Guillain-Barré syndrome and SARS-CoV-2 infection: a systematic review and meta-analysis on a debated issue and evidence for the 'Italian factor'.

BACKGROUND AND PURPOSE: The association between Guillain-Barré syndrome (GBS) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is debated. This study reappraises, after three pandemic years, the epidemiological data and the features of GBS in SARS-CoV-2 patients. METHODS: A systematic review and meta-analysis of case reports/series and cohort studies published between 1 January 2020 and 19 April 2023 was performed. RESULTS: In all, 209 case reports/series (304 patients) and 26 cohort studies were included. The risk of GBS in northern Italy during the first pandemic wave was 2.85 times increased (95% confidence interval [CI] 1.54; 5.25) whereas in some countries the risk during the first pandemic year was 0.17 times reduced (risk ratio 0.83, 95% CI 0.75; 0.93). The incidence of GBS in SARS-CoV-2 Italian hospitalized cohorts was 8.55 per 1000 (95% CI 5.33; 12.49) with an estimated incidence of 0.13 GBS per 1000 in the SARS-CoV-2 infected population. In European cohorts the pooled rate of GBS with SARS-CoV-2 infection was 61.3% of the total. GBS patients with SARS-CoV-2 infection showed more frequently, but not differently from non-infected patients, the classical clinical presentation and the demyelinating subtype. Cranial nerves were more frequently involved in SARS-CoV-2 infected patients. CONCLUSIONS: An increased risk of GBS occurred in northern Italy during early COVID-19 pandemic. The recognition of the 'Italian factor' reconciles contrasting results of the epidemiological studies. The slightly reduced GBS risk in other countries and the relatively high frequency of GBS associated with SARS-CoV-2 infection can be explained by the adopted health measures that decreased the circulation of other GBS infective antecedents.

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.

Conduction slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies: Electrophysiology meets pathology.

Nerve conduction studies are usually the first diagnostic step in peripheral nerve disorders and their results are the basis for planning further investigations. However, there are some commonplaces in the interpretation of electrodiagnostic findings in peripheral neuropathies that, although useful in the everyday practice, may be misleading: (1) conduction block and abnormal temporal dispersion are distinctive features of acquired demyelinating disorders; (2) hereditary neuropathies are characterized by uniform slowing of conduction velocity; (3) axonal neuropathies are simply diagnosed by reduced amplitude of motor and sensory nerve action potentials with normal or slightly slow conduction velocity. In this review, we reappraise the occurrence of uniform and non-uniform conduction velocity slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies attempting, with a translational approach, a correlation between electrophysiological and pathological features as derived from sensory nerve biopsy in patients and animal models. Additionally, we provide some hints to navigate in this complex field.

Autoimmune nodo-paranodopathies 10 years later: Clinical features, pathophysiology and treatment.

BACKGROUND AND AIMS: Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize the neuropathies with antiganglioside antibodies and later expanded to include neuropathies with antibodies to nodal and paranodal axoglial complexes, characterizes disorders in which the nodal region is critical in the pathogenesis. These neuropathies, although presenting electrophysiologic demyelinating features do not show pathologic evidence of segmental demyelination, or, although being classified as axonal, can show reversible nerve conduction failure and rapid recovery contrary with the communal concept of an axonal neuropathy. METHODS: In this personal view is reported, with a splitting approach, an update on autoimmune nodo-paranodopathies, classified according to the domains of peripheral nerve fiber, the target antigens and the antibody class and subclass involved. The clinical features, the electrophysiologic findings, the results of the immunopathological and ultrastructural studies, the pathophysiology and treatment are also described. RESULTS AND INTERPRETATION: The nodo-paranodopathy category integrates the clinical classification of autoimmune neuropathies and expands the traditional dichotomous demyelinating and axonal classification. It helps to a better systematization pointing to the domain and target antigens of the autoimmune process, it resolves conflicting pathologic and electrophysiologic findings, reconciles the contradiction that axonal neuropathies may be rapidly reversible, avoids taxonomical confusion and possible misdiagnoses. Finally this categorization, through the identification of the specific antibody and its prevalent class and subclass, clarifies the pathophysiological mechanisms and addresses to a more targeted therapeutic approach.

BDNF polymorphism and interhemispheric balance of motor cortex excitability: a preliminary study.

