Demyelinating polyradiculoneuropathy during dabrafenib and trametinib treatment for metastatic melanoma: A case report.

BACKGROUND: Melanoma is an aggressive malignancy, historically characterized with a poor prognosis and few treatment options. The advent of target therapy with BRAF and MEK inhibitors, as well as immunotherapy, changed this scenario and improved the prognosis of patients with BRAF V600E mutation. These therapies are generally well tolerated. Neurological toxicities, especially polyradiculopathy, are very rare with BRAF inhibitors and MEK inhibitors although some cases have been described in recent years, regardless of the type of target therapies combination used. CASE REPORT: We report the case of a patient with BRAF V600E-mutated metastatic melanoma treated with dabrafenib and trametinib who has developed a demyelinating polyradiculoneuropathy. CONCLUSION: This case, once more, should draw our attention to the possibility of rare, but potentially serious side effects, even in the case of generally well-tolerated treatments. Especially in the presence of side effects, it is important a close relationship between clinicians and patients for the management of adverse events and the choice of the best treatment strategy.

A diagnostic score for anti-myelin-associated-glycoprotein neuropathy or chronic inflammatory demyelinating polyradiculoneuropathy in patients with anti-myelin-associated-glycoprotein antibody.

BACKGROUND AND PURPOSE: A diagnostic score was developed to discriminate anti-myelin-associated-glycoprotein (MAG) neuropathy from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and applied it to patients with atypical anti-MAG neuropathy. METHODS: The clinical and electrophysiological features of patients with a diagnosis of typical anti-MAG neuropathy were compared to those of patients with a diagnosis of CIDP. The association of each feature with the diagnosis was assessed in the two groups. Features showing a significant association with the diagnosis were included in a multivariable logistic regression model and adjusted odds ratios were estimated for each feature. A score ranging from 1 to 3 was applied to each feature based on the magnitude of the estimated odds ratios. The score was then applied to patients with a clinical diagnosis of CIDP who also had high anti-MAG antibody titers (CIDP-MAG). RESULTS: Thirty-one anti-MAG neuropathy patients, 45 typical CIDP patients and 16 CIDP-MAG patients were included. Scores in anti-MAG antibody patients ranged from 1 to 5 and in CIDP patients from -7 to -1. Using the score, 4/16 CIDP-MAG patients were diagnosed to have anti-MAG neuropathy and 12/16 patients to have CIDP. Response to intravenous immunoglobulin in the CIDP-MAG patients classified as CIDP was similar to that of definite CIDP patients and higher than that of anti-MAG neuropathy patients. CONCLUSIONS: Our score allowed an accurate discrimination to be made, amongst patients with anti-MAG antibodies, of those affected by CIDP and the patients with anti-MAG neuropathy. This score may help proper treatment to be chosen for patients with anti-MAG antibodies with a CIDP-like presentation.

Peripheral neuropathies after BRAF and/or MEK inhibitor treatment: A pharmacovigilance study.

Reports suggested the potential occurrence of peripheral neuropathies (PN) in patients treated with BRAF (BRAFi) and/or MEK inhibitors (MEKi) for BRAF-activated tumours. We aimed to better characterize these PN. We queried the French pharmacovigilance database for all cases of PN attributed to BRAFi and/or MEKi. Fifteen patients were identified. Two main clinical PN phenotypes were seen. Six patients presented a length-dependent, axonal polyneuropathy: symptoms were mostly sensory and affecting the lower limbs; management and outcome were variable. Nine patients developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness and ataxia; cranial nerves were involved in four cases; most patients received intravenous immunoglobulins or glucocorticoids, with variable outcome; one patient was rechallenged with a different BRAFi/MEKi combination with a rapid relapse in symptoms. In conclusion, patients under BRAFi/MEKi therapy may develop treatment-induced PN. Two main phenotypes can occur: a symmetric, axonal, length-dependent polyneuropathy and a demyelinating polyradiculoneuropathy.

[Therapeutic plasmapheresis procedures: An alternative to the disruption of the supply of polyvalent immunoglobulin in autoimmune pathologies. Medico-economic study]. / Les techniques de plasmaphérèse thérapeutique : une alternative à la rupture d'approvisionnement en immunoglobuline polyvalente dans les pathologies auto-immunes. Étude médico-économique.

