants and what is not considered CIDP. Initiating pathologic factors is not known for typical CIDP or variants. New treatment approaches are based on immunologic mechanisms. Rare patients with a CIDP-like clinical pattern are found to have antibodies to proteins at and around the node of Ranvier and are not considered to be CIDP but a nodal-paranodopathy. Although occurring mainly in adults, CIDP also occurs in children. CIDP may have clinical and electrodiagnostic features that overlap with hereditary neuropathies, and the latter might show some response to treatment. Articles published in the past year that address these issues are discussed in this review.

What Is in the Literature.

ABSTRACT: This issue of What Is in the Literature focuses on articles on amyotrophic lateral sclerosis over the past year. Amyotrophic lateral sclerosis remains a challenging disorder with progression to death. Within the past year, a phase 2 trial of a drug combination showed slowing in the rate of progression. While awaiting a phase 3 trial or approval by the Food and Drug Administration, selected articles that aid the diagnosis, contribute to care, or add to general knowledge about the disease are reviewed.

Pathogenic effect of TP73 Gene Variants in People With Amyotrophic Lateral Sclerosis.

OBJECTIVE: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we utilized sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in TP73. METHODS: We analyzed exome sequences of 87 sporadic ALS patients and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit, TP73, a regulator of apoptosis, differentiation, and a binding partner as well as homolog of the tumor suppressor gene TP53, we assayed mutation effects using in vitro and in vivo experiments. C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were perform in vitro. In vivo, we used CRISPR/Cas9 targeting of zebrafish tp73 to assay motor neuron number and axon morphology. RESULTS: Five heterozygous rare, nonsynonymous mutations in TP73 were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in TP73. Patient TP73 mutations caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance. Immunoprecipitation of mutant ΔN-p73 demonstrated that patient mutations hinder ΔN-p73's ability to bind p53. CRISPR/Cas9 knockout of tp73 in zebrafish led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. CONCLUSION: Together, these results strongly suggest that variants in TP73 correlate with risk for ALS and indicate a novel role for apoptosis in ALS disease pathology.

What is in the Literature.

ABSTRACT: This edition of What is in the Literature focuses on chronic immune neuropathies as they represent treatable conditions. There are formal criteria to solidify the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but patients are encountered who have clinical and electrodiagnostic features of CIDP but do not fulfill diagnostic criteria. These patients are addressed in recent publications. CIDP (and variants) and other forms of immune-mediated neuropathies (multifocal motor neuropathy) are responsive early on to treatment, but long-term factors are less well described, and a number of publications focus on extended consequences. Acute immune neuropathies have been described in the setting of viral illness, and recent publications look at the question as to whether they are associated with the COVID-19 pandemic. Finally, idiopathic sensory neuropathies are the most common polyneuropathy, and consensus efforts to codify features into subtypes can be used clinically for a more precise diagnosis.

I Want to Row Across the Atlantic. But You Have Amyotrophic Lateral Sclerosis!

ABSTRACT: We describe an individual with slowly progressive amyotrophic lateral sclerosis who decided to enter the Talisker Whisky Atlantic Challenge, a rowing event across the Atlantic Ocean, and completes it in 51 days in a 5-man boat.

What Is in the Literature.

What is in the Literature focuses on peripheral neuropathies with new and practical information related to the diagnosis, treatment, and management. Diagnostic and treatment guidelines are available for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but not all clinicians follow them resulting in erroneous diagnoses and prolonged treatment. Secondary axonal loss in CIDP causes increased connective tissue in muscle. Antibodies to proteins at the node of Ranvier are found in a small percentage of patients with CIDP. The differential diagnosis for CIDP-like neuropathies includes amyloid neuropathy and POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) and amyloidosis. Upper limits for cerebral spinal fluid protein are 0.45 g/L and cell count <10/µL, but both may be too low. Hyperactive reflexes may occur in Guillain-Barré syndrome and should not exclude the diagnosis. In severely affected Guillain-Barré syndrome patients, a second dose of intravenous immune globulin within 4 weeks of onset is not likely to be effective.

The motor unit and quantitative electromyography.

