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.

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.

Acute-onset polyradiculoneuropathy after SARS-CoV2 vaccine in the West and North Midlands, United Kingdom.

INTRODUCTION/AIMS: We aimed to determine whether specific severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccines may be associated with acute-onset polyradiculoneuropathy and if they may result in particular clinical presentations. METHODS: We retrospectively reviewed records of all persons presenting with acute-onset polyradiculoneuropathy from January 1, 2021, to June 30, 2021, admitted to two Neuroscience centers, of the West and North Midlands, United Kingdom. We compared subjects with previous SARS-CoV2 vaccine exposure with a local cohort of persons with acute-onset polyradiculoneuropathy admitted between 2005 and 2019 and compared admission numbers for the studied time frame with that of the previous 3 years. RESULTS: Of 24 persons with acute-onset polyradiculoneuropathy, 16 (66.7%) presented within 4 weeks after first SARS-CoV2 vaccine. Fourteen had received the AstraZeneca vaccine and one each, the Pfizer and Moderna vaccines. The final diagnosis was Guillain-Barré syndrome (GBS) in 12 and acute-onset chronic inflammatory demyelinating polyneuropathy in 4. Among AstraZeneca vaccine recipients, facial weakness in nine persons (64.3%), bulbar weakness in seven (50%), and the bifacial weakness and distal paresthesias GBS variant in three (21.4%), were more common than in historical controls (P = .01; P = .004, and P = .002, respectively). A 2.6-fold (95% confidence interval: 1.98-3.51) increase in admissions for acute-onset polyradiculoneuropathy was noted during the studied time frame, compared to the same period in the previous 3 years. DISCUSSION: Despite a low risk, smaller than that of SARS-CoV2 infection and its complications, exposure to the first dose of AstraZeneca SARS-CoV2 vaccine may be a risk factor for acute-onset polyradiculoneuropathy, characterized by more common cranial nerve involvement.

[A case of meningoencephalitis and polyradiculoneuropathy induced by combination therapy with ipilimumab and nivolumab].

A 76-year-old man with renal cell carcinoma exhibited consciousness disturbance and high fever after two cycles of combination therapy with ipilimumab and nivolumab. His cerebrospinal fluid (CSF) showed a protein concentration of 385 mg/dl, a cell count of 147/mm3, an interleukin-6 concentration of 1,280 pg/ml, and an adenosine deaminase concentration of 24.8 U/l. Contrast-enhanced FLAIR images were notable for diffuse meningeal enhancement. He was diagnosed with meningoencephalitis caused by an immune-related adverse event from immune checkpoint inhibitors (ICIs). His symptoms improved after repeated intravenous methylprednisolone pulse therapy and oral prednisolone. The meningeal enhancement disappeared, and the CSF findings became almost normal. As consciousness levels improved, we observed quadriplegia and peripheral neuropathy with antiganglioside antibodies, which led to a diagnosis of polyradiculoneuropathy. This is a rare case of a patient with overlapping meningoencephalitis and polyradiculo-neuropathy induced by ICIs.

Polyradiculoneuropathy induced by immune checkpoint inhibitors: a case series and review of the literature.

OBJECTIVE: The purpose of the present study is to report the clinical characteristics of polyradiculoneuropathy induced by immune checkpoint inhibitors (ICIs). METHODS: We retrospectively reviewed lists of all inpatients with neurological immune-related adverse events (irAEs) treated at the neurology departments of three hospitals in January 2017 and December 2019. We also performed a review of the previous case reports with polyradiculoneuropathy induced by ICI therapy. RESULTS: We had 4 patients with polyradiculoneuropathy following ICI therapy. We comprehensively reviewed our 4 patients and 32 previous case reports. There were 28 men and 8 women with a mean onset age of 61 years. ICI monotherapy was performed in 27 patients, whereas the combination of ICIs was administered in 9 patients. All patients except 2 showed limb weakness, which was observed symmetrically and predominantly in the legs rather than the arms. Bulbar involvement was observed in 7 patients. The laboratory findings were demyelination in electrophysiological studies and elevated protein with lymphocytes in the cerebrospinal fluid. Disease severity was ranked on the Hughes functional scale; 17 patients were grade 4 or greater. The treatment responses to corticosteroid and intravenous methylprednisolone were favorable. Intravenous immunoglobulin was also used in combination with steroids. Seven patients died, including 4 who on mechanical ventilation. CONCLUSION: Polyradiculoneuropathy induced by ICIs has a distinct subset of neurological irAEs and requires early recognition.

Oxaliplatin induces hypomyelination and reduced neuregulin 1 expression in the rat sciatic nerve.

Oxaliplatin causes severe peripheral neuropathy. In this study, we examined hypomyelination in the peripheral nerve in oxaliplatin-induced neuropathy rat model. Gene expression of neuregulin 1 (NRG1), a myelination regulatory factor, is reduced in the dorsal root ganglion (DRG) in DNA microarray analysis. Oxaliplatin increased the g-ratio and reduced levels of myelin protein zero in sciatic nerve, suggesting the hypomyelination. Moreover, oxaliplatin reduced NRG1 mRNA levels in the DRG and decreased levels of cleaved NRG1 type III protein in the sciatic nerve. Our results indicate that oxaliplatin induces hypomyelination and reduced NRG1 expression.

Skin-derived precursor Schwann cell myelination capacity in focal tibial demyelination.

INTRODUCTION: Skin-derived precursor cells (SKPs) are neural crest progenitor cells that can attain a Schwann cell-like phenotype through in vitro techniques (SKP-SCs). We hypothesized that SKP-SCs could produce mature myelin and, in doing so, facilitate the recovery of a focal demyelination injury. METHODS: We unilaterally injected DiI-labeled, green fluorescent protein (GFP)-producing SKP-SCs into the tibial nerves of 10 adult Lewis rats (with contralateral media control), 9 days after bilateral doxorubicin injury (0.38 µg). Tibial compound motor action potentials (CMAPs) were followed for 57 days. A separate morphometric cohort also included a Schwann cell injection group. RESULTS: SKP-injected nerves recovered fastest in terms of electrophysiology and morphometry. SKP-SCs formed morphologically mature myelin, accounting for 15.3 ± 5.3% of the total myelin in SKP-SC-injected nerves. CONCLUSIONS: SKP-SCs are robustly capable of myelination. They improve the recovery of a focal tibial nerve demyelination model by myelinating a measured percentage of axons.

Multifocal radiculoneuropathy during ipilimumab treatment of melanoma.

INTRODUCTION: Ipilimumab, a monoclonal anti-CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. METHODS: In this investigation we undertook a retrospective review of patient records. RESULTS: After 3 doses of ipilimumab, a 31-year-old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749 mg/dl. Nerve pathology showed inflammation around the endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. CONCLUSIONS: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood-nerve barrier due to a microvasculopathy.

Distal acquired demyelinating symmetric neuropathy after vaccination.

Neuropathy after vaccination is a rare event. Chronic immune-mediated polyneuropathy developing in the postvaccination period is distinctly unusual and not well described. Almost all such patients have been reported as having typical chronic inflammatory demyelinating polyneuropathy. Distal acquired demyelinating symmetric neuropathy, unlike classic chronic inflammatory demyelinating polyneuropathy, is characterized by distally predominant sensory symptoms with no or mild distal weakness. We describe the clinical, laboratory, and neurophysiological findings of 2 patients who developed distal acquired demyelinating symmetric neuropathy after vaccination. Immunomodulatory therapy led to clinical improvement in both cases. The literature is reviewed with attention to the clinical features of chronic immune-mediated neuropathies that follow vaccination.

Drug-induced dysimmune demyelinating neuropathies.

Drug-induced peripheral neurotoxicity usually manifests as a length-dependent, "dying back" axonal, predominantly sensory polyneuropathy. Rarely, immune-mediated demyelinating neuropathies occur during initial or maintenance treatment with immunomodulatory, immunosuppressive or antineoplastic agents. Medication-induced immune perturbation presumably triggers a dysimmune attack directed at unidentified peripheral nerve myelin epitopes; true peripheral nerve toxicity (i.e., dependent on accumulative dose or serum level) plays no identified role. The mechanisms that underlie a paradoxical and unpredictable immune exacerbation are unclear, and may depend on patient age, drug dosage and schedule, time of treatment relative to disease course, and host genetic factors. Suspicion and recognition of a non-toxic, immune-mediated demyelinating process has management (targeted immunotherapy) and prognostic (mostly favorable) implications.

Polyethylene glycol interferon alpha-2b-induced immune-mediated polyradiculoneuropathy.

