Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.

BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria. METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally. RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%. CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.

Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. METHODS: This study was performed within the population-based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6-78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome-wide association studies. RESULTS: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]diabetes, p < 1.0  = 1.21, 95% confidence interval [CI] = 1.05-1.39 and ORBMI, p < 1.0  = 1.21, 95% CI = 1.04-1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR vitamin B12, p < 5e-6  = 0.79, 95% CI = 0.68-0.92 and ORalcohol, p < 5e-8  = 1.17, 95% CI = 1.02-1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGSp < 5e-8 and polyneuropathy. CONCLUSIONS: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well-known clinical risk factors and polyneuropathy.

Electrodiagnostic subtyping in Guillain-Barré syndrome: Use of criteria in practice based on a survey study in IGOS.

Electrodiagnostic (EDx) studies are helpful in diagnosing and subtyping of Guillain-Barré syndrome (GBS). Published criteria for differentiation into GBS subtypes focus on cutoff values, but other items receive less attention, although they may influence EDx subtyping: (a) extensiveness of EDx testing, (b) nerve-specific considerations, (c) distal compound muscle action potential (CMAP)-amplitude requirements, (d) criteria for conduction block and temporal dispersion. The aims of this study were to investigate how these aspects were approached by neuromuscular EDx experts in practice and how this was done in previously published EDx criteria for GBS. A completed questionnaire was returned by 24 (of 49) members of the electrophysiology expertise group from the International GBS Outcome Study. Six published EDx criteria for GBS subtyping were compared regarding these aspects. The indicated minimal number of motor nerves to study varied among respondents and tended to be more extensive in equivocal than normal studies. Respondents varied considerably regarding usage of compression sites for subtyping (median/wrist, ulnar/elbow, peroneal/fibular head): 29% used all variables from all sites, 13% excluded all sites, and 58% used only some sites and/or variables. Thirty-eight percent of respondents required a minimal distal CMAP amplitude to classify distal motor latency as demyelinating, and 58% did for motor conduction velocity. For proximal/distal CMAP-amplitude ratio and F-wave latency, a requisite minimal CMAP amplitude was more often required (79%). Also, the various published criteria sets showed differences on all items. Practical use of EDx criteria for subtyping GBS vary extensively across respondents, potentially lowering the reproducibility of GBS subtyping.

Changes in motor nerve excitability in acute phase Guillain-Barré syndrome.

BACKGROUND: The most common subtypes of Guillain-Barré syndrome (GBS) are acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). In the first days after the onset of weakness, standard nerve conduction studies (NCS) may not distinguish GBS subtypes. Reduced nerve excitability may be an early symptom of nerve dysfunction, which can be determined with the compound muscle action potential (CMAP) scan. The aim of this study was to explore whether early changes in motor nerve excitability in GBS patients are related to various subtypes. METHODS: Prospective case-control study in 19 GBS patients from The Netherlands and 22 from Bangladesh. CMAP scans were performed within 2 days of hospital admission and NCS 7-14 days after onset of weakness. CMAP scans were also performed in age- and country-matched controls. RESULTS: CMAP scan patterns of patients who were classified as AMAN were distinctly different compared to the CMAP scan patterns of the patients who were classified as AIDP. The most pronounced differences were found in the stimulus intensity parameters. CONCLUSIONS: CMAP scans made at hospital admission demonstrate several characteristics that can be used as an early indicator of GBS subtype.

