Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects.

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Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects.

Brain. 2016 Mar 26;

Authors: Manso C, Querol L, Mekaouche M, Illa I, Devaux JJ

Abstract
Paranodal axoglial junctions formed by the association of contactin-1, contactin-associated protein 1, and neurofascin-155, play important functions in nerve impulse propagation along myelinated axons. Autoantibodies to contactin-1 and neurofascin-155 define chronic inflammatory demyelinating polyradiculoneuropathy subsets of patients with specific clinical features. These autoantibodies are mostly of the IgG4 isotype, but their pathogenicity has not been proven. Here, we investigated the mechanisms how IgG subclasses to contactin-1 affect conduction. We show that purified anti-contactin-1 IgG1 and IgG4 bind to paranodes. To determine whether these isotypes can pass the paranodal barrier, we incubated isolated sciatic nerves with the purified antibody or performed intraneural injections. We found that IgG4 diffused into the paranodal regionsin vitroor after intraneural injections. IgG4 infiltration was slow and progressive. In 24 h, IgG4 accessed the paranode borders near the nodal lumen, and completely fill the paranodal segments by 3 days. By contrast, control IgG, anti-contactin-1 IgG1, or even anti-contactin-associated-protein-2 IgG4 did not pass the paranodal barrier. To determine whether chronic exposure to these antibodies is pathogenic, we passively transferred anti-contactin-1 IgG1 and IgG4 into Lewis rats immunized with P2 peptide. IgG4 to contactin-1, but not IgG1, induced progressive clinical deteriorations combined with gait ataxia. No demyelination, axonal degeneration, or immune infiltration were observed. Instead, these animals presented a selective loss of the paranodal specialization in motor neurons characterized by the disappearance of the contactin-associated protein 1/contactin-1/neurofascin-155 complex at paranodes. Paranode destruction did not affect nodal specialization, but resulted in a moderate node lengthening. The sensory nerves and dorsal root ganglion were not affected in these animals. Electrophysiological examination further supported these results and revealed strong nerve activity loss affecting predominantly small diameter or slow conducting motor axons. These deficits partly matched with those found in patients: proximal motor involvement, gait ataxia, and a demyelinating neuropathy that showed early axonal features. The animal model thus seemed to replicate the early deteriorations in these patients and pointed out that paranodal loss in mature fibres results in conduction defects, but not conduction slowing. Our findings indicate that IgG4 directed against contactin-1 are pathogenic and are reliable biomarkers of a specific subset of chronic inflammatory demyelinating polyneuropathy patients. These antibodies appear to loosen the paranodal barrier, thereby favouring antibody progression and causing paranodal collapse.

PMID: 27017186 [PubMed - as supplied by publisher]

Does ability to walk reflect general functionality in inflammatory neuropathies?

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Does ability to walk reflect general functionality in inflammatory neuropathies?

J Peripher Nerv Syst. 2016 Mar 10;

Authors: Draak TH, Gorson KC, Vanhoutte EK, van Nes SI, van Doorn PA, Cornblath DR, van den Berg LH, Faber CG, Merkies IS, PeriNomS Study Group

Abstract
BACKGROUND: The "ability to walk" is considered a benchmark for good clinical recovery and prognosis, particularly in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, it has never been determined whether being "able to walk" represents general functionality.
OBJECTIVE: To examine whether the ability to walk outside independently reflects general functional improvement in patients with GBS, CIDP, and gammopathy-related neuropathy (MGUSP).
METHODS: A total of 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59), and MGUSP (23) were serially examined (1-year). Predefined arbitrary cut-offs (so-called patients' Functional-Acceptable-Clinical-Thresholds [FACTs]) were taken at the 50th, 75th, and 90th percentile of the Inflammatory-Rasch-built-Overall-Disability-Scale (I-RODS(©) ). We determined the proportion of patients able to walk outside independently that reached the postulated cut-offs.
RESULTS: A mean total of 85%, 39%, and 12% of all patients able to walk reached 50th, 75th, and 90th percentile thresholds, respectively. These findings were not neuropathy type related.
CONCLUSION: Our findings show that assessing only one construct of functionality (e.g. walking ability) does not reflect the full scope of daily/social functional deficits perceived by patients. The ability to walk shows a patient is doing better, but not necessarily doing well. The I-RODS(©) bypasses these limitations.

PMID: 26968437 [PubMed - as supplied by publisher]

[Retinal and brain infarctions secondary to acute carotid thrombosis in ovarian hyperstimulation syndrome].

