Objectives
To evaluate, in a prospective study, high-resolution ultrasound (HRUS) changes of nerve segments in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and their relationships ...with clinical and electrodiagnostic (EDX) characteristics.
Methods
Twenty-three consecutive patients with CIDP were included in a 3-year follow-up (FU) study. Each patient underwent neurologic examination, EDX and HRUS study. HRUS was performed on median, ulnar and peroneal nerves, yielding a total of 319 scanned nerve segments. INCAT and MRC-sum scores, motor nerve conduction velocity (NCV), compound muscle action potential (cMAP) amplitude, and nerve cross-sectional area (NCSA) were collected at baseline and at FU end, and were used for statistical analysis. Twenty-two healthy individuals, matched to patients for age and BMI, served as controls.
Results
NCSA was higher in patients than in controls (
p
< 0.0001) and showed significant direct correlation with disease severity, and inverse correlation with NCV and cMAP amplitude, both at baseline and at FU end. Disease duration, clinical scores and EDX were predictors of NCSA enlargement at both time points. During FU, NCSA increased in 51% of nerve segments (
p
= 0.006), in correlation with INCAT increase and with NCV and cMAP reduction. Considering EDX changes in subgroups that reflect the different types of nerve damage, NCSA significantly increased in those nerve segments that from normal EDX switched to prevalent myelinopathic EDX characteristics.
Conclusions
Peripheral nerve size tends to increase over time in patients with CIDP, in correlation with clinical and EDX changes, in particular in those nerve segments that undergo a predominantly demyelinating damage.
Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if ...the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported.
We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10–14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24–73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31–237 months). IM was suspected by CK elevation in all patients (ranging 800–3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.
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•Inflammatory myopathy occurs in less than 3% of myasthenic patients.•All myasthenia-myositis patients have AChR antibodies and most of them has thymoma.•Three main clinical groups of muscle involvement: distal, proximal and subclinical.•Distal and subclinical involvement could be underestimated.•Distal myositis has poor clinical outcome and could require early aggressive therapy.
Introduction
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi’s sarcoma ...(KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
Case reports
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
Conclusions
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Aim
Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively ...analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease.
Methods
IENFD and QST data of 14 ATTRv-PN patients and 14 asymptomatic carriers were retrospectively analyzed together with clinical and paraclinical data such as disease stage and severity, neuropathic pain scales, and sural SNAP amplitude.
Results
Given an estimated time to the predicted age of onset of symptomatic disease of 20.27 + / − 7.9 years, small nerve fiber loss seems to be unexpectedly early in carriers. Moreover, carriers showed skin denervation at the proximal (thigh) site, suggesting a non-length-dependent neuropathic process. IENFD at ankle correlated with disease severity and other paraclinical variables such as sural nerve potential amplitude and QST parameters. Patients at earlier stages of the disease did not show significant differences in ankle IENFD compared with asymptomatic carriers, but significant differences in terms of QST parameters, small fiber neuropathy symptoms, and neuropathic pain.
Conclusions
Skin biopsy can disclose an early non-length-dependent small fiber loss in ATTRv-PN and, together with QST, could provide a useful insight disease onset and progression.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare form of treatable severe progressive sensory-motor and autonomic polyneuropathy. Albeit usually axonal, late-onset ...ATTRv-PN can show clear demyelinating features at electrodiagnostic studies, sometimes fulfilling CIDP diagnostic criteria. High-resolution nerve ultrasonography (HRUS) is an emerging useful supportive tool in the diagnosis of CIDP. Herein, we present a late-onset ATTRv-PN patient in which both clinical-neurophysiological and HRUS features could have led to a CIDP misdiagnosis. Nerve alterations at HRUS and MRI have already been reported in ATTRv-PN, albeit not in ATTRv-PN patients with clinical and electrodiagnostic features of CIDP. Our case shows that ATTRv-PN could present the same morphological nerve alterations pattern of CIDP at ultrasonography, adding HRUS findings as a further source of misdiagnosis late-onset ATTRv-PN.