INTRODUCTION: The supply of human polyvalent immunoglobulin has been under severe pressure for several years. This has led to a prioritisation of indications and a record increase in the amount of reimbursement without solving the problem of demand. Treatment by therapeutic plasmapheresis appears to be an alternative to be considered for the treatment of certain dysimmune diseseases. To discuss this alternative, we are conducting a medico-economic study comparing the polyvalent immunoglobulin strategy versus different therapeutic plasmapheresis system in the treatment of a chronic dysimmune disease. POPULATION AND METHOD: The medico-economic study was conducted using the example of a 75 kg patient with chronic polyradiculoneuritis dependent on chronic therapy with a comparison of sequential treatment with one session of therapeutic plasmapheresis versus a course of intravenous polyvalent immunoglobulin. The medico-economic study includes an evaluation from a public health care system perspective complemented by a hospital-based approach that justifies estimating the cost of different therapeutic plasmapheresis systems based on a bottom-up micro-costing approach. RESULTS: From the point of view of the care system, for information, a 20 g bottle of polyvalent immunoglobulin has a similar cost to a therapeutic plasmapheresis session. In our example, the cost of a maintenance treatment repeated every 2 to 4 weeks in chronic polyradiculoneuritis in a 75 kg patient is 1284.13 euros for a therapeutic plasmapheresis session versus 7331.60 to 9426.84 euros for a 1.5 to 2 mg/kg polyvalent immunoglobulin treatment. Furthermore, from the point of view of the hospital system, the cost of the different TT techniques evaluated varies moderately with the cost depending mainly on the quantity of albumin infused or the medical device used. CONCLUSION: In the chronic sequential treatment of chronic polyradiculoneuritis, the cost of therapeutic plasmapheresis could be lower than with polyvalent immunoglobulin from a healthcare system perspective. The cost to the health care facility between different therapeutic plasmapheresis techniques differs little. This study provides arguments suggesting that if therapeutic plasmapheresis can be implemented with a dedicated technical platform, it is a serious alternative to be considered without additional costs.

[Herpes zoster duplex associated with Ramsay Hunt syndrome and cervical zoster paresis. A case report].

A 63-year-old Japanese female in an immunocompetent state developed right Ramsay Hunt syndrome and left shoulder pain, and left upper limb motor paresis with herpes zoster (HZ) duplex in the right auricle and left shoulder regions. With her Ramsay Hunt syndrome, neural deafness, tinnitus and vestibular symptoms were observed, and she lacked facial nerve palsy. Cerebrospinal fluid (CSF) findings revealed an increase in lymphocytes (21 cells/µl) and protein content (29 mg/dl), and polymerase chain reaction for varicella-zoster virus DNA in CSF was negative. Cervical root MRI using 3D Nerve VIEW (Philips) imaging showed high-intensity lesions on the C5-C8 spinal roots with contrast enhancements. No abnormalities were observed in the median or ulnar motor sensory nerve conduction velocity conduction studies including the F wave. PubMed search revealed no report of a patient with this profile, and to the best of our knowledge HZ duplex with concomitant neurological impairments has not been reported. We compare our present case with several similar cases from the literature.

Childhood-onset multifocal motor neuropathy with IgM antibodies to GM2 and GalNac-GD1a.

BACKGROUND: Multifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20-70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies. CASE REPORT: A 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment. CONCLUSION: Although childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN.

Prognostic factor of poor outcome in anti-MAG neuropathy: clinical and electrophysiological analysis of a French Cohort.

BACKGROUND: Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases. METHOD: We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used. RESULTS: Forty-seven patients were included in the study; of these, 61% had a classical 'distal demyelinating pattern', 34.2% had a 'CIDP-like pattern', and the others had an 'axonal pattern'. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination. CONCLUSION: Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a 'red flag' for the prompt initiation of rituximab to try to delay long-term disability.

Routine blood monitoring in maintenance immunoglobulin treatment of inflammatory neuropathy: Is it clinically relevant?

