Judith Drenthen

Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis.

Guillain–Barré syndrome (GBS) is a potentially life-threatening postinfectious disease characterized by rapidly progressive, symmetrical weakness of the extremities. About 25% of patients develop respiratory insufficiency and many show signs of autonomic dysfunction. Diagnosis can usually be made on clinical grounds, but lumbar puncture and electrophysiological studies can help to substantiate the diagnosis and to differentiate demyelinating from axonal subtypes of GBS. Molecular mimicry of pathogen-borne antigens, leading to generation of crossreactive antibodies that also target gangliosides, is part of the pathogenesis of GBS; the subtype and severity of the syndrome are partly determined by the nature of the antecedent infection and specificity of such antibodies. Intravenous immunoglobulin and plasma exchange are proven effective treatments but many patients have considerable residual deficits. Discrimination of patients with treatment-related fluctuations from those with acute-onset chronic inflammatory demyelinating polyneuropathy is important, as these conditions may require different treatments. Novel prognostic models can accurately predict outcome and the need for artificial ventilation, which could aid the selection of patients with a poor prognosis for more-individualized care. This Review summarizes the clinical features of and diagnostic criteria for GBS, and discusses its pathogenesis, treatment and prognosis.

Diagnosis of Guillain-Barre 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.

Prediction of respiratory insufficiency in Guillain-Barré syndrome

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.

Guillain–Barré syndrome subtypes related to Campylobacter infection

Background In Guillain–Barré syndrome (GBS), the diversity in electrophysiological subtypes is unexplained but may be determined by geographical factors and preceding infections. Acute motor axonal neuropathy (AMAN) is a frequent GBS variant in Japan and one study proposed that in Japan, Campylobacter jejuni infections exclusively elicit AMAN. In The Netherlands C jejuni is the predominant type of preceding infection yet AMAN is rare. This may indicate that not all Dutch GBS patients with C jejuni infections have AMAN. Objective To determine if GBS patients with a preceding C jejuni infection in The Netherlands exclusively have AMAN. Methods Retrospective analysis of preceding infections in relation to serial electrophysiology and clinical data from 123 GBS patients. C jejuni related cases were defined as having preceding diarrhoea and positive C jejuni serology. Electrophysiological characteristics in C jejuni related cases were compared with those in viral related GBS patients. In addition, eight GBS patients from another cohort with positive stool cultures for C jejuni were analysed. Results 17 (14%) of 123 patients had C jejuni related GBS. C jejuni patients had lower motor and higher sensory action potentials compared with viral related cases. Nine (53%) C jejuni patients had either AMAN or inexcitable nerves. However, three (18%) patients fulfilled the criteria for acute inflammatory demyelinating polyneuropathy (AIDP). Also, two (25%) of eight additional patients with a C jejuni positive stool sample had AIDP. Conclusion In The Netherlands, C jejuni infections are strongly, but not exclusively, associated with axonal GBS. Some patients with these infections fulfil current criteria for demyelination.

Motor unit tracking with high-density surface EMG

Following (tracking) individual motor units over time can provide important new insights, both into the relationships among various motor unit (MU) morphological and functional properties and into how these properties are influenced by neuromuscular disorders or interventions. The present study aimed to determine whether high-density surface EMG (HD-sEMG) recordings, which use an array of surface electrodes over a muscle, can increase the yield of MU tracking studies in terms of the number of MUs that can be tracked. For that purpose, four HD-sEMG recording sessions were performed on the thenar muscles of ten healthy subjects. Decomposition of the recorded composite responses yielded a study total of 2849 motor unit action potentials (MUAPs). MUAPs that were found in both of the first two sessions, performed on the same day, were defined as trackable MUAPs. Our results show that 22 (median value; range, 13-34) MUAPs per nerve were trackable, which represented approximately 5% of the total MU population. Of these trackable MUAPs, 16 (11-26) could also be found in one or both of the third and fourth sessions, which were performed between 1 and 13 weeks after the initial studies. Nine (4-18) MUAPs were found in all four sessions. Many of the characteristic MUAP shapes matched well between sessions, even when these sessions were several weeks apart. However, some MUAPs seem very sensitive to changes in arm position or in the muscles morphology (e.g., to changes in muscle fiber length due to variable degrees of thumb flexion or extension), particularly those from larger and/or superficial MUs. Standardization is, therefore, essential to detect even small MUAP changes, as may occur with pathology or interventions. If this is accomplished, MU tracking with HD-sEMG may prove to be a powerful tool for a promising type of neurophysiological investigation.

Prevalence of polyneuropathy in the general middle-aged and elderly population

Objective: To determine the prevalence of chronic polyneuropathy in an unselected community-dwelling population of middle-aged and elderly people. Methods: The current study was embedded in the prospective, population-based Rotterdam Study. Between June 2013 and October 2015, 1,310 participants (mean age 70 years, 55% female) were screened for the presence of polyneuropathy. This screening consisted of a questionnaire, neurologic examination, and nerve conduction studies. Polyneuropathy was diagnosed by a consensus panel that categorized participants into no, possible, probable, or definite polyneuropathy, depending on the level of abnormality of the screening. Medical records were scrutinized to evaluate whether the disorder was diagnosed before and laboratory investigations were performed to determine the presence of associated risk factors. Results: Prevalence of definite polyneuropathy was 5.5% (95% confidence interval 4.4–6.9), age-standardized to the population of the Netherlands 4.0% (3.1–5.3). Prevalence was higher in male participants (6.7% compared to 4.5%) and increased with age. When combining probable and definite polyneuropathy, age-standardized prevalence was 9.4% (7.9–11.1). Almost half of the polyneuropathies (49%) were newly diagnosed. The majority of polyneuropathies were idiopathic (46%). Diabetes, present in 31% of participants with polyneuropathy, was the most commonly found risk factor. Conclusions: Prevalence of polyneuropathy in the general middle-aged and elderly population is at least 4%, and increases with age. Almost half of the cases were newly diagnosed, indicating that the presence of polyneuropathy is underreported or underdiagnosed. Currently, almost half of the polyneuropathies are idiopathic. Future prospective cohort studies should focus on identifying new determinants of polyneuropathy.

