Evaluation of peripherin in biofluids of patients with motor neuron diseases.

Peripherin (PRPH), a type III intermediate filament, assembles with neurofilaments in neurons of the peripheral nervous system, including lower motor neurons (LMN). To evaluate the role of PRPH in LMN degeneration, we assessed PRPH and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum of 91 patients with motor neuron diseases (MND) and 69 controls. Overall, we found PRPH to be more concentrated in serum than in CSF. Serum PRPH resulted significantly increased in MND patients but it was unrelated to CSF-NfL or survival in the amyotrophic lateral sclerosis (ALS) subset. PRPH might represent a marker of LMN involvement.

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.

Free light chains in cerebrospinal fluid of multiple sclerosis patients negative for IgG oligoclonal bands.

The detection of IgG oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is, as yet, the recommended biochemical marker for the diagnosis of multiple sclerosis (MS). Aim of this study was to investigate the behaviour of free light chains (FLC) in OCBs negative (OCBs-) MS patients compared with that in OCBs positive (OCBs+) MS patients and in a control group (CG) of subjects without cerebrospinal inflammatory disease. At multiple comparisons between the three groups, statistically significant differences (p < .001 for all) were found for κFLC. Conversely, λFLC values evidenced a greater overlapping in the three groups. Receiver operating characteristics (ROC) curves made with κFLC values, evidenced the greater differences of areas under curves (AUCs) between OCBs- and OCBs+ (AUCs: κFLC 0.98, QκFLC 0.98, κFLC index 0.96) with respect to the differences between OCBs- and CG (AUCs: κFLC 0.77, QκFLC 0.86, κFLC index 0.77): indeed >50% of MS OCBs- subjects studied evidenced the same values of κFLC, QκFLC and κFLC index found in CG. Conversely, if the aim is to select MS subjects while avoiding undertaking the more complex isoelectrofocusing test, values with absolute specificity for MS (QκFLC = 15, sensitivity = 0.76 and κFLCindex = 3.09, sensitivity = 0.72) could be used. The values found in this study call for confirmation with data from more subjects, including those with other CSF inflammatory diseases. Anyway, the most important finding was that, for some OCBs- subjects, κFLC are more effective than OCBs in diagnosing MS.

Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis: Neurofilament Light Chain Levels in Definite Subtypes of Disease.

Importance: A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed. Objectives: To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS. Design, Setting, and Participants: In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department. Main Outcomes and Measures: Levels of NFL. Results: The study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P < .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P < .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS. Conclusions and Relevance: This study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.

The Association between Serum Cytokines and Damage to Large and Small Nerve Fibers in Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism.

Polyneuropathy with anti-sulfatide and anti-MAG antibodies: clinical, neurophysiological, pathological features and response to treatment.

IgM paraproteins often present reactivity to myelin-associated glycoprotein (MAG) and sulfatide. We describe the clinical and neurophysiological findings, and therapy response in 21 patients with IgM paraproteinemic neuropathy (15 with anti-MAG antibodies, 1 with anti-sulfatide antibodies, and 5 with both reactivity), and in 2 with anti-sulfatide positivity and no hematological disease. All patients complained of sensory symptoms, the majority had demyelinating neuropathy. Indirect immunofluorescence on human normal sural nerves disclosed different staining patterns. Eight of 13 patients (6 anti-MAG, 1 anti-sulfatide, 1 both anti-sulfatide and anti-MAG antibodies) improved after Rituximab. IVIg, steroids and plasma-exchange were also administered with different responses.

Cerebrospinal fluid IL-1ß correlates with cortical pathology load in multiple sclerosis at clinical onset.

The cerebrospinal fluid levels of interleukin-1 beta and structural magnetic resonance parameters of cortical damage, i.e., cortical lesion number and volume, and global cortical thickness, were analysed in multiple sclerosis patients at clinical onset. Cerebrospinal fluid interleukin-1 beta levels strongly correlated with cortical lesion load and cortical thickness, while correlation with white matter lesion load was modest. Interleukin-1 beta, intrathecally produced by infiltrating lymphocytes and activated microglia, may constitute a possible link between inflammation and neurodegeneration in multiple sclerosis.

Vascular endothelial growth factor helps differentiate neuropathies in rare plasma cell dyscrasias.

POEMS syndrome and amyloidosis are rare plasma cell diseases that share common features, including polyneuropathy. The aim of this study was to investigate serum vascular endothelial growth factor (sVEGF) in patients with amyloidosis and to evaluate changes in response to treatment. Twenty-five patients [17 primary light-chain amyloidosis (AL-A), 7 transthyretin amyloidosis (TTR-A), 1 senile wild-type TTR-A] were studied. sVEGF was analyzed by ELISA. Sera from 8 myeloma and 7 POEMS patients were also evaluated. The median sVEGF level was 420 pg/ml in AL-A and 179 pg/ml in TTR-A patients; this was significantly lower than in POEMS syndrome (median 2580 pg/ml, P = 0.0002 and 0.001, respectively). sVEGF of AL-A patients showed no changes in response to treatment. sVEGF was not increased in amyloid patients regardless of neuropathy, and did not mirror the course of the disease. sVEGF should be tested in patients with overlapping and atypical clinical features.