BACKGROUND: Pre-treatment screening for IgA deficiency and close monitoring of full blood count(FBC) and renal function is recommended with intravenous immunoglobulin(IVIg) therapy in neurological diseases. AIMS: To examine the frequency of biochemically defined and clinically significant episodes of treatment associated haemolysis, neutropenia, thrombocytopenia and acute kidney injury(AKI) in a cohort of patients on maintenance Immunoglobulin(Ig) therapy for inflammatory neuropathy. METHODS: A retrospective review of routine blood monitoring in patients from two UK specialist peripheral nerve centres. Accepted definitions for clinically and biochemically significant haemolysis, neutropenia, thrombocytopenia and AKI were used. RESULTS: 1919 infusion episodes in 90 patients were analysed. Age(mean(S.D)) = 58.09(14.4)years, 63% male, 72% CIDP(28% MMN), 97% IVIg(3% SCIg). Dose = 1.57(0.79)g/kg/month or 97.1(37.3)g/infusion, frequency:3.9(1.4) weeks. Relative IgA deficiency was noted in 2 individuals (prevalence:2.2%, 95%C.I.:0-5.2) who received a combined total of 38 infusions(3800 g IVIg) without adverse event. No clinically significant episodes of haemolysis, neutropenia, thrombocytopenia or AKI occurred in relation to treatment. An asymptomatic drop>10 g/L haemoglobin(Hb) occurred in 3.5%(95%CI:2.7-4.3) of treatment episodes in 38 individuals, mean reduction:17.7(7.4)g/L; lowest Hb:86 g/L. Lower pre-treatment haemoglobin correlated with risk of recurrent Ig-related drop(p:0.007). Two patients with chronic renal failure(stage 1 and 3) received 28(IV) and 104(SC) infusions respectively(6416 g) without impact on estimated glomerular filtration rate(eGFR). CONCLUSIONS: No clinically significant Ig-related episodes of haemolysis or AKI were identified in this representative cohort. This suggests that routine monitoring is not essential in long-term Ig use but should be considered when clinically indicated.

[Varicella-zoster virus-associated polyradiculoneuritis with concomitant herpes zoster eruption: a case report].

A 76-year-old Japanese female who was treated with long-term use of prednisolone at 10 mg/day for interstitial pneumonia developed acute right-dominant lower limb paralysis and then upper limb paralysis with herpes zoster eruptions on the right C7-Th1 dermatomes. On admission, right predominant quadriplegia was observed with sensory symptoms; Hughes functional grade was level 4; the hand grip power was right, 0, and left, 7 kg, the deep tendon reflexes were abolished throughout without pathologic reflexes. Twenty days after the onset of the symptoms, the cerebrospinal fluid (CSF) revealed mild increases of lymphocytes (13 cells/µl) and protein content (73 mg/dl). Varicella-zoster virus (VZV) PCR was negative in the CSF, but an enzyme immunoassay for VZV was positive in her serum and CSF, and the high titers were prolonged. Peripheral nerve conduction and F wave studies suggested right-dominant demyelinating polyradiculoneuropathy. A T1-weighted MR contrast image exhibited right-dominant high-intensity lesions on the C7-Th1 spinal roots and similar lesions on the L4-5 spinal roots. We compared with several similar cases from the literature and proposed that VZV itself involves the pathogenesis of the polyradiculoneuritis in immunocompromised hosts.

Human immune globulin 10% with recombinant human hyaluronidase in multifocal motor neuropathy.

OBJECTIVE: The primary aim was to determine the safety of treatment with human immune globulin 10% with recombinant human hyaluronidase (fSCIg) compared to intravenous immunoglobulin (IVIg) in a prospective open-label study in patients with multifocal motor neuropathy (MMN). METHODS: Our study consisted of two phases: the IVIg phase (visits 1-3; 12 weeks), in which patients remained on IVIg treatment, and the fSCIg phase (visits 4-7; 36 weeks), in which patients received fSCIg treatment. After visit 3, IVIg was switched to an equivalent dose and frequency of fSCIg. Outcome measures were safety, muscle strength, disability and treatment satisfaction. RESULTS: Eighteen patients were enrolled in this study. Switching to fSCIg reduced the number of systemic adverse events (IVIg 11.6 vs. fSCIg 5.0 adverse events/per person-year, p < 0.02), and increased the number of local reactions at the injection site (IVIg 0 vs. fSCIg 3.3 local reactions/per person-year, p < 0.01). Overall, no significant differences in muscle strength and disability between fSCIg and IVIg were found. Treatment with fSCIg was perceived as optimal treatment option by 8 of the 17 patients (47.1%) and they continued with fSCIg after study closure because of improved independence and flexibility to administer treatment. CONCLUSION: Treatment with fSCIg can be considered a safe alternative for patients with MMN on IVIg treatment. fSCIg could be a favorable option in patients who prefer self-treatment and more independency, and in patients who experience systemic adverse events on IVIg or have difficult intravenous access.