Paraparetic Guillain-Barré syndrome

Objective: To define the clinical and diagnostic characteristics of paraparetic Guillain-Barré syndrome (GBS) with weakness restricted to the legs, compared with the classic quadriparetic GBS. Methods: Prospectively collected data from a cohort of 490 patients with GBS, previously involved in therapeutic or clinical studies, were used to define the demography, clinical presentation, diagnostic investigations, and clinical course in patients with paraparesis during a 6-month follow-up. Results: Forty patients (8%) presented with a paraparesis without weakness of arms and hands. In 29 patients (73%), normal strength of upper extremities persisted during the follow-up period. Patients with paraparesis compared to patients with quadriparesis had a milder form of GBS, with less frequent cranial nerve involvement and less severe leg weakness, despite the fact that the majority of these patients were unable to walk unaided. Median time between onset of weakness and study entry was 6 days (interquartile range 4–11 days) for patients with paraparesis compared with 5 days (interquartile range 3–8 days) for patients with quadriparesis (p = 0.031). Fifty percent of patients with paraparesis presented with arm sensory deficits and 73% had reduced or absent arm reflexes. Nerve conduction studies demonstrated arm nerve involvement in 89% of these patients. At 6 months of follow-up, 98% of patients with paraparesis were able to walk unaided compared with 81% of the patients with quadriparesis (p = 0.008). There was no association between paraparesis and age, sex, or preceding infections. Conclusions: Paraparesis is an atypical clinical presentation or subform of GBS in which the diagnosis is usually supported by the presence of sensory deficits, reduced reflexes, or abnormal nerve conduction of the arms.

Residual fatigue in Guillain-Barré syndrome is related to axonal loss

Objective: To determine the occurrence of residual loss of peripheral nerve axons by motor unit number estimation (MUNE) and conventional nerve conduction studies (NCS) in patients with and without severe fatigue. Methods: Thirty-nine patients at a median of 8 years (range 1–23 years) after diagnosis of Guillain-Barré syndrome were neurologically examined and divided in 2 subgroups based on the presence of severe fatigue (defined as a fatigue severity score ≥5). All patients were investigated with standard NCS and MUNE. Normal values for MUNE were collected in 14 healthy controls. Results: MUNE of the thenar muscles was lower in the 15 patients with severe fatigue (median 125, interquartile range 65–141) compared with the 24 patients without severe fatigue (median 258, interquartile range 120–345) (p = 0.002). In the healthy controls, MUNE was 358 (245–416). Severe fatigue was also related to lower sensory nerve action potential amplitude of the median (p = 0.01) and ulnar nerve (p = 0.03). The 2 subgroups did not differ regarding neurologic deficits, disability, and the remaining conventional motor NCS. Conclusion: This study demonstrates that severe fatigue after Guillain-Barré syndrome is related to more pronounced axonal loss, represented by lower MUNEs and lower sensory nerve action potentials.

Reproducibility of the CMAP scan

INTRODUCTION The CMAP scan is a surface EMG method based on the successive activation of motor units. It provides information about reinnervation processes, the number of functional motor units and nerve excitability. The CMAP scan has potential value as a follow-up tool in monitoring disease progression, recovery or aging of the peripheral nerves. In this study, we assessed its interobserver and different-day reproducibility. METHODS Two investigators recorded CMAP scans in ten healthy subjects, each on two different days. Intraclass correlation coefficients (ICCs) and coefficients of variation (CoVs) were calculated for the parameters extracted from the CMAP scan. RESULTS All CMAP scan parameters had a good different day (ICCs >0.8 and CoVs <15%) and interobserver reproducibility (ICCs >0.7 and CoVs ≤ 15%). Different-day reproducibility was better than interobserver reproducibility. CONCLUSION CMAP scan test-retest variability is small, suggesting that as a follow-up tool it may be sensitive to fairly small (patho)physiological changes in the studied variables.

The CMAP scan as a tool to monitor disease progression in ALS and PMA

Abstract Amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA) are characterized by a loss of motor units (MUs), reinnervation and, eventually, muscle fibre loss. These three aspects are all reflected in the compound muscle action potential scan (CMAP scan, a high-detail stimulus response curve), which visualizes large MU potentials as ‘steps’. We explored changes in the CMAP scan over time, combined the information on steps and CMAP amplitude into a CMAP scan-based progression score (CSPS), and correlated this score with motor unit number estimates (MUNE). Ten patients (three PMA, seven ALS; age 37−77 years) were included. CMAP scan and MUNE measurements were performed five times during a three-month period. Nine patients had additional measurements. The follow-up period was 3−24 months. Results demonstrated that abnormalities in steps preceded a decline in maximum CMAP amplitude during follow-up. Usually, both steps and maximum CMAP amplitude changed between recordings. The correlation between the CSPS and MUNE was −0.80 (p < 0.01). In conclusion, the CMAP scan can be used to visualize and quantify disease progression in a muscle affected by MND. The CSPS is a measure of MU loss that is quick and easy to obtain and that, in contrast to MUNE, has no sample bias.