Anti-ganglioside autoantibodies in type 1 diabetes.

Type 1 diabetes is an autoimmune disease that is accompanied by an immune response against pancreatic cells. As gangliosides are expressed in both peripheral nerves and pancreatic cells, we examined the possibility of correlation between type 1 diabetes, anti-ganglioside autoantibodies, and neuropathy. Fifty diabetic patients and 30 controls with other autoimmune diseases underwent neurological examination and search for antibodies to gangliosides, glutamic acid decarboxylase (GAD(65)), and tyrosine phosphatase (IA2). Sixteen (32%) diabetic patients had neuropathy. Twelve diabetic sera were found to have anti-ganglioside autoantibodies. Twenty sera were positive for anti-GAD(65) and nine for anti-IA2 antibody. Sera from three control patients had anti-ganglioside autoantibodies. No significant correlation was found between autoantibodies, neuropathy, and disease duration. Disease duration was shorter in patients with antibodies to GAD(65) and IA2 and longer in neuropathic patients. The higher prevalence of antibodies in diabetic patients compared to controls may reflect the common pattern of antigens shared by peripheral nerve and pancreatic islet cells.

Neurological complications of celiac disease and autoimmune mechanisms: a prospective study.

Humoral immune mechanisms may have a role in the neurological complications of celiac disease (CD). We assessed 71 CD patients for neurologic manifestations and presence of serum antibodies to neural antigens. Sixteen patients (22.5%) were found to have neurological deficits including headache, depression, entrapment syndromes, peripheral neuropathy, and epilepsy. Antibody reactivity to neural antigens was detected in 30/71 (42.2%) patients. There was no clear correlation between anti-neural reactivity and neurologic dysfunction. Follow-up of 62 patients did not reveal change in electrophysiology or antibodies, regardless of diet. However, in 2 patients with neuropathy, symptoms improved or worsened depending on the diet.

Antibodies to muscle and ganglionic acetylcholine receptors (AchR) in celiac disease.

BACKGROUND: About 2.5% of patients with idiopathic peripheral neuropathy or idiopathic dysautonomia have underlying celiac disease (CD). Antibodies to ganglioside have been reported in CD patients with neuropathy. No data are so far available on the presence in CD of acetylcholine receptor (AChR) antibodies. Muscle AChR antibodies are found in patients with myasthenia gravis, and ganglionic AChR antibodies in patients with autoimmune autonomic neuropathy. OBJECTIVE: To determine the frequency of AChR antibodies in CD patients and assess possible correlations with neurological manifestations. METHODS: Seventy CD patients (16 M, 54 F, mean age 36 years) underwent neurological and electrophysiological evaluation. AChR antibodies were detected with radioimmunoprecipitation assay. Sera from 15 age-matched patients with systemic lupus erythematosus (SLE) and 10 with Sjogren syndrome were studied as controls. RESULTS: None of our CD patients complained of autonomic symptoms or fatigable weakness. Borderline titres (0.03-0.05 nmol/l) of ganglionic AChR antibodies were present in 4 patients, one affected with type I diabetes and one with subclinical neuropathy. Three of the 4 patients underwent cardiovascular autonomic function tests, which showed no abnormalities. Low levels of ganglionic AChR antibodies (0.05-0.10 nmol/l) were found in 2 SLE control patients, one of whom had a severe sicca complex. Muscle AChR antibodies (>1.0 nmol/l) were found in two CD patient and one control patient with SLE. Neither had symptoms or signs of myasthenia gravis. DISCUSSION AND CONCLUSIONS: CD is occasionally associated with neurologic disease, and with antibody reactivity to neuronal antigens. None of our CD patients had autonomic failure or significant levels of ganglionic AChR antibodies. Two CD patient and one control with SLE had muscle AChR antibodies without clinical evidence of myasthenia. The presence of antibodies in CD and in SLE patients may reflect a non-specific autoimmune response in these patients or may indicate subclinical autoimmune autonomic and neuromuscular involvement.

Anti-heparan sulfate antibodies in neurological disease.

Antibodies to heparan sulfate (HS) have previously been found in association with peripheral neuropathy. We tested sera from patients with neuropathies and with other neurological diseases for antibodies to HS using an avidin-biotin enzyme-linked immunosorbent assay (ELISA) system. Increased titers of anti-HS antibodies were found in 3.4% of patients with neuropathy, and in 3% of patients with other neurological diseases. In all cases, however, an inflammatory disease was present, including chronic inflammatory neuropathy, cerebral vasculitis, or multiple sclerosis. Antibodies to HS appear not to be specific for neuropathy, as they occur in several inflammatory diseases. They might contribute to the associated breakdown of the blood-brain or blood-nerve barrier.