Generalized myasthenia gravis (gMG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Approximately 80-90% of patients display antibodies directed against the nicotinic ...acetylcholine receptor (AChR). A major drive of AChR antibody-positive MG pathology is represented by complement activation. The role of the complement cascade has been largely demonstrated in patients and in MG animal models. Complement activation at the NMJ leads to focal lysis of the post-synaptic membrane, disruption of the characteristic folds, and reduction of AChR. Given that the complement system works as an activation cascade, there are many potential targets that can be considered for therapeutic intervention. Preclinical studies have confirmed the efficacy of complement inhibition in ameliorating MG symptoms. Eculizumab, an antibody directed towards C5, has recently been approved for the treatment of AChR antibody-positive gMG. Other complement inhibitors, targeting C5 as well, are currently under phase III study. Complement inhibitors, however, may present prohibitive costs. Therefore, the identification of a subset of patients more or less prone to respond to such therapies would be beneficial. For such purpose, there is a critical need to identify possible biomarkers predictive of therapeutic response, a field not yet sufficiently explored in MG. This review aims to give an overview of the complement cascade involvement in MG, the evolution of complement-inhibiting therapies and possible biomarkers useful to tailor and monitor complement-directed therapies.
Summary
Myasthenia gravis (MG) is a neurological autoimmune disorder characterized by muscle weakness and fatigue. It is a B cell–mediated disease caused by pathogenic antibodies directed against ...various components of the neuromuscular junction (NMJ). Despite the wide range of adverse effects, current treatment is still based on non-specific immunosuppression, particularly on long-term steroid usage. The increasing knowledge regarding the pathogenic mechanisms of MG has however allowed to create more target-specific therapies. A very attractive therapeutic approach is currently offered by monoclonal antibodies (mAbs), given their ability to specifically and effectively target different immunopathological pathways, such as the complement cascade, B cell–related cluster of differentiation (CD) proteins, and the human neonatal Fc receptor (FcRn). Up to now, eculizumab, a C5-directed mAb, has been approved for the treatment of generalized MG (gMG) and efgartigimod, a FcRn inhibitor, has just been approved by the U.S. Food and Drug Administration for the treatment of anti-acetylcholine receptor (AChR) antibody positive gMG. Other mAbs are currently under investigation with encouraging preliminary results, further enriching the new range of therapeutic possibilities for MG. This review article provides an overview of the present status of mAb-based therapies for MG, which offer an exciting promise for better outcomes by setting the basis of a precision medicine approach.
Introduction
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) remains a diagnostic challenge due to clinical, neurophysiological, and laboratory findings suggestive of other ...diagnoses, particularly chronic inflammatory demyelinating polyneuropathy (CIDP). In this cross-sectional prospective study, we aimed to investigate the utility of high-resolution ultrasonography of peripheral nerves as a diagnostic tool to differentiate ATTRv-PN from CIDP.
Methods
In 11 treatment-naive patients with genetically confirmed late-onset ATTRv-PN and 25 patients with CIDP, we collected clinical, electrodiagnostic, and high-resolution ultrasonography data of the peripheral nerves. In each patient, we used high-resolution ultrasonography to assess 26 nerve sites.
Results
Of the 11 patients with ATTRv-PN, two had electrodiagnostic study data compatible with a CIDP diagnosis. High-resolution ultrasonography showed that the cross-sectional area of the brachial plexus, median nerve at the axilla, arm, and forearm, ulnar nerve at the forearm, and peroneal nerve at the popliteal fossa were significantly smaller in the 11 ATTRv-PN patients than in CIDP patients. However, in the two patients with electrodiagnostic study data compatible with a CIDP diagnosis, high-resolution nerve ultrasonography data were comparable to those in patients with CIDP.
Conclusion
Although high-resolution ultrasonography of peripheral nerves provides reliable information in patients with ATTRv-PN, its usefulness as a standalone diagnostic tool to differentiate ATTRv-PN from CIDP might be limited.
Myasthenia gravis (MG) is a neurological B-cell mediated autoimmune disorder affecting the neuromuscular junction. MG therapeutics have always relied on nonselective immunosuppression with oral ...steroids and non-steroidal immunosuppressants, mainly with good clinical response. However, clinical stabilization is often reached at the cost of many troublesome side effects and up to 15% of MG patients are deemed as refractory to conventional immunosuppression. This highlights the need of a more targeted and efficacious therapeutic approach. Results from the randomized-controlled period of the CHAMPION study demonstrate a good safety, tolerability, and efficacy profile of ravulizumab compared to placebo. Like eculizumab, ravulizumab is an anti-C5 monoclonal antibody, but with an enhanced pharmacokinetic profile, that allows dosing every 8 weeks.
We provide an overview of ravulizumab biological features and results from the phase III CHAMPION MG (NCT03920293) study.
Data of the CHAMPION MG trial demonstrate that ravulizumab is effective and safe in the treatment of generalized MG. Having a rapid clinical effect, with long-term clinical response, ravulizumab could represent a selective immunosuppressive drug of choice in the future therapeutic algorithm of MG, where conventional immunosuppressants slowly leave room for newer drugs with a more targeted mechanism of action.
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