Electromyography (EMG) assesses the anatomic motor unit (A-MU), but knowledge of its anatomy, physiology, and changes with pathology is limited. The electrophysiological motor unit (E-MU) and its motor unit potential (E-MUP) represents a fraction of the A-MU. Routine EMG assesses a limited number of E-MUP waveform characteristics (metrics) and their magnitudes qualitatively scaled in a nonlinear manner. Another approach is quantitative EMG (QEMG), whereby 20+ E-MUPs are extracted and both basic and derived metrics obtained and values expressed quantitatively. In diseased muscle, many E-MUP metrics may be normal, which complicates diagnostic interpretation. In QEMG, E-MUP metrics can be clustered and statistical analyses performed to assign probabilities that E-MUPs (and the muscle) are normal, neuropathic, or myopathic. In this article we review what is known about the A-MU, the restricted E-MU, E-MUP metrics, and what QEMG offers currently and in the future.

What Is in the Literature.

This installment of what is in the literature is on amyotrophic lateral sclerosis (ALS). The pathophysiology of ALS remains open and the role of genes, a foothold into pathophysiology, but there are >22 genes identified, and the mechanisms are not known for any. Despite the lack of a firm understanding of pathophysiology, drug trials continue based on possible mechanisms, but no new drugs beyond riluzole and edaravone have been positive in phase 3 trials. There are a number of formal stem cell trials underway, and the results of a phase 2 trial are described. Major efforts to make trials more sensitive are being considered. There are a number of articles with helpful and practical findings for the diagnosis and management of ALS.

Hydration measured by doubly labeled water in ALS and its effects on survival.

We present a study of hydration in ALS patients and its effects on survival. This was a multicenter study over 48 weeks in 80 ALS patients who underwent 250 individual measurements using doubly labeled water (DLW). Total body water (TBW) and water turnover (a surrogate for water intake) were 3.4% and 8.6% lower, respectively, in patients compared to age- and gender-matched healthy controls, and both significantly decreased over study duration. In 20% of patients, water turnover measured over 10 d was 2 standard deviations below the mean value in healthy controls. In a separate clinic cohort of 208 patients, water intake estimated from a de novo equation created from common clinical endpoints was a prognostic indicator of survival. Regardless of nutritional state assessed by BMI, survival was two-fold longer in the group above the median for estimated water intake, suggesting that hydration may be a more important predictor of survival than malnutrition. Risk factors for poor hydration were identified. Water intake equations recommended by US Centers for Medicare and Medicaid Services in healthy elderly were inaccurate for use in ALS patients. We developed equations to estimate TBW and water intake in ALS patients for use in clinics to accurately estimate hydration and improve clinical care.

What is in the Literature?

This edition of "What is in the Literature?" will focus on motor neuron disease (MND), including adult forms [amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), progressive bulbar palsy (PBA), and monomelic mononeuropathy (MMND)], and childhood forms [spinal muscle atrophy (SMA)].

The evolving genetic risk for sporadic ALS.

OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. METHODS: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. RESULTS: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. CONCLUSIONS: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.

What's in the Literature?

The Guillain-Barré syndrome (GBS) is one of the few neuropathies well known to the general public, in part because of its association with swine flu vaccinations in 1976. GBS has again reached the general public with its possible association with Zika virus. The virus, borne by infected Aedes aegypti mosquitos, is being linked to birth defects when pregnant women are bitten and infected. There are early reports also linking GBS to Zika infection, which could expose a wider range of infected people to the neuropathy. This summer infected Aedes mosquitos will likely reach southern portions of the United States, and travelers to countries where Aedes is endemic will increase. It is important to appreciate that the neurologic consequences of Zika virus are being actively investigated, and firm associations and consequences are yet to be established. Small fiber neuropathies are common and can be due to a number of underlying diseases, and a recent review also indicates that many are idiopathic. One cause is Sjögren syndrome, and a case series reviews clinical features. The diagnosis and underlying features of primary lateral sclerosis are a clinical challenge. Similarities between primary lateral sclerosis and hereditary spastic paraparesis (HSP) have long been noted. With a wide spectrum of gene mutations associated with HSP, clinical distinction between the 2 disorders is problematic. A review covers the wide spectrum of HSP. With no cure, the progression of amyotrophic lateral sclerosis (ALS) to respiratory failure is predictable. This could easily result in marked depression among patients, and 2 studies have explored the frequency and severity of depression. The cause of ALS remains unknown, and when no hereditary factor is apparent, environmental questions arise as possible contributing factor(s). The most notable association is with military service, although specific occupational or environmental linkages are not well sorted out. Two recent reports address these issues. There is good news for ALS patients with muscle cramps with the results of a multicenter randomized and placebo-controlled trial showing that mexiletine is effective in reducing this common symptom. The treatment of myasthenia gravis with various agents, the use of patient-reported outcome measures in myasthenia gravis, and the occurrence of myocarditis in this disease are reviewed. Necrotizing autoimmune neuropathies, the co-occurrence of inclusion body myositis and a form of T-cell leukemia are discussed as are valosin-containing protein (VCP)-opathy and bone health in patients with dystrophinopathy.