Polyethylene glycol-interferon alpha (PEG-IFNalpha) has been used as the standard treatment for hepatitis C virus (HCV) infection. There have been no previous reports of polyradiculoneuropathy with anti-ganglioside antibodies induced by PEG-IFNalpha-2b. We report a 59-year-old man who developed polyradiculoneuropathy during treatment with PEG-IFN alpha-2b for chronic HCV infection. Serum levels of anti-asialo-GM1 (GA1) and anti-GM1 antibodies were elevated. Cessation of therapy with double filtration plasmapheresis resulted in marked improvement in his symptoms accompanied by a reduction in the antibody level. PEG-IFN alpha-2b may induce peripheral neuropathy mediated by anti-GA1 and anti-GM1 antibodies.

A case of spontaneously recovering multifocal motor neuropathy with conduction blocks (MMNCB) during anti-TNF alpha therapy for ankylosing spondylitis.

We report the case of a 54-year-old patient affected by ankylosing spondylitis who developed multifocal motor neuropathy with conduction blocks after 8 months of infliximab treatment. TNF alpha antagonist therapy has been associated with the development of both central nervous system and peripheral nervous system disorders, mainly of the demyelinating type. To our knowledge, this seems to be the second reported case of infliximab-related typical multifocal motor neuropathy with conduction blocks in which no other underlying causes of neuropathy were present. It is also the first in which typical multifocal motor neuropathy with conduction blocks spontaneously recovered without Ig.ev treatment and did not reappear over a long follow-up period. In our opinion, this strengthens the hypothesis of an actual adverse effect of infliximab in this patient. Finally, our case is the first one occurring in a patient with ankylosing spondylitis.

[Acute polyneuritis and polyradiculoneuritis: uncommon causes and their pathomechanisms]. / Akute Polyneuritiden und Polyradikuloneuritiden: Ungewöhnliche Ursachen und deren Pathomechanismen.

Although the total incidence rate of acute inflammatory polyneuropathies is low, it is the most frequent cause of acute progressive, generalized paresis in developed countries (> 50 %). The most common form of the disease is the Guillain-Barré syndrome (GBS). Even though the clinical and pathologic spectrum of GBS has substantially grown over the last decade, about 15 % of cases of acute polyneuritis or polyradiculoneuritis do not fulfil the revised and extended diagnostic criteria and classification for GBS and its variants. The underlying pathogenesis still remains unclear. It is assumed that these "untypical" acute inflammatory polyneuropathies and cases fulfilling the GBS criteria are variants of the same underlying immune disorder, but that pathogenetic mechanisms produce different acute neurological syndromes. Thus, immunotherapy (which is not GBS-specific) is also effective for treating acute inflammatory polyneuropathies that do not fulfil the diagnostic criteria for GBS, and early diagnosis and treatment of these cases is essential. Since no reliable serological and electrodiagnostic markers of autoimmune neuropathies are currently available, the diagnosis is based on its clinical presentation. However, clinical symptoms are variable, and a rational diagnostic decision can be challenging. Thus, it is important to know that acute inflammatory polyneuropathies not fulfilling the diagnostic criteria of GBS are less often preceded by an infective condition but frequently associated with uncommon causes and triggers. This report presents our experiences with uncommon variants of inflammatory polyneuropathies and polyradiculoneuritides that do not fulfil the international diagnostic criteria for GBS. We provide a detailed review of the pertinent literature discussing possible pathomechanisms, its clinical associations and possible dispositions.

Nodular amiodarone lung disease.

The antiarrhythmic drug amiodarone accumulates in many organs of the body. Amiodarone lung disease (ALD) most commonly manifests clinically as an interstitial pneumonitis. The few reports of nodular ALD generally have been in the clinical and radiographic literature. No detailed histopathologic analysis of nodular ALD is available. We report 4 patients with nodular ALD, all of whom had excision of a nodule and none had a preoperative diagnosis of ALD. The radiographic suspicion before excisional biopsy in all 4 cases was malignancy. The initial pathologic suspicion in all 4 cases was either an abscess or vasculitis. In 3 of the 4 cases, where the dosages were known, each patient received 800 mg/d for 7 or more months. All cases have strikingly similar histopathology, with vacuolated histiocytes massed within alveoli to form macroscopic nodules with tissue breakdown. Ultrastructural examination of lung and peripheral nerve in 1 case showed the characteristic inclusions of amiodarone in the cytoplasm of swollen histiocytes. Vacuolated histiocytes filled with these inclusions indicate the effect of the drug, but in these 4 cases there was tissue destruction, which indicated disease. The necrotizing nature of the massed histiocytes in the absence of infection or obstruction suggests the correct etiologic diagnosis even when the history of administration of the drug is not available at initial review.