Inhibition of Protease-Activated Receptor-2 Activation in Parkinson's Disease Using 1-Piperidin Propionic Acid.

In Parkinson's disease, neuroinflammation is a double-edged sword; when inflammation occurs it can have harmful effects, despite its important role in battling infections and healing tissue. Once triggered by microglia, astrocytes acquire a reactive state and shift from supporting the survival of neurons to causing their destruction. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson's disease. Protein aggregates and PAR2 expression were analyzed using Thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson's patients, treated or untreated with 1-PPA. A significant decrease in amyloid aggregates was observed after 1-PPA treatment in all patients. A parallel decrease in PAR2 expression, which was higher in sporadic Parkinson's patients, was also observed both at the transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease in IL-1ß, IL-6, and TNF-α, together with a decreased expression of PAR2. In conclusion, 1-PPA determines the reduction in neuroglia inflammation and amyloid aggregates formation, suggesting that the pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.

Genetic mutations in Parkinson's disease: screening of a selected population from North-Eastern Italy.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings. METHODS: Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features. RESULTS: A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion "age of onset < 55 years" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03). CONCLUSIONS: Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.

Immune landscape of the enteric nervous system differentiates Parkinson's disease patients from controls: The PADUA-CESNE cohort.

BACKGROUND: Gastrointestinal dysfunction has emerged as a prominent early feature of Parkinson's Disease, shedding new light on the pivotal role of the enteric nervous system in its pathophysiology. However, the role of immune-cell clusters and inflammatory and glial markers in the gut pathogenetic process needs further elucidation. OBJECTIVES: We aimed to study duodenum tissue samples to characterize PD's enteric nervous system pathology further. Twenty patients with advanced PD, six with early PD, and 18 matched controls were included in the PADUA-CESNE cohort. METHODS: Duodenal biopsies from 26 patients with early to advanced stage PD and 18 age-matched HCs were evaluated for the presence of surface markers (CD3+, CD4+, CD8+, CD20+, CD68+, HLA-DR), presence of misfolded alpha-synuclein and enteric glial alteration (GFAP). Correlation of immulogic pattern and clinical characteristic were analyzed. RESULTS: The findings validate that in patients with Parkinson's Disease, the activation and reactive gliosis are linked to the neurodegeneration triggered by the presence of misfolded alpha-synuclein in the enteric nervous system. This process intensifies from the initial to the advanced stages of the disease. The clusters of T- and B-lymphocytes in the enteric system, along with the overall expression of HLA-DR in antigen-presenting cells, exceeded those in the control group. Conversely, no differences in terms of macrophage populations were found. CONCLUSIONS: These findings broaden our understanding of the mechanisms underlying the enteric nervous system's involvement in PD and point to the gastrointestinal system as a potential therapeutic target, especially in the early stages of the disease. Moreover, our results propose a role of T- and B-lymphocytes in maintaining inflammation and ultimately influencing alpha-synuclein misfolding and aggregation.

Assessment of diagnostic criteria for multifocal motor neuropathy in patients included in the Italian database.

BACKGROUND AND PURPOSE: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real-life data in multifocal motor neuropathy (MMN) patients. METHODS: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty-six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis. Analyses were conducted on 73 patients with a confirmed MMN diagnosis and 11 patients who did not meet the diagnostic criteria. RESULTS: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria were variably applied. AUTHOR: When applying the American Association of Electrodiagnostic Medicine criteria, an additional 17% of patients fulfilled the criteria for probable/definite diagnosis whilst a further 9.5% missed the diagnosis. In 17% of the patients only compound muscle action potential amplitude, but not area, was measured and subsequently recorded in the database by the treating physician. Additional investigations, including anti-GM1 immunoglobulin M antibodies, cerebrospinal fluid analysis, nerve ultrasound and magnetic resonance imaging, supported the diagnosis in 46%-83% of the patients. Anti-GM1 immunoglobulin M antibodies and nerve ultrasound demonstrated the highest sensitivity. Additional tests were frequently performed outside the EFNS/PNS guideline recommendations. CONCLUSIONS: This study provides insights into the real-world diagnostic and management strategies for MMN, highlighting the challenges in applying diagnostic criteria.

Rapidly progressive multiple system atrophy in a patient carrying LRRK2 G2019S mutation.