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[Retinal and brain infarctions secondary to acute carotid thrombosis in ovarian hyperstimulation syndrome].

Neurologia. 2008 Jun;23(5):319-21

Authors: Querol L, Martínez-Corral M, Martí E, Martí-Fábregas J

Abstract
INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is an uncommon but potentially life-threatening iatrogenic condition that may appear following ovulation induction in the course of some fertility treatments. This may lead to further complications, some of which may be severe, such as thromboembolic events. Though rarely, it can therefore be a potential cause of stroke.
CLINICAL CASE: We report the case of a 34-year old woman under ovulation induction treatment who developed retinal and brain infarctions secondary to internal carotid occlusion. Oral anticoagulation was administered and recovery was good in spite of the persistence of carotid occlusion in follow-up magnetic ressonance imaging- angiographies.
CONCLUSIONS: This is the first case of carotid occlusion following an OHSS reported in Spain and the eighth one published in the literature. Current literature on cerebrovascular complications in OHSS is also briefly reviewed.

PMID: 18247184 [PubMed - indexed for MEDLINE]

PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis.

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PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis.

J Autoimmun. 2013 Jun;43:1-9

Authors: Larman HB, Laserson U, Querol L, Verhaeghen K, Solimini NL, Xu GJ, Klarenbeek PL, Church GM, Hafler DA, Plenge RM, Nigrovic PA, De Jager PL, Weets I, Martens GA, O'Connor KC, Elledge SJ

Abstract
Autoimmune disease results from a loss of tolerance to self-antigens in genetically susceptible individuals. Completely understanding this process requires that targeted antigens be identified, and so a number of techniques have been developed to determine immune receptor specificities. We previously reported the construction of a phage-displayed synthetic human peptidome and a proof-of-principle analysis of antibodies from three patients with neurological autoimmunity. Here we present data from a large-scale screen of 298 independent antibody repertoires, including those from 73 healthy sera, using phage immunoprecipitation sequencing. The resulting database of peptide-antibody interactions characterizes each individual's unique autoantibody fingerprint, and includes specificities found to occur frequently in the general population as well as those associated with disease. Screening type 1 diabetes (T1D) patients revealed a prematurely polyautoreactive phenotype compared with their matched controls. A collection of cerebrospinal fluids and sera from 63 multiple sclerosis patients uncovered novel, as well as previously reported antibody-peptide interactions. Finally, a screen of synovial fluids and sera from 64 rheumatoid arthritis patients revealed novel disease-associated antibody specificities that were independent of seropositivity status. This work demonstrates the utility of performing PhIP-Seq screens on large numbers of individuals and is another step toward defining the full complement of autoimmunoreactivities in health and disease.

PMID: 23497938 [PubMed - indexed for MEDLINE]

Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.

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Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.

Ann Neurol. 2013 Mar;73(3):370-80

Authors: Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez E, Diaz-Manera J, Suárez-Calvet X, Navas M, Araque J, Gallardo E, Illa I

Abstract
OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a frequent autoimmune neuropathy with a heterogeneous clinical spectrum. Clinical and experimental evidence suggests that autoantibodies may be involved in its pathogenesis, but the target antigens are unknown. Axoglial junction proteins have been proposed as candidate antigens. We examined the reactivity of CIDP patients' sera against neuronal antigens and used immunoprecipitation for antigen unraveling.
METHODS: Primary cultures of hippocampal neurons were used to select patients' sera that showed robust reactivity with the cell surface of neurons. The identity of the antigens was established by immunoprecipitation and mass spectrometry, and subsequently confirmed with cell-based assays, immunohistochemistry with teased rat sciatic nerve, and immunoabsorption experiments.
RESULTS: Four of 46 sera from patients with CIDP reacted strongly against hippocampal neurons (8.6%) and paranodal structures on peripheral nerve. Two patients' sera precipitated contactin-1 (CNTN1), and 1 precipitated both CNTN1 and contactin-associated protein 1 (CASPR1). Reactivity against CNTN1 was confirmed in 2 cases, whereas the third reacted only when CNTN1 and CASPR1 were cotransfected. No other CIDP patient or any of the 104 controls with other neurological diseases tested positive. All 3 patients shared common clinical features, including advanced age, predominantly motor involvement, aggressive symptom onset, early axonal involvement, and poor response to intravenous immunoglobulin.
INTERPRETATION: Antibodies against the CNTN1/CASPR1 complex occur in a subset of patients with CIDP who share common clinical features. The finding of this biomarker may help to explain the symptoms of these patients and the heterogeneous response to therapy in CIDP.