Cardiovascular health and chronic axonal polyneuropathy: A population-based study.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common, usually multifactorial, disease for which there is no treatment yet available. We investigated the association between cardiovascular health, defined by the health score of the American Heart Association, and chronic axonal polyneuropathy. METHODS: Between June 2013 and January 2017, we investigated participants of the Rotterdam Study, a population-based cohort study. Participants were screened for polyneuropathy and categorized as having no, possible, probable or definite polyneuropathy. The cardiovascular health score (range 0-14; higher score reflecting better health) consisted of four health behaviours (diet, physical activity, smoking and body mass index) and three health factors (blood pressure, serum cholesterol and fasting glucose level). RESULTS: We included 1919 participants, of whom 120 (6.3%) had definite polyneuropathy. The median (interquartile range [IQR]) age was 69.0 (58.6-73.7) years and 53.4% were women. A higher cardiovascular health score was associated with a lower prevalence of definite polyneuropathy (per point increase: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84-0.96). Optimal cardiovascular health (score≥10) was strongly associated with a lower prevalence of definite polyneuropathy (OR 0.55, 95% CI 0.32-0.90). An increase in health factors and health behaviour scores separately was associated with a lower prevalence of polyneuropathy (per point increase: OR 0.82, 95% CI 0.71-0.95 and OR 0.86, 95% CI 0.78-0.96, respectively). The association between a lower cardiovascular health score and lower sural nerve amplitude was not significant after correction for covariates (difference 0.07µV, 95% CI -0.02-0.17). CONCLUSIONS: Better cardiovascular health, consisting of both modifiable health behaviours and health factors, is associated with a lower prevalence of chronic axonal polyneuropathy.

Misdiagnosis and diagnostic pitfalls of chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: The aim of this study was to determine the frequency of over- and underdiagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to identify related diagnostic pitfalls. METHODS: We conducted a retrospective study in Dutch patients referred to the Erasmus University Medical Centre Rotterdam between 2011 and 2017 with either a diagnosis of CIDP or another diagnosis that was revised to CIDP. We used the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2010 diagnostic criteria for CIDP to classify patients into three groups: overdiagnosis, underdiagnosis, or confirmed diagnosis of CIDP. Clinical and laboratory features and treatment history were compared between groups. RESULTS: A referral diagnosis of CIDP was revised in 32% of patients (31/96; overdiagnosis). Of 81 patients diagnosed with CIDP, 16 (20%) were referred with another diagnosis (underdiagnosis). In the overdiagnosed patients, 20% of muscle weakness was asymmetric, 48% lacked proximal muscle weakness, 29% only had distal muscle weakness, 65% did not fulfil the electrodiagnostic criteria for CIDP, 74% had an elevated cerebrospinal fluid (CSF) protein level, and 97% had another type of neuropathy. In the underdiagnosed patients, all had proximal muscle weakness, 50% had a clinically atypical CIDP, all fulfilled the electrodiagnostic criteria for CIDP, and 25% had an increased CSF protein level. CONCLUSION: Over- and underdiagnosis of CIDP is common. Diagnostic pitfalls include lack of attention to proximal muscle weakness as a diagnostic hallmark of CIDP, insufficient recognition of clinical atypical phenotypes, overreliance on CSF protein levels, misinterpretation of nerve conduction studies and poor adherence to electrodiagnostic criteria, and failure to exclude other causes of polyneuropathy.

Antecedent infections in Guillain-Barré syndrome in endemic areas of arbovirus transmission: A multinational case-control study.

Half of the world's population is at risk of arthropod-borne virus (arbovirus) infections. Several arbovirus infections have been associated with Guillain-Barré syndrome (GBS). We investigated whether arboviruses are driving GBS beyond epidemic phases of transmission and studied the antibody response to glycolipids. The protocol of the International Guillain-Barré syndrome Outcome Study (IGOS), an observational prospective cohort study, was adapted to a case-control design. Serum samples were tested for a recent infection with Zika virus (ZIKV), dengue virus (DENV), chikungunya (CHIKV) virus, hepatitis E virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), Campylobacter jejuni, and Mycoplasma pneumoniae, and for antibodies to glycolipids. Forty-nine patients were included from Brazil (63%), Argentina (14%), and Malaysia (22%). Evidence of a recent infection was found in 27/49 (55%) patients: C jejuni (n = 15, 31%), M pneumoniae (n = 5, 10%), CHIKV (n = 2, 4%), EBV (n = 1, 2%), C jejuni and M pneumoniae (n = 2, 4%), CMV and DENV (n = 1, 2%), and C jejuni and DENV (n = 1, 2%). In 22 patients, 35 paired controls were collected. Odds ratio for recent infections did not significantly differ between cases and controls. No typical anti-ganglioside antibody binding was associated with recent arbovirus infection. We conclude that arbovirus infections occur in GBS patients outside of epidemic viral transmission, although not significantly more than in controls. Broad infection and anti-ganglioside antibody serology are important to establish the most likely pathogenic trigger in GBS patients. Larger studies are necessary to determine the association between arboviruses and GBS.