BACKGROUND: Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. CASE: We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. CONCLUSIONS: LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.

Neurotransmitter and receptor systems in the subthalamic nucleus.

The Subthalamic Nucleus (STh) is a lens-shaped subcortical structure located ventrally to the thalamus, that despite being embryologically derived from the diencephalon, is functionally implicated in the basal ganglia circuits. Because of this strict structural and functional relationship with the circuits of the basal ganglia, the STh is a current target for deep brain stimulation, a neurosurgical procedure employed to alleviate symptoms in movement disorders, such as Parkinson's disease and dystonia. However, despite the great relevance of this structure for both basal ganglia physiology and pathology, the neurochemical and molecular anatomy of the STh remains largely unknown. Few studies have specifically addressed the detection of neurotransmitter systems and their receptors within the structure, and even fewer have investigated their topographical distribution. Here, we have reviewed the scientific literature on neurotransmitters relevant in the STh function of rodents, non-human primates and humans including glutamate, GABA, dopamine, serotonin, noradrenaline with particular focus on their subcellular, cellular and topographical distribution. Inter-species differences were highlighted to provide a framework for further research priorities, particularly in humans.

The pharmacological management of the behavioral aspects of Parkinson's disease: an update.

INTRODUCTION: Behavioural symptoms are common manifestations of Parkinson's disease and include depression, anxiety, impulse control disorders, hallucinations, psychosis, and cognitive dysfunction. They remain inadequately addressed in many patients despite their relevance for quality of life and disability. This applies also to impulse control disorders where the most common approach in recent literature is to refrain from using dopamine agonists without consideration about their potential benefit on motor complications. AREAS COVERED: We conducted a narrative review searching for articles on behavioral symptoms in Parkinson disease and selected those which included involved neurotransmitters such as dopamine, noradrenaline, serotonin, acetylcholine. We specifically focused our search on open-label and randomized double-blind studies and biomarkers which could best characterize these clinical manifestations. EXPERT OPINION: Management of Parkinson disease behavioural manifestations lacks clear guidelines and standardized protocols beside general suggestions of dose adjustments in dopamine replacement therapy and use of antidepressants or antipsychotic drugs with little consideration of patients' age, sex, comorbidities, and motor status. We suggest a pragmatic approach which includes education of affected patients and caring people, dealing with complex cases by experienced multidisciplinary teams, use of cognitive behavioural therapy, and psychological counselling to complement drug treatment.

Unclassified clinical presentations of chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: To assess the ability of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) clinical criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to include within their classification the whole spectrum of clinical heterogeneity of the disease and to define the clinical characteristics of the unclassifiable clinical forms. METHODS: The 2021 EAN/PNS clinical criteria for CIDP were applied to 329 patients fulfilling the electrodiagnostic (and in some cases also the supportive) criteria for the diagnosis of CIDP. Clinical characteristics were reviewed for each patient not strictly fulfilling the clinical criteria ('unclassifiable'). RESULTS: At study inclusion, 124 (37.5%) patients had an unclassifiable clinical presentation, including 110 (89%) with a typical CIDP-like clinical phenotype in whom some segments of the four limbs were unaffected by weakness ('incomplete typical CIDP'), 10 (8%) with a mild distal, symmetric, sensory or sensorimotor polyneuropathy confined to the lower limbs with cranial nerve involvement ('cranial nerve predominant CIDP') and 4 (1%) with a symmetric sensorimotor polyneuropathy limited to the proximal and distal areas of the lower limbs ('paraparetic CIDP'). Eighty-one (65%) patients maintained an unclassifiable presentation during the entire disease follow-up while 13 patients progressed to typical CIDP. Patients with the unclassifiable clinical forms compared with patients with typical CIDP had a milder form of CIDP, while there was no difference in the distribution patterns of demyelination. CONCLUSIONS: A proportion of patients with CIDP do not strictly fulfil the 2021 EAN/PNS clinical criteria for diagnosis. These unclassifiable clinical phenotypes may pose diagnostic challenges and thus deserve more attention in clinical practice and research.

Risk of disease relapse, safety and tolerability of SARS-CoV-2 vaccination in patients with chronic inflammatory neuropathies.