Population-based risks for cancer in patients with ALS.

OBJECTIVE: To estimate the risks for cancer (overall and site-specific) in an amyotrophic lateral sclerosis (ALS) cohort. METHODS: In this observational longitudinal study, ALS and cancer cases were identified in a computerized Utah genealogy database (Utah Population Database) linked to a statewide cancer registry and death certificates. Hazard ratios (HRs) were estimated as the ratio of observed to expected number of cancers. Site-specific rates for cancer were estimated within the Utah Population Database; sex, birth year (5-year range), and birth state (Utah or not) cohorts were used to estimate the expected number of cancers among ALS cases. To account for an overall shortened lifespan, Cox regression was used to include years at risk in estimation of cancer risks for ALS cases. RESULTS: An overall decreased hazard (hazard ratio [HR] 0.80, p = 0.014, 95% confidence interval [CI] 0.66-0.96) was found for cancer of any site in 1,081 deceased patients with ALS. A decreased hazard was found for lung cancer (HR 0.23, p = 0.002, CI 0.05-0.63). An increased hazard was found for salivary (HR 5.27, p = 0.041, 95% CI 1.09-15.40) and testicular (HR 3.82, p = 0.042, 95% CI 1.06-9.62) cancers. A nonsignificant hazard was observed for cutaneous malignant melanoma (HR 1.62, p = 0.12, 95% CI 0.88-2.71) for which increased risk has previously been reported. CONCLUSIONS: Using a unique population database, the overall risk of cancer of any site was found to be significantly reduced in cases with ALS, as was the risk of lung cancer. Significantly increased risk was observed for salivary and testicular cancers.

Relationship of creatine kinase to body composition, disease state, and longevity in ALS.

Our objective was to explore if creatine kinase (CK) levels correlate with survival in amyotrophic lateral sclerosis (ALS), and whether a correlation is independent of other well-studied predictors such as location of onset, gender, age, fat free mass, spasticity, cramps, and fasciculations. We analyzed data from 80 ALS patients from a 48-week non-interventional longitudinal multicenter nutrition study with long term follow-up. The overall mean CK was 214 ± 191.8 U/l (range 22-1992 U/l). Forty-five percent of patients had at least one high CK value (> 200 U/l), and about half maintained a high CK value, but there was no trend over the study period. Male gender and extremity onset were significantly associated with high CK. In univariate analysis, age, bioelectric impedance spectroscopy (BIS) fat free mass, spasticity, and fasciculations were not associated with CK level. There was an association between CK and muscle cramps (p < 0.001). In survival analysis, low CK (≤ 200 U/l) was associated with a longer overall survival (p = 0.02), when adjusting for location of onset, age, race, gender, BIS fat free mass, and study site. In conclusion, CK may be a useful marker for ALS survival, which has implications for clinical care and the design of future clinical trials.

Practical rules for electrodiagnosis in suspected multifocal motor neuropathy.

Multifocal motor neuropathy (MMN) with conduction block (CB) is a rare chronic immune-mediated neuropathy, but important to diagnose as it is treatable. The key features in prototypic MMN are electrodiagnostic demonstration of focal CB away from common sites of entrapment and normal sensory conduction across these sites. However, there are challenges in distinguishing CB from the effects of abnormal temporal dispersion. Consensus electrodiagnostic criteria, reinforced by modeling studies, are available to support definite or probable CB. In addition, consideration of technical issues can guard against false-positive and false-negative conclusions. These include limb temperature, stimulus site, inadvertent stimulating electrode movement, and supramaximal and submaximal responses, as well as the possibility of Martin-Gruber anastamosis. Robust evidence supports the treatment of MMN with intravenous immunoglobulin, and guidelines have been developed. Application of practical and simple rules including a 4-step diagnostic algorithm can help practitioners correctly diagnose this treatable condition and improve patient outcomes.