How to Identify Responders and Nonresponders to Dorsal Root Ganglion-Stimulation Aimed at Eliciting Motor Responses in Chronic Spinal Cord Injury: Post Hoc Clinical and Neurophysiological Tests in a Case Series of Five Patients.

OBJECTIVE: While integrity of spinal pathways below injury is generally thought to be an important factor in the success-rate of neuromodulation strategies for spinal cord injury (SCI), it is still unclear how the integrity of these pathways conveying the effects of stimulation should be assessed. In one of our institutional case series of five patients receiving dorsal root ganglion (DRG)-stimulation for elicitation of immediate motor response in motor complete SCI, only two out of five patients presented as responders, showing immediate muscle activation upon DRG-stimulation. The current study focuses on post hoc clinical-neurophysiological tests performed within this patient series to illustrate their use for prediction of spinal pathway integrity, and presumably, responder-status. MATERIALS AND METHODS: In a series of three nonresponders and two responders (all male, American Spinal Injury Association [ASIA] impairment scale [AIS] A/B), a test-battery consisting of questionnaires, clinical measurements, as well as a series of neurophysiological measurements was performed less than eight months after participation in the initial study. RESULTS: Nonresponders presented with a complete absence of spasticity and absence of leg reflexes. Additionally, nonresponders presented with close to no compound muscle action potentials (CMAPs) or Hofmann(H)-reflexes. In contrast, both responders presented with clear spasticity, elicitable leg reflexes, CMAPs, H-reflexes, and sensory nerve action potentials, although not always consistent for all tested muscles. CONCLUSIONS: Post hoc neurophysiological measurements were limited in clearly separating responders from nonresponders. Clinically, complete absence of spasticity-related complaints in the nonresponders was a distinguishing factor between responders and nonresponders in this case series, which mimics prior reports of epidural electrical stimulation, potentially illustrating similarities in mechanisms of action between the two techniques. However, the problem remains that explicit use and report of preinclusion clinical-neurophysiological measurements is missing in SCI literature. Identifying proper ways to assess these criteria might therefore be unnecessarily difficult, especially for nonestablished neuromodulation techniques.

The Dorsal Root Ganglion as a Novel Neuromodulatory Target to Evoke Strong and Reproducible Motor Responses in Chronic Motor Complete Spinal Cord Injury: A Case Series of Five Patients.

OBJECTIVES: Current strategies for motor recovery after spinal cord injury (SCI) aim to facilitate motor performance through modulation of afferent input to the spinal cord using epidural electrical stimulation (EES). The dorsal root ganglion (DRG) itself, the first relay station of these afferent inputs, has not yet been targeted for this purpose. The current study aimed to determine whether DRG stimulation can facilitate clinically relevant motor response in motor complete SCI. MATERIALS AND METHODS: Five patients with chronic motor complete SCI were implanted with DRG leads placed bilaterally on level L4 during five days. Based on personalized stimulation protocols, we aimed to evoke dynamic (phase 1) and isotonic (phase 2) motor responses in the bilateral quadriceps muscles. On days 1 and 5, EMG-measurements (root mean square [RMS] values) and clinical muscle force measurements (MRC scoring) were used to measure motor responses and their reproducibility. RESULTS: In all patients, DRG-stimulation evoked significant phase 1 and phase 2 motor responses with an MRC ≥4 for all upper leg muscles (rectus femoris, vastus lateralis, vastus medialis, and biceps femoris) (p < 0.05 and p < 0.01, respectively), leading to a knee extension movement strong enough to facilitate assisted weight bearing. No significant differences in RMS values were observed between days 1 and 5 of the study, indicating that motor responses were reproducible. CONCLUSION: The current paper provides first evidence that bilateral L4 DRG stimulation can evoke reproducible motor responses in the upper leg, sufficient for assisted weight bearing in patients with chronic motor complete SCI. As such, a new target for SCI treatment has surfaced, using existing stimulation devices, making the technique directly clinically accessible.