BACKGROUND AND PURPOSE: The aim was to evaluate the risk of relapse after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, and its safety and tolerability, in patients with chronic inflammatory neuropathies. METHODS: In this multicenter, cohort and case-crossover study, the risk of relapse associated with SARS-CoV-2 vaccination was assessed by comparing the frequency of relapse in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) patients who underwent or did not undergo vaccination. Frequency of relapse in the 3 months prior to and after vaccination, and safety and tolerability of SARS-CoV-2 vaccination, were also assessed. RESULTS: In all, 336 patients were included (278 CIDP, 58 MMN). Three hundred and seven (91%) patients underwent SARS-CoV-2 vaccination. Twenty-nine patients (9%) did not undergo vaccination. Mild and transient relapses were observed in 16 (5%) patients (13 CIDP, 3 MMN) after SARS-CoV-2 vaccination and in none of the patients who did not undergo vaccination (relative risk [RR] 3.21, 95% confidence interval [CI] 0.19-52.25). There was no increase in the specific risk of relapse associated with type of vaccine or diagnosis. Comparison with the 3-month control period preceding vaccination revealed an increased risk of relapse after vaccination (RR 4.00, 95% CI 1.35-11.82), which was restricted to CIDP patients (RR 3.25, 95% CI 1.07-9.84). The safety profile of SARS-CoV-2 vaccination was characterized by short-term, mild-to-moderate local and systemic adverse events. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in CIDP and MMN patients does not seem to be associated with an increased risk of relapse at the primary end-point, although a slightly increased risk in CIDP patients was found compared to the 3 months before vaccination.

Duodenal alpha-Synuclein Pathology and Enteric Gliosis in Advanced Parkinson's Disease.

BACKGROUND: The role of the gut-brain axis has been recently highlighted as a major contributor to Parkinson's disease (PD) physiopathology, with numerous studies investigating bidirectional transmission of pathological protein aggregates, such as α-synuclein (αSyn). However, the extent and the characteristics of pathology in the enteric nervous system have not been fully investigated. OBJECTIVE: We characterized αSyn alterations and glial responses in duodenum biopsies of patients with PD by employing topography-specific sampling and conformation-specific αSyn antibodies. METHODS: We examined 18 patients with advanced PD who underwent Duodopa percutaneous endoscopic gastrostomy and jejunal tube procedure, 4 untreated patients with early PD (disease duration <5 years), and 18 age- and -sex-matched healthy control subjects undergoing routine diagnostic endoscopy. A mean of four duodenal wall biopsies were sampled from each patient. Immunohistochemistry was performed for anti-aggregated αSyn (5G4) and glial fibrillary acidic protein antibodies. Morphometrical semiquantitative analysis was performed to characterize αSyn-5G4+ and glial fibrillary acidic protein-positive density and size. RESULTS: Immunoreactivity for aggregated α-Syn was identified in all patients with PD (early and advanced) compared with controls. αSyn-5G4+ colocalized with neuronal marker ß-III-tubulin. Evaluation of enteric glial cells demonstrated an increased size and density when compared with controls, suggesting reactive gliosis. CONCLUSIONS: We found evidence of synuclein pathology and gliosis in the duodenum of patients with PD, including early de novo cases. Future studies are required to evaluate how early in the disease process duodenal pathology occurs and its possible contribution to levodopa effect in chronic patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gastrointestinal barriers to levodopa transport and absorption in Parkinson's disease.

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.

Clinical, cognitive, and morphometric profiles of progressive supranuclear palsy phenotypes.