PMID: 23280477 [PubMed - indexed for MEDLINE]

Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.

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Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.

J Peripher Nerv Syst. 2012 Jun;17(2):158-68

Authors: Rojas-García R, Querol L, Gallardo E, De Luna Salva N, Juarez C, Garces M, Fages E, Casasnovas C, Illa I

Abstract
There is as yet no consensus for considering pure acute sensory ataxic neuropathy (ASAN) as a variant of Guillain-Barré syndrome (GBS). Reactivity against gangliosides sharing disialosyl epitopes has been reported in these patients. The aim of this study was to determine the spectrum of reactivity against gangliosides in ASAN and to define the clinical pattern. From our database we identified patients with suspicion of ASAN. We defined ASAN as the presence of ataxia of peripheral origin with loss of proprioception, and areflexia, absence of ophthalmoplegia and no or minimal muscle weakness. Patients who met these criteria were retrospectively reviewed for their spectrum of reactivity against gangliosides and clinical features. We identified 12 patients fulfilling pre-defined criteria for ASAN. Reactivity against gangliosides containing disialosyl epitopes was present in seven patients. Concomitant reactivity against other gangliosides was present in 6/7 patients. All patients presented good prognosis and an antecedent illness was present in nine. Our results support the previously described clinico-immunological association between ASAN and disialosyl specificity, and widen the spectrum of reactivity against gangliosides. The acute presentation with a monophasic course, and good prognosis in all cases, together with transient immunoglobulin G antiganglioside antibodies and infectious antecedent in 7/12 patients support the inclusion of ASAN as a GBS variant.

PMID: 22734901 [PubMed - indexed for MEDLINE]

Long-lasting treatment effect of rituximab in MuSK myasthenia.

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Long-lasting treatment effect of rituximab in MuSK myasthenia.

Neurology. 2012 Jan 17;78(3):189-93

Authors: Díaz-Manera J, Martínez-Hernández E, Querol L, Klooster R, Rojas-García R, Suárez-Calvet X, Muñoz-Blanco JL, Mazia C, Straasheijm KR, Gallardo E, Juárez C, Verschuuren JJ, Illa I

Abstract
OBJECTIVE: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients.
METHODS: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied.
RESULTS: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3.
CONCLUSION: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

PMID: 22218276 [PubMed - indexed for MEDLINE]

Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review.

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Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review.

Sex Transm Dis. 2010 Feb;37(2):123-5

Authors: Suarez-Calvet M, Rojas-Garcia R, Querol L, Sarmiento LM, Domingo P

Abstract
Peripheral nerve disorders are a common complication in HIV patients, reaching 15% of them. Several patterns and aetiologies have been described, being lumbosacral poliradiculoneuropathy one of them. We describe an HIV-1-infected patient who developed lumbosacral poliradiculoneuropathy caused by Human herpesvirus 2 and review the literature about this uncommon condition.

PMID: 19858783 [PubMed - indexed for MEDLINE]

Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation.

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Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation.

Biol Blood Marrow Transplant. 2009 Nov;15(11):1439-46

Authors: Barba P, Piñana JL, Valcárcel D, Querol L, Martino R, Sureda A, Briones J, Delgado J, Brunet S, Sierra J

Abstract
Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140 mg/m(2) (n=119), cyclophosphamide (Cy) 120 mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval [CI] 11-23). CNS complications included nonfocal encephalopathies in 11 patients, meningoencephalitis in 5 patients, and stroke or hemorrhage in 4. PNS complications consisted of 5 cases of mononeuropathies and 3 cases of polyneuropathies. Drug-related toxicity was responsible for 10 of the 31 events (32%) (8 caused by CsA). Interestingly, 14 of the 23 CNS events (61%) and only 1 of the 8 PNS complications (13%) appeared before day +100 (P=.01). Overall, patients presenting NC showed a trend for higher 1-year nonrelapse mortality (NRM) (37% versus 20%, P=.08). In patients with CNS involvement, 1-year NRM was significantly worse (42% versus 20%, P=.02). CNS NC also had a negative impact on 4-year overall survival (OS; 33% versus 45%, P=.05). In conclusion, our study showed that NC are observed after allo-RIC and have diverse features. NC affecting the CNS have earlier onset and worse outcome than those involving the PNS.

PMID: 19822304 [PubMed - indexed for MEDLINE]