Anti-Neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo.

Neurofascin-155 (Nfasc155) is an essential glial cell adhesion molecule expressed in paranodal septate-like junctions of peripheral and central myelinated axons. The genetic deletion of Nfasc155 results in the loss of septate-like junctions and in conduction slowing. In humans, IgG4 antibodies against Nfasc155 are implicated in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies are associated with an aggressive onset, a refractoriness to intravenous immunoglobulin, and tremor of possible cerebellar origin. Here, we examined the pathogenic effects of patient-derived anti-Nfasc155 IgG4. These antibodies did not inhibit the ability of Nfasc155 to complex with its axonal partners contactin-1/CASPR1 or induce target internalization. Passive transfer experiments revealed that IgG4 antibodies target Nfasc155 on Schwann cell surface, and diminished Nfasc155 protein levels and prevented paranodal complex formation in neonatal animals. In adult animals, chronic intrathecal infusions of antibodies also induced the loss of Nfasc155 and of paranodal specialization and resulted in conduction alterations in motor nerves. These results indicate that anti-Nfasc155 IgG4 perturb conduction in absence of demyelination, validating the existence of paranodopathy. These results also shed light on the mechanisms regulating protein insertion at paranodes.

Erythropoietin reduces nerve demyelination, neuropathic pain behavior and microglial MAPKs activation through erythropoietin receptors on Schwann cells in a rat model of peripheral neuropathy.

Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)-induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests were conducted. Immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of microglial and mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, activation. Enzyme-linked immunosorbent assay and microdialysis were applied to measure pro-inflammatory cytokine and glutamate responses, respectively. EPO pre-treatment dose-dependently ameliorated neuropathic pain behavior, decreased microglial and MAPKs activation, and diminished the release of pro-inflammatory cytokines and glutamate in the ipsilateral cuneate nucleus after CCI. Moreover, EPO pre-treatment preserved myelination of the injured median nerve on morphological investigation and suppressed injury-induced discharges. We also observed that EPO receptor (EPOR) expression was up-regulated in the injured nerve after CCI. Double immunofluorescence showed that EPOR was localized to Schwann cells. Furthermore, siRNA-mediated knockdown of EPOR expression eliminated the therapeutic effects of EPO on attenuating the microglial and MAPKs activation, pro-inflammatory cytokine responses, injury discharges, and neuropathic pain behavior in CCI rats. In conclusion, binding of EPO to its receptors on Schwann cells maintains myelin integrity and blocks ectopic discharges in the injured median nerve, that in the end contribute to attenuation of neuropathic pain via reducing glutamate release from primary afferents and inhibiting activation of microglial MAPKs and production of pro-inflammatory cytokines.

How We Treat Autoimmune Small Fiber Polyneuropathy with Immunoglobulin Therapy.

Intravenous immunoglobulin therapy is FDA approved for the immune-mediated peripheral nerve disorders Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. Immunoglobulin therapy has been used increasingly with significant efficacy in the treatment of patients with disabling autoimmune forms of dysautonomia, which are most often small fiber (autonomic and/or sensory) polyneuropathies. It is recognized by most who treat these disorders, however, that patients with autonomic dysfunction treated with intravenous immunoglobulin therapy develop aseptic meningitis or severe lingering headache more frequently than other patient populations when this therapy is dosed in the traditional fashion. We discuss our combined 27 years of experience with the use of immunoglobulin and other immune modulatory therapy in patients with autoimmune small fiber polyneuropathy.

Transfusion-acquired hepatitis E infection misdiagnosed as severe critical illness polyneuromyopathy in a heart transplant patient.