Preclinical studies have demonstrated that brain-derived neurotrophic factor (BDNF) plays a crucial role in the homeostatic regulation of cortical excitability and excitation/inhibition balance. Using transcranial magnetic stimulation techniques, we investigated whether BDNF polymorphism could influence cortical excitability of the left and right primary motor cortex in healthy humans. Twenty-nine participants were recruited and genotyped for the presence of the BDNF Val66Met polymorphism, namely homozygous for the valine allele (Val/Val), heterozygotes (Val/Met), and homozygous for the methionine allele (Met/Met). Blinded to the latter, we evaluated inhibitory and facilitatory circuits of the left (LH) and right motor cortex (RH) by measuring resting (RMT) and active motor threshold (AMT), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). For each neurophysiological metric, we also considered the interhemispheric balance expressed by the laterality index (LI). Val/Val participants (n = 21) exhibited an overall higher excitability of the LH compared with the RH, as probed by lower motor thresholds, lower SICI, and higher ICF. Val/Val participants displayed positive LI, especially for AMT and ICF (all P < 0.05), indicating higher LH excitability and more pronounced interhemispheric excitability imbalance as compared with Met carriers. Our preliminary results suggest that BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability.NEW & NOTEWORTHY BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability. Specifically, Val/Val carriers display higher excitability of the left compared with the right primary motor cortex, whereas Met carriers do not show any significant corticomotor excitability imbalance. These preliminary results are relevant to understanding aberrant interhemispheric excitability and excitation/inhibition balance in neurological disorders.

New classification of autoimmune neuropathies based on target antigens and involved domains of myelinated fibres.

Autoimmune neuropathies are named by eponyms, by descriptive terminology or because of the presence of specific antibodies and are traditionally classified, on the basis of pathology and electrophysiology, as primary demyelinating or axonal. However, autoimmune disorders targeting specific molecules of the nodal region, although not showing pathological evidence of demyelination, can exhibit all the electrophysiological changes considered characteristic of a demyelinating neuropathy and acute neuropathies with antiganglioside antibodies, classified as axonal and due to nodal dysfunction, can present with reversible conduction failure and prompt recovery that appear contradictory with the common view of an axonal neuropathy. These observations bring into question the concepts of demyelinating and axonal nerve conduction changes and the groundwork of the classical dichotomous classification.We propose a classification of autoimmune neuropathies based on the involved domains of the myelinated fibre and, when known, on the antigen. This classification, in our opinion, helps to better systematise autoimmune neuropathies because points to the site and molecular target of the autoimmune attack, reconciles some contrasting pathological and electrophysiological findings, circumvents the apparent paradox that neuropathies labelled as axonal may be promptly reversible and finally avoids taxonomic confusion and possible misdiagnosis.

Guillain-Barré syndrome and COVID-19: A 1-year observational multicenter study.

BACKGROUND AND PURPOSE: Many single cases and small series of Guillain-Barré syndrome (GBS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported during the coronavirus disease 19 (COVID-19) outbreak worldwide. However, the debate regarding the possible role of infection in causing GBS is still ongoing. This multicenter study aimed to evaluate epidemiological and clinical findings of GBS diagnosed during the COVID-19 pandemic in northeastern Italy in order to further investigate the possible association between GBS and COVID-19. METHODS: Guillain-Barré syndrome cases diagnosed in 14 referral hospitals from northern Italy between March 2020 and March 2021 were collected and divided into COVID-19-positive and COVID-19-negative. As a control population, GBS patients diagnosed in the same hospitals from January 2019 to February 2020 were considered. RESULTS: The estimated incidence of GBS in 2020 was 1.41 cases per 100,000 persons/year (95% confidence interval 1.18-1.68) versus 0.89 cases per 100,000 persons/year (95% confidence interval 0.71-1.11) in 2019. The cumulative incidence of GBS increased by 59% in the period March 2020-March 2021 and, most importantly, COVID-19-positive GBS patients represented about 50% of the total GBS cases with most of them occurring during the two first pandemic waves in spring and autumn 2020. COVID-19-negative GBS cases from March 2020 to March 2021 declined by 22% compared to February 2019-February 2020. CONCLUSIONS: Other than showing an increase of GBS in northern Italy in the "COVID-19 era" compared to the previous year, this study emphasizes how GBS cases related to COVID-19 represent a significant part of the total, thus suggesting a relation between COVID-19 and GBS.

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.

Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions.

OBJECTIVE: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19. METHODS: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered. RESULTS: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002). CONCLUSIONS: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.