The International Parkinson's and Movement Disorder Society (MDS) criteria for progressive supranuclear palsy (PSP) have broadened the clinical spectrum of the disease and established phenotypic characterization according to the predominant manifestation at onset. The objective of this study is to describe clinical/cognitive and imaging features of a monocentric cohort of PSP patients, highlighting different patterns of functional disability according to the assigned phenotype. We retrospectively reviewed clinical/imaging data of 53 PSP patients diagnosed with probable PSP according to the MDS criteria and 40 age/sex-matched healthy controls (HCs). Neurological/neuropsychological assessments were performed using standardized scales, as well as comprehensive magnetic resonance imaging (MRI) morphometric measurements. In our cohort, there were 24/53 PSP-RS (Richardson's syndrome), 13/53 PSP-P (Parkinsonism), 7/53 PSP-PGF (Progressive gait freezing), and 9/53 PSP-Cog (Cognitive impairment). PSP-Cog presented the worst motor profiles, the highest percentages of dementia and impaired functional autonomy; 4/9 PSP-Cog and 2/7 PSP-PGF died. PSP-P had the lowest motor/cognitive burden. All MRI parameters had good discriminative efficacy vs. HCs, with P/M 2.0 discriminating PSP-PGF from PSP-RS and PSP-Cog. We highlighted discrete clinical and imaging patterns that best characterize different PSP phenotypes. PSP-Cog and PSP-PGF/RS manifest greater incidence of dementia and motor disability, respectively, while PSP-P has a more benign course. The identification of different phenotypes may be the expression of different progression patterns requiring tailored approaches in terms of follow-up and treatment. These findings support the concept of discrete patterns of Tau pathology within the PSP spectrum and encourage research for phenotype-specific outcome measures.

Peripheral nerve involvement in wild-type transthyretin amyloidosis.

INTRODUCTION AND AIMRPOSE: Neurological involvement other than carpal tunnel syndrome (CTS) has rarely been observed in wild-type transthyretin amyloidosis (ATTRwt). The aim of our study was to investigate peripheral nerve involvement in ATTRwt. METHODS: Patients diagnosed with ATTRwt (negative molecular testing, confirmed cardiac uptake at bone scintigraphy, Perugini score 2 or 3) were considered. Sixteen men (mean age 75 ± 6.2, range 65-86 years) were enrolled. Neurological examination (Neuropathy Impairment Score, NIS), questionnaires on autonomic function and quality of life (QoL), electrodiagnostic studies (EDX), nerve ultrasound, and Sudoscan (electrochemical skin conductance, ESC) were performed. The presence of peripheral neuropathy was defined according to the detection of any abnormal finding at lower limbs other than CTS at EDX studies, regardless of NIS scores. RESULTS: Ten (62.5%) ATTRwt had abnormal NIS scores. At EDX, CTS was observed in 13/16 (81.2%), with 3/16 (18.8%) presenting also axonal peripheral neuropathy. Extensive workup ruled out common causes of neuropathy. Eight (50%) ATTRwt patients had orthostatic hypotension (OH). Abnormal ESC was observed in 9/14 (64%) ATTRwt patients. DISCUSSION: Despite being uncommon, we observed peripheral nervous system involvement in ATTRwt (large and small fiber dysfunction). Being elderly, ATTRwt patients may have age-related conditions acting as confounding factors for the diagnosis of neuropathy that however can be detected with a careful examination and use of specific tests, including those for autonomic dysfunction.

Cutaneous amyloid is a biomarker in early ATTRv neuropathy and progresses across disease stages.

OBJECTIVE: To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient-reported measures in the earliest disease stage of hereditary ATTR amyloidosis (ATTRv). METHODS: In a cross-sectional study, we analyzed 88 individuals with TTR mutations, 47 of whom were in the earliest disease stage and without clinically evident neuropathy, 12 healthy controls, and 13 disease controls with diabetes. All participants' neuropathy symptoms and signs were assessed using validated patient and clinician-reported measures and 3-mm skin punch biopsies were immunostained using protein gene product 9.5 and Congo Red. RESULTS: Amyloid can be detected in the earliest disease stages in up to 86% of patients with ATTRv amyloidosis. Amyloid was not detected in healthy individuals or individuals with diabetic peripheral neuropathy supporting a sensitivity of 86% and a specificity of 100%. The cutaneous deposition of amyloid correlates with neuropathy sensory symptoms, measured with the Neuropathy Total Symptom Score-6 (R = 0.46, p < 0.01); pain measured with the Brief Pain Symptom Inventory (R = 0.44, p < 0.05); autonomic symptoms, measured with the Boston Autonomic Symptom Questionnaire (R = 0.38, p < 0.05); and quality of life measured with the Norfolk Diabetic Neuropathy Quality of Life Questionnaire (R = 0.44, p < 0.05). Individuals with amyloid deposition were more likely to have sensory symptoms, pain, autonomic impairment, and reduced quality of life than ATTRv patients without amyloid deposition. INTERPRETATION: These findings have implications for understanding the earliest manifestations of the clinical phenotype of ATTRv-associated neuropathy, for the pathophysiological construct of disease staging, and for timing the introduction of disease-modifying therapy.