High body mass and kidney dysfunction relate to worse nerve function, even in adults without neuropathy.

Polyneuropathy is a prevalent and disabling disorder. Despite extensive evaluation, the cause often remains unknown. Factors that predispose for the development of polyneuropathy need to be identified. We investigated the effect of anthropometric and metabolic factors on peripheral nerve function in 908 participants of the population-based Rotterdam Study without any symptoms or signs of polyneuropathy. Participants underwent nerve conduction studies of the sural and peroneal nerve. Data on age, height, weight, waist circumference, diabetes, lipid levels, hypertension, and kidney function were collected. Regression analyses were used to investigate determinants of nerve action potential amplitudes. The frequency of abnormal sural sensory nerve action potential (SNAP) amplitudes increased with age from 1% under 60 years to 23% over 80 years. Similarly, the frequency of abnormal peroneal nerve compound motor action potential (CMAP) amplitudes increased from 4% to 13%. High weight and body mass index were independently associated with reduced sural SNAP amplitudes and peroneal CMAP amplitudes. Participants with hypertension and kidney dysfunction were more likely to have abnormal sural SNAP amplitudes. Older age, high weight, hypertension, and moderate kidney dysfunction might thus lead to peripheral nerve dysfunction in persons yet without symptoms or signs of polyneuropathy.

Motor nerve excitability after childhood Guillain-Barré syndrome.

Residual motor nerve dysfunction after pediatric Guillain-Barré syndrome (GBS) was determined in an observational cross-sectional cohort study in patients who previously developed GBS during childhood (<18 years). Ulnar motor nerve dysfunction was defined by compound motor action potential (CMAP) scan in patients after a follow up of at least 1 year compared with age-matched healthy controls, in relation to clinical course and outcome. A total of 37 persons previously diagnosed with GBS in childhood were included with a mean age at current examination of 20.6 years (4-39 years). The median time between diagnosis and follow-up was 11 years (range: 1-22 years). CMAP scanning indicated ulnar motor nerve dysfunction in 25 (68%) participants. The most frequent abnormality was a reduction in nerve excitability observed both in those with residual limb weakness and in the majority of those with complete recovery. CMAP scan characteristics were not related to prognostic factors or outcome. In conclusion, GBS in childhood results in residual motor nerve excitability disturbances, even in those completely recovered, probably reflecting altered physiology of regenerated peripheral nerves.

Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study.

OBJECTIVE: Diabetes mellitus is a known risk factor for polyneuropathy, but the role of pre-diabetes and metabolic syndrome remains unclear. We aimed to investigate the role of these factors in a community-dwelling middle-aged and elderly population. METHODS: 1256 participants of the population-based Rotterdam Study (mean age 70.0, 54.5% females) were screened for polyneuropathy with a questionnaire, neurological examination and nerve conduction studies. Data on type 2 diabetes and components of metabolic syndrome were also collected. Logistic regression was used to investigate associations of diabetes, pre-diabetes and metabolic syndrome and its separate components with polyneuropathy. Linear regression was used to investigate associations with nerve conduction parameters in participants without polyneuropathy. FINDINGS: Diabetes was associated with polyneuropathy (OR 3.01, 95% CI 1.60 to 5.65), while impaired fasting glucose was not (OR 1.55, 95% CI 0.70 to 3.44). Metabolic syndrome was associated with polyneuropathy (OR 1.92, 95% CI 1.09 to 3.38), with a stronger association when more components of the syndrome were present. Analysing separate components of metabolic syndrome revealed associations for elevated waist circumference (OR 2.84, 95% CI 1.35 to 5.99) and elevated triglycerides (OR 2.01, 95% CI 1.11 to 3.62). Similar associations were found after excluding participants with diabetes. In participants without polyneuropathy, metabolic syndrome associated with lower sural sensory nerve action potential amplitudes. CONCLUSIONS: Metabolic syndrome, abdominal obesity and dyslipidaemia, are strongly associated with polyneuropathy, irrespective of the presence of diabetes. Metabolic syndrome also associates with impaired nerve function in people without polyneuropathy. Our study therefore suggests that cardiometabolic disturbances have an impact on peripheral nerve function that extends beyond clinically manifest disease.

Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria.

Guillain-Barré syndrome is an acute polyradiculoneuropathy with a variable clinical presentation. Accurate diagnostic criteria are essential for patient care and research, including clinical trials and vaccine safety studies. Several diagnostic criteria for Guillain-Barré syndrome have been proposed, including the recent set by the Brighton Collaboration. In the present study we describe in detail the key diagnostic features required to meet these Brighton criteria in a study population of 494 adult patients with Guillain-Barré syndrome, previously included in therapeutic and observational studies. The patients had a median age of 53 years (interquartile range 36-66 years) and males slightly predominated (56%). All patients developed bilateral limb weakness which generally involved both upper and lower extremities. The weakness remained restricted to the legs in 6% and to the arms in 1% of the patients. Decreased reflexes in paretic arms or legs were found initially in 91% of patients and in all patients during follow-up. Ten (2%) patients however showed persistence of normal reflexes in paretic arms. Disease nadir was reached within 2 weeks in 80%, within 4 weeks in 97% and within 6 weeks in all patients. A monophasic disease course occurred in 95% of patients, of whom 10% had a treatment-related fluctuation. A clinical deterioration after 8 weeks of onset of weakness occurred in 23 (5%) patients. Cerebrospinal fluid was examined in 474 (96%) patients. A mild pleocytosis (5 to 50 cells/µl) was found in 15%, and none had more than 50 cells/µl. An increased cerebrospinal fluid protein concentration was found only in 64% of patients, highly dependent on the timing of the lumbar puncture after onset of weakness (49% at the first day to 88% after 2 weeks). Nerve electrophysiology was compatible with the presence of a neuropathy in 99% of patients, but only 59% fulfilled the current criteria for a distinct subtype of Guillain-Barré syndrome. Patients with a complete data set (335) were classified according to the Brighton criteria, ranging from a high to a low level of diagnostic certainty, as level 1 in 61%, level 2 in 33%, level 3 in none, and level 4 in 6% of patients. Patients categorized in these levels did not differ with respect to proportion of patients with preceding events, initial clinical manifestations or outcome. The observed variability in the key diagnostic features of Guillain-Barré syndrome in the current cohort study, can be used to improve the sensitivity of the diagnostic criteria.

Limb motor nerve dysfunction in Miller Fisher syndrome.

Typical Miller Fisher syndrome (MFS) lacks limb muscle weakness, but some patients may unpredictably progress to severe Guillain-Barré syndrome. The compound muscle action potential (CMAP) scan is a recently developed non-invasive, painless, and reproducible method for detecting early changes in motor nerve excitability. This technique was used to monitor subclinical limb motor nerve dysfunction during disease course in typical MFS. Three Miller Fisher patients with preserved limb muscle strength and normal routine nerve conduction studies were included. Frequent serial CMAP scanning of the median nerve was performed during acute phase and follow-up and was related to clinical course and outcome. All patients showed an abnormal increase in the range of stimulus intensities at the day of hospital admission, indicating reduced motor nerve excitability already at the earliest stage of disease. Median nerve dysfunction progressed in parallel or even before clinical deterioration, and improved with clinical recovery. Our study shows that typical MFS is a more general neuropathy, affecting peripheral motor nerves even in patients with preserved limb strength and conduction velocity. CMAP scanning is a sensitive technique for early detection of subclinical motor nerve dysfunction and for monitoring disease activity in immune-mediated neuropathies.

Age-Related Changes in Neurologic Examination and Sensory Nerve Amplitude in the General Population: Aging of the Peripheral Nervous System.