Hyper-reflexia in Guillain-Barré syndrome: systematic review.

Areflexia or hyporeflexia is a mandatory clinical criterion for the diagnosis of Guillain-Barré syndrome (GBS). A systematic review of the literature from 1 January 1993 to 30 August 2019 revealed 44 sufficiently detailed patients with GBS and hyper-reflexia, along with one we describe. 73.3% of patients were from Japan, 6.7% from the USA, 6.7% from India, 4.4% from Italy, 4.4% from Turkey, 2.2% from Switzerland and 2.2% from Slovenia, suggesting a considerable geographical variation. Hyper-reflexia was more frequently associated with antecedent diarrhoea (56%) than upper respiratory tract infection (22.2%) and the electrodiagnosis of acute motor axonal neuropathy (56%) than acute inflammatory demyelinating polyneuropathy (4.4%). Antiganglioside antibodies were positive in 89.7% of patients. Hyper-reflexia was generalised in 90.7% of patients and associated with reflex spread in half; it was present from the early progressive phase in 86.7% and disappeared in a few weeks or persisted until 18 months. Ankle clonus or Babinski signs were rarely reported (6.7%); spasticity never developed. 53.3% of patients could walk unaided at nadir, none needed mechanical ventilation or died. 92.9% of patients with limb weakness were able to walk unaided within 6 months. Electrophysiological studies showed high soleus maximal H-reflex amplitude to maximal compound muscle action potential amplitude ratio, suggestive of spinal motoneuron hyperexcitability, and increased central conduction time, suggestive of corticospinal tract involvement, although a structural damage was never demonstrated by MRI. Hyper-reflexia is not inconsistent with the GBS diagnosis and should not delay treatment. All GBS variants and subtypes can present with hyper-reflexia, and this eventuality should be mentioned in future diagnostic criteria for GBS.

Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic.

A systematic review from 1 January to 30 June 2020 revealed 42 patients with Guillain-Barré syndrome (GBS) associated with SARS-CoV-2 infection. Single cases and small series were reported from 13 countries, the majority from Europe (79.4%) and especially from Italy (30.9%). SARS-CoV-2 infection was demonstrated by nasopharyngeal swab (85.7%) and serology (14.3%). Median time between COVID-19 and GBS onset in 36 patients was 11.5 days (IQR: 7.7-16). The most common clinical features were: limb weakness (76.2%), hypoareflexia (80.9 %), sensory disturbances (66.7 %) and facial palsy (38.1%). Dysautonomia occurred in 19%, respiratory failure in 33.3% and 40.5% of patients were admitted in intensive care unit. Most patients (71.4%) had the classical clinical presentation but virtually all GBS variants and subtypes were reported. Cerebrospinal fluid (CSF) albumin-cytological dissociation was found in 28/36 (77.8%) and PCR for SARS-CoV-2 was negative in 25/25 patients. Electrodiagnosis was demyelinating in 80.5% and levels 1 and 2 of Brighton criteria of diagnostic certainty, when applicable, were fulfilled in 94.5% patients. Antiganglioside antibodies were positive in only 1/22 patients. Treatments were intravenous immunoglobulin and/or plasma exchange (92.8%) with, at short-time follow-up, definite improvement or recovery in 62.1% of patients. One patient died. In conclusion, the most frequent phenotype of GBS in SARS-CoV-2 infection is the classical sensorimotor demyelinating GBS responding to the usual treatments. The time interval between infectious and neuropathic symptoms, absence of CSF pleocytosis and negative PCR support a postinfectious mechanism. The abundance of reports suggests a pathogenic link between SARS-CoV-2 infection and GBS but a case-control study is greatly needed.

Electrodiagnostic accuracy in polyneuropathies: supervised learning algorithms as a tool for practitioners.