This is the case of a 56-year-old man who underwent heart transplantation. Within the first postoperative days, his respiratory and limb muscles weakened, which was attributed to critical illness polyneuromyopathy (CIPM). At day 70 post transplantation, he had increased liver enzyme levels and acute hepatitis E virus (HEV) infection was diagnosed. HEV RNA was found in the serum, stools, and cerebrospinal fluid. Results of further investigations suggested a possible HEV-related polyradiculoneuropathy. At transplantation, the patient was negative for immunoglobulin (Ig)G, IgM, and HEV RNA. A trace-back procedure identified the source of infection and concluded that HEV infection was contracted from blood transfusion 12 days prior to transplantation from an HEV RNA-positive donor. Tests of the organ donor for HEV were negative. Phylogenetic analysis revealed sequence homology between the HEV-3 strain of the patient and the HEV-3 strain of the blood donor. Despite ribavirin treatment, the patient died on day 153 post transplantation from multiorgan failure. In conclusion, patients with hepatitis or neuropathic illness who have received blood products should be screened for HEV.

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.

Anti-MAG (myelin-associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal IgM autoantibodies that recognize the carbohydrate epitope HNK-1 (human natural killer-1). This glycoepitope is highly expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers. Because the pathogenicity and demyelinating properties of anti-MAG autoantibodies are well established, current treatments are aimed at reducing autoantibody levels. However, current therapies are primarily immunosuppressive and lack selectivity and efficacy. We therefore hypothesized that a significant improvement in the disease condition could be achieved by selectively neutralizing the pathogenic anti-MAG antibodies with carbohydrate-based ligands mimicking the natural HNK-1 glycoepitope 1. In an inhibition assay, a mimetic (2, mimHNK-1) of the natural HNK-1 epitope blocked the interaction of MAG with pathogenic IgM antibodies from patient sera but with only micromolar affinity. Therefore, considering the multivalent nature of the MAG-IgM interaction, polylysine polymers of different sizes were substituted with mimetic 2. With the most promising polylysine glycopolymer PL84(mimHNK-1)45 the inhibitory effect on patient sera could be improved by a factor of up to 230,000 per epitope, consequently leading to a low-nanomolar inhibitory potency. Because clinical studies indicate a correlation between the reduction of anti-MAG IgM levels and clinical improvement, an immunological surrogate mouse model for anti-MAG neuropathy producing high levels of anti-MAG IgM was developed. The observed efficient removal of these antibodies with the glycopolymer PL84(mimHNK-1)45 represents an important step toward an antigen-specific therapy for anti-MAG neuropathy.

Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation.

OBJECTIVE: The objective of this work was to report on the outcome of eculizumab treatment in pediatric patients with recurrent acute predominantly motor, demyelinating neuropathy with conduction block, and chronic hemolysis attributed to p.Cys89Tyr mutation in the CD59 gene. METHODS: Four patients were recruited from our new registry of patients with homozygosity for the p.Cys89Tyr mutation on CD59. Participants received repeated intravenous eculizumab. In this 24-month open-label phase IIa study, we aimed to determine whether eculizumab reduces chronic hemolysis, and cumulative doses of steroids and intravenous immunoglobulin (IVIG), and ameliorates neurological deficits, compared to pretreatment status. Treatment response was evaluated every 2 to 4 weeks over 104 weeks and included examination with gross motor scoring by American Spinal Injury Association Impairment Scale and Inflammatory Neuropathy Cause and Treatment disability score, laboratory examination, well-being [12-item Short Form Health Survey; SF-12]). Neurological relapses and cumulative dose of IVIGs and/or corticosteroids before and after treatment were documented. Red blood cells (RBCs) and neutrophils were stained to evaluate C5b-9 deposition. ClinicalTrials.gov: NCT01579838. RESULTS: Dramatic and significant neurological amelioration in the upper limbs and trunk with more-modest amelioration in the lower limbs was observed in all patients. Corticosteroid and IVIG treatment was completely stopped. No patient relapsed during treatment despite infections, and there were no hospital admissions. Decreased C3bi and C5b-9 deposition on RBCs and neutrophils was documented (p < 0.0001). The SF-12 health questionnaires indicated significant improvement (p < 0.003). INTERPRETATION: Eculizumab was safely administered to these patients. Marked clinical improvement suggests that eculizumab may be a life-saving treatment for patients with acute predominantly motor, demyelinating neuropathy with conduction block, and secondary axonal damage attributed to primary p.Cys89Tyr mutation in the CD59 gene. Ann Neurol 2016;80:708-717.

Analgesia epidural continua para trabajo de parto en una paciente con polineuropatía desmielinizante periférica / Continuous epidural analgesia for labour and delivery in a patient with demyelinating peripheral polyneuropathy

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