From Biology to Treatment of Monoclonal Gammopathies of Neurological Significance.

Monoclonal gammopathy and peripheral neuropathy are common diseases of elderly patients, and almost 10% of patients with neuropathy of unknown cause have paraprotein. However, growing evidence suggests that several hematological malignancies synthesize and release monoclonal proteins that damage the peripheral nervous system through different mechanisms. The spectrum of the disease varies from mild to rapidly progressive symptoms, sometimes affecting not only sensory nerve fibers, but also motor and autonomic fibers. Therefore, a multidisciplinary approach, mainly between hematologists and neurologists, is recommended in order to establish the correct diagnosis of monoclonal gammopathy of neurological significance and to tailor therapy based on specific genetic mutations. In this review, we summarize the spectrum of monoclonal gammopathies of neurological significance, their distinctive clinical and neurophysiological phenotypes, the most relevant pathophysiological events and new therapeutic approaches.

Update on therapy of chronic immune-mediated neuropathies.

Chronic immune-mediated neuropathies, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), neuropathies associated with monoclonal gammopathy, and multifocal motor neuropathy (MMN), are a group of disorders deemed to be caused by an immune response against peripheral nerve antigens. Several immune therapies have been reported to be variably effective in these neuropathies including steroids, plasma exchange, and high-dose intravenous (IVIg) or subcutaneous (SCIg) immunoglobulins. These therapies are however far from being invariably effective and may be associated with a number of side effects leading to the use of immunosuppressive agents whose efficacy has not been so far confirmed in randomized trials. More recently, new biological agents, such as rituximab, have proved to be effective in patients with neuropathy associated with IgM monoclonal gammopathy and are currently tested in CIDP.

Progressive brachial plexus enlargement in hereditary transthyretin amyloidosis.

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers. Thirty-eight subjects were evaluated (mean follow-up 17.1 months), among them 21 had polyneuropathy while 17 were pre-symptomatic carriers. CSA significantly increased at brachial plexus in both groups (p = 0.008 and p = 0.012) pointing to progressive brachial plexus enlargement as a longitudinal biomarker of both disease progression and disease occurrence in pre-symptomatic carriers.

Oligoclonal IgG bands in chronic inflammatory polyradiculoneuropathies.

BACKGROUND: Cerebrospinal fluid (CSF) albumincytologic dissociation represents a supportive diagnostic criterion of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Few studies have investigated possible systemic or intrathecal humoral immune response activation in CIDP.Aim of our study was to investigate whether the search of oligoclonal IgG bands (OCBs) might provide additional data helpful in CIDP diagnostic work-up. METHODS: Forty-eight consecutive patients with CIDP (34 men, mean age 59.4, range 16-83) were recruited. CSF analysis included nephelometric measurement of albumin and IgG concentrations, calculation of QALB, QAlbLIM and intrathecal IgG synthesis, and OCBs detection with isoelectric focusing. Data were compared with those from CSF and serum of 32 patients with Guillain-Barré syndrome (GBS), 18 patients with anti-myelin associated glycoprotein (MAG) antibody neuropathy, 4 patients with multifocal motor neuropathy and 32 patients with non-inflammatory neuropathies (NINPs). RESULTS: Patients with CIDP and anti-MAG antibody neuropathy had significantly higher CSF albumin concentrations and QALB values than NINPs (p=0.0003 and p=0.0095, respectively). A total of 9 (19%) patients with CIDP presented identical serum and CSF OCBs ('mirror pattern') versus 3 patients (16.6%) with anti-MAG antibody neuropathy, 13 patients (40.6%) with GBS and 12.5% patients with NINPs. Only one patient with CIDP showed unique-to-CSF OCBs. First-line therapy was effective in 80.4% of patients with CIDP, irrespective of CSF findings. CONCLUSIONS: Compared with NINP, CIDP, GBS and anti-MAG antibody neuropathies had a significantly increased CSF protein and blood-spinal nerve root barrier damage. Intrathecal humoral immune response is rare in our patients with CIDP. Systemic oligoclonal activation is more frequent, but not significantly different from what was detected in the control groups.

Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies.

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.