OBJECTIVE: The interpretation of electrophysiological findings may lead to misdiagnosis in polyneuropathies. We investigated the electrodiagnostic accuracy of three supervised learning algorithms (SLAs): shrinkage discriminant analysis, multinomial logistic regression, and support vector machine (SVM), and three expert and three trainee neurophysiologists. METHODS: We enrolled 434 subjects with the following diagnoses: chronic inflammatory demyelinating polyneuropathy (99), Charcot-Marie-Tooth disease type 1A (124), hereditary neuropathy with liability to pressure palsy (46), diabetic polyneuropathy (67), and controls (98). In each diagnostic class, 90% of subjects were used as training set for SLAs to establish the best performing SLA by tenfold cross validation procedure and 10% of subjects were employed as test set. Performance indicators were accuracy, precision, sensitivity, and specificity. RESULTS: SVM showed the highest overall diagnostic accuracy both in training and test sets (90.5 and 93.2%) and ranked first in a multidimensional comparison analysis. Overall accuracy of neurophysiologists ranged from 54.5 to 81.8%. CONCLUSIONS: This proof of principle study shows that SVM provides a high electrodiagnostic accuracy in polyneuropathies. We suggest that the use of SLAs in electrodiagnosis should be exploited to possibly provide a diagnostic support system especially helpful for the less experienced practitioners.

Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground.

Peripheral neuropathies are classified as primarily demyelinating or axonal. Microstructural alterations of the nodal region are the key to understand the pathophysiology of neuropathies with antibodies to gangliosides and the new category of nodo-paranodopathy has been proposed to better characterise these disorders and overcome some inadequacies of the dichotomous classification. Recently, the research in autoimmune neuropathies has been boosted by reports of patients carrying immunoglobulin G4 antibodies against paranodal axo-glial proteins with distinct phenotypes and showing loss of transverse bands, terminal myelin loop detachment, nodal widening and axonal loss. These patients have been classified up to now as chronic inflammatory demyelinating polyradiculoneuropathy but, in our opinion, better fit into the nodo-paranodopathy category because nerve injury is due to dismantling of the paranode, segmental de-remyelination is absent and the pathogenic mechanism is not inflammatory. Evidence from nerve conductions and electron microscopy studies in patients and mutant animal models can reconcile the apparent contrast between the electrophysiological 'demyelinating' features, explainable just by the paranodal involvement and the axonal pathology. These patients broaden the autoimmune nodo-paranodopathy category and re-emphasise the usage of the term that pointing to the site of nerve injury reminds specific pathophysiological mechanisms, reconciles contrasting electrophysiological and pathological findings, and avoids misdiagnosis and taxonomic confusion. In our opinion, the nodo-paranodopathy term more adequately classifies the peripheral nerve disorders due to an autoimmune attack directed and limited to the nodal region integrating the traditional classification of peripheral neuropathies.

Miller Fisher syndrome, Bickerstaff brainstem encephalitis and Guillain-Barré syndrome overlap with persistent non-demyelinating conduction blocks: a case report.

BACKGROUND: Miller Fisher syndrome (MFS) and Bickerstaff's Brainstem Encephalitis (BBE) share some clinical features and a common immunological profile characterized by anti-GQ1b antibodies. Some MFS patients overlap with Guillain-Barré syndrome (GBS) or BBE. We report a patient with MFS, BBE, and axonal GBS overlap in whom serial electrophysiological studies showed persistent motor conduction blocks (CBs). CASE PRESENTATION: A 61-year-old man acutely developed ophtalmoparesis, ataxia and areflexia suggesting MFS. Paresthesias, severe weakness, and drowsiness rapidly developed indicating an overlap with BBE and GBS. Preceding infection with Mycoplasma Pneumoniae and anti-GQ1b antibodies were detected. On day 4, nerve conduction study showed reduced or non-recordable compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) without demyelinating features, indicating the electrodiagnosis of acute motor and sensory axonal neuropathy and suggesting a poor prognosis. Intravenous immunoglobulins (IVIg) were given but clinical status worsened to ophthalmoplegia, tetraplegia and coma needing mechanical ventilation. A second IVIg course was given and the patient was weaned off ventilation on day 41 and transferred to rehabilitation on day 57 with partial resolution of the ophthalmoplegia and limited recovery of muscle strength. Electrophysiology showed, after 10 weeks, greatly improved distal CMAP amplitudes suggesting the resolution of distal CBs while CBs in intermediate and proximal nerve segments emerged. CBs unusually persisted for four to 6 months without development of abnormal temporal dispersion. A third IVIg course was started on day 179 and the resolution of CBs mirrored the clinical improvement. CONCLUSIONS: GQ1b gangliosides are expressed in the nodal region of oculomotor nerves, muscle spindle afferents, peripheral nerves and possibly in the brainstem reticular formation. Anti-GQ1b antibodies may explain the complex symptomatology and the overlap between MFS, BBE, and GBS. CBs that persisted and recovered without the development of temporal dispersion suggest that weakness was due to a sustained, antibody-mediated, attack at the nodal region inducing a non-demyelinating conduction failure as expression of an acute onset, long lasting, nodopathy. Serial electrophysiological studies allowed not only to understand the underlying pathophysiology and formulate a more correct prognosis but also to guide the treatment.