BACKGROUND AND OBJECTIVES: Chronic axonal polyneuropathy is a common disease of the peripheral nervous system with increasing prevalence with age. Typical neurologic signs are present in patients with polyneuropathy but may also occur in individuals without disease. Owing to limited knowledge on normal aging of the peripheral nervous system, it can be difficult to distinguish peripheral nerve dysfunction due to disease from variations in normal aging. Therefore, we described the changes in neurologic examination and nerve conduction studies that accompany aging in the general population. METHODS: In this cross-sectional population-based study, we screened participants for chronic polyneuropathy in a controlled environment using standardized methods including a symptom questionnaire, neurologic examination, and nerve conduction studies (NCS). Inclusion criteria were 40 years or older and living in a suburb of Rotterdam, the Netherlands. Participants not diagnosed with chronic polyneuropathy, based on the discussion of findings in the screening by an expert team, were included to determine the effect of age (range 41-96 years) on features of neurologic examination and NCS using frequency calculations and quantile regression analysis. RESULTS: In total, 4,179 participants (mean age 64.5 ± 12.7 years, 54.9% female) were included of whom 3,780 (90.5%) did not fulfil the criteria for polyneuropathy. In the population without polyneuropathy, the frequency of normal features at neurologic examination declined with age, most pronounced for vibration sense at the hallux (from 6.6 [SD ± 1.5] in 40-49 years to 3.6 [SD ± 3.1] in 80 years or older) and Achilles tendon reflexes (absent in 9% in 40-49 years up to 33% in 80 years or older). Superficial pain sensation and patellar tendon reflexes remained stable over time. Sural sensory nerve action potential (SNAP) amplitude declined with age from 11.2 µV in 40-49 years to 3.3 µV in 80 years or older. Nonrecordable SNAP amplitudes were found in 25.1% of the participants older than 80 years, more often in men (30.3%) than in women (21.0%). DISCUSSION: This study showed the effect of age on features of neurologic examination and sural nerve amplitude in the general population. These findings are helpful to distinguish features suggesting polyneuropathy from variations of normal aging of the peripheral nervous system.

Feasibility of Ultrasound Measurements of Peripheral Sensory Nerves in Head and Neck Area in Healthy Subjects.

Background: Current diagnostic methods for nerve compression headaches consist of diagnostic nerve blocks. A less-invasive method that can possibly aid in the diagnosis is ultrasound, by measuring the cross-sectional area (CSA) of the affected nerve. However, this technique has not been validated, and articles evaluating CSA measurements in the asymptomatic population are missing in the current literature. Therefore, the aim of this study was to determine the feasibility of ultrasound measurements of peripheral extracranial nerves in the head and neck area in asymptomatic individuals. Methods: The sensory nerves of the head and neck in healthy individuals were imaged by ultrasound. The CSA was measured at anatomical determined measurement sites for each nerve. To determine the feasibility of ultrasound measurements, the interrater reliability and the intrarater reliability were determined. Results: In total, 60 healthy volunteers were included. We were able to image the nerves at nine of 11 measurement sites. The mean CSA of the frontal nerves ranged between 0.80 ± 0.42 mm2 and 1.20 ± 0.43 mm2, the mean CSA of the occipital nerves ranged between 2.90 ± 2.73 mm2 and 3.40 ± 1.91 mm2, and the mean CSA of the temporal nerves ranged between 0.92 ± 0.26 mm2 and 1.40 ± 1.11 mm2. The intrarater and interrater reliability of the CSA measurements was good (ICC: 0.75-0.78). Conclusions: Ultrasound is a feasible method to evaluate CSA measurements of peripheral extracranial nerves in the head and neck area. Further research should be done to evaluate the use of ultrasound as a diagnostic tool for nerve compression headache.

Multiplet discharges after electrical stimulation: new evidence for distal excitability changes in motor neuron disease.

We hypothesized that action potentials evoked by distal stimulation might trigger ectopic activity (multiplet discharges, MDs). By studying MDs, we investigated the involvement of the axonal part of the peripheral motor neuron in amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). We performed stimulated high-density surface EMG recordings of the thenar muscles in 10 ALS/PMA patients, five recordings per patient over a three-month period. Furthermore, motor unit number estimates (MUNE) and ALSFRS-R scores were obtained in sessions 1 and 5. MDs were found in all patients, in 21% of the sampled motor units, and in response to 2.4% of the stimulations. The interspike interval range of the MD components was 2.9-6.5 ms, which is compatible only with a distal MD origin. The number of MDs, as percentage of the number of applied stimuli, was correlated with a decline in ALSFRS-R (r =0.80, p =0.006) and MUNE (r =0.72, p =0.02). In conclusion, MDs can be elicited with electrical stimulation in ALS and PMA patients. Analysis of MD characteristics provides further indications for pathophysiological excitability changes in the most distal part of the motor neuron. MDs are associated with clinical deterioration.

Prevalence and Risk Factor Profiles for Chronic Axonal Polyneuropathy in the General Population.

BACKGROUND AND OBJECTIVES: Chronic axonal polyneuropathy is a common disease with increasing prevalence with age. It majorly impacts quality of life and leads to difficulties with various activities. Persons with polyneuropathy often not seek medical care and thus the societal burden of disease is likely underreported. Given the aging populations contemporary data on the prevalence as well as risk factor profiles of polyneuropathy in the general population are required. Therefore, we estimated the current and expected prevalence, and investigated the (co-)occurrence of risk factors in participants with chronic axonal polyneuropathy. METHODS: Between June 2013 and January 2020, participants of the population-based Rotterdam Study underwent extensive in-person examination to diagnose polyneuropathy. Age-standardized prevalence's were calculated for populations aged ≥40 years of the Netherlands, Europe, United States and the world population. Putative risk factors were identified using laboratory findings, interviews, questionnaire data and a review of medical records. RESULTS: In total, 4114 participants were included (mean age 64.3 years, 55.2% females) of whom 167 had chronic axonal polyneuropathy. More than half (54.5%) had yet not received the diagnosis through regular care. Age-standardized prevalence's were 3.3% (95% CI 2.8-4.0) for the European, 3.0% (95% CI 2.5-3.5) for the US and 2.3% (95% CI 1.9-2.8) for the world population. Based on the expected age distributions, the prevalence of chronic axonal polyneuropathy will increase with ±25% in the next 20 years. Known risk factors were present in 62.9% (N=105) of the cases with polyneuropathy and most often included diabetes (34.1%) and vitamin deficiencies (15.1%). Importantly, combinations of various risk factors were found in 20.4% (N=34) of cases with polyneuropathy. DISCUSSION: Prevalence of chronic axonal polyneuropathy increases with age and is expected to further rise over time. Combinations of multiple known risk factors are often present, indicating the need for a full diagnostic workup, even when a single risk factor for polyneuropathy is known. These findings suggest that cumulative effects of multiple risk factors are important in the development and course of disease.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

Prediction of respiratory insufficiency in Guillain-Barré syndrome.

OBJECTIVE: Respiratory insufficiency is a frequent and serious complication of the Guillain-Barré syndrome (GBS). We aimed to develop a simple but accurate model to predict the chance of respiratory insufficiency in the acute stage of the disease based on clinical characteristics available at hospital admission. METHODS: Mechanical ventilation (MV) in the first week of admission was used as an indicator of acute stage respiratory insufficiency. Prospectively collected data from a derivation cohort of 397 GBS patients were used to identify predictors of MV. A multivariate logistic regression model was validated in a separate cohort of 191 GBS patients. Model performance criteria comprised discrimination (area under receiver operating curve [AUC]) and calibration (graphically). A scoring system for clinical practice was constructed from the regression coefficients of the model in the combined cohorts. RESULTS: In the derivation cohort, 22% needed MV in the first week of admission. Days between onset of weakness and admission, Medical Research Council sum score, and presence of facial and/or bulbar weakness were the main predictors of MV. The prognostic model had a good discriminative ability (AUC, 0.84). In the validation cohort, 14% needed MV in the first week of admission, and both calibration and discriminative ability of the model were good (AUC, 0.82). The scoring system ranged from 0 to 7, with corresponding chances of respiratory insufficiency from 1 to 91%. INTERPRETATION: This model accurately predicts development of respiratory insufficiency within 1 week in patients with GBS, using clinical characteristics available at admission. After further validation, the model may assist in clinical decision making, for example, on patient transfer to an intensive care unit.