Zika virus infection and Guillain-Barré syndrome: a review focused on clinical and electrophysiological subtypes.

In 2016, we have seen a rapid emergence of Zika virus-associated Guillain-Barré syndrome (GBS) since its first description in a French-Polynesian patient in 2014. Current evidence estimates the incidence of GBS at 24 cases per 100 000 persons infected by Zika virus. This will result in a sharp rise in the number of GBS cases worldwide with the anticipated global spread of Zika virus. A better understanding of the pathogenesis of Zika-associated GBS is crucial to prepare us for the current epidemic. In this review, we evaluate the existing literature on GBS in association with Zika and other flavivirus to better define its clinical subtypes and electrophysiological characteristics, demonstrating a demyelinating subtype of GBS in most cases. We also recommend measures that will help reduce the gaps in knowledge that currently exist.

Nodopathies of the peripheral nerve: an emerging concept.

Peripheral nerve diseases are traditionally classified as demyelinating or axonal. It has been recently proposed that microstructural changes restricted to the nodal/paranodal region may be the key to understanding the pathophysiology of antiganglioside antibody mediated neuropathies. We reviewed neuropathies with different aetiologies (dysimmune, inflammatory, ischaemic, nutritional, toxic) in which evidence from nerve conductions, excitability studies, pathology and animal models, indicate the involvement of the nodal region in the pathogenesis. For these neuropathies, the classification in demyelinating and axonal is inadequate or even misleading, we therefore propose a new category of nodopathy that has the following features: (1) it is characterised by a pathophysiological continuum from transitory nerve conduction block to axonal degeneration; (2) the conduction block may be due to paranodal myelin detachment, node lengthening, dysfunction or disruption of Na(+) channels, altered homeostasis of water and ions, or abnormal polarisation of the axolemma; (3) the conduction block may be promptly reversible without development of excessive temporal dispersion; (4) axonal degeneration, depending on the specific disorder and its severity, eventually follows the conduction block. The term nodopathy focuses to the site of primary nerve injury, avoids confusion with segmental demyelinating neuropathies and circumvents the apparent paradox that something axonal may be reversible and have a good prognosis.

Polyneuropathy associated with duodenal infusion of levodopa in Parkinson's disease: features, pathogenesis and management.

Patients with Parkinson's disease (PD) treated with oral levodopa have a higher prevalence of chronic, prevalently sensory, usually mild axonal polyneuropathy (PNP). Several studies showed a positive association among PNP, cumulative levodopa dosage, low serum B12 and high-homocysteine and methylmalonic acid level. Anecdotal severe acute or subacute PNPs thought to be Guillain-Barré syndrome have been reported in patients receiving continuous intraduodenal infusion of levodopa/carbidopa intestinal gel (LCIG). We report an additional acute case and by a systematic literature search we also reviewed the clinical and laboratory features of 13 other acute and 21 subacute PNP cases occurring during LCIG treatment. In series with at least nine patients, the mean frequency of acute and subacute PNP is 13.6% and the mortality rate at 6 months in acute cases is 14%. The great majority of PNP cases displayed axonal sensory-motor and reduced vitamin B12 levels, and alterations of metabolites of 1-carbon pathway were found in most patients. We discuss the possible role of high-levodopa dosage, vitamin B12, B6 and folate deficiency and accumulation of homocysteine and methylmalonic acid in the pathogenesis to conclude that there is enough, although circumstantial, evidence that alterations of 1-carbon pathway are implicated also in acute and subacute PNP during LCIG usage. There is no solid proof for a dysimmune pathogenesis and in our opinion acute, subacute and chronic PNP, either after oral levodopa or LCIG, represent a continuum. Finally, we propose recommendations for prevention and management of PNP occurring during LCIG treatment.

Frequency and time to relapse after discontinuing 6-month therapy with IVIg or pulsed methylprednisolone in CIDP.

BACKGROUND: We reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening. METHODS: By March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1-60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up. RESULTS: Twenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1-57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7-60). Worsening occurred 1-24 months (median 4.5) after IVIg discontinuation and 1-31 months (median 14) after IVMP discontinuation (p=0.0126). CONCLUSIONS: A similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP.