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Muscle & Nerve Feb 2021Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients' ability to walk and... (Review)
Review
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients' ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment-refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.
Topics: Adrenal Cortex Hormones; Amyloid Neuropathies; Cerebrospinal Fluid; Charcot-Marie-Tooth Disease; Diagnosis, Differential; Diagnostic Errors; Disease Progression; Electrodiagnosis; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Immunologic Factors; Infusions, Subcutaneous; Medical Overuse; Neural Conduction; Outcome Assessment, Health Care; POEMS Syndrome; Paraneoplastic Polyneuropathy; Paraproteinemias; Peripheral Nerves; Plasma Exchange; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 32914902
DOI: 10.1002/mus.27046 -
JAMA Oct 2023Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.
IMPORTANCE
Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.
OBJECTIVE
To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.
DESIGN, SETTING, AND PARTICIPANTS
NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group.
INTERVENTIONS
Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).
MAIN OUTCOMES AND MEASURES
Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.
RESULTS
Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.
CONCLUSIONS AND RELEVANCE
In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.
Topics: Adult; Humans; Male; Middle Aged; Female; Prealbumin; Quality of Life; Amyloid Neuropathies, Familial; Oligonucleotides, Antisense; Polyneuropathies; Disease Progression
PubMed: 37768671
DOI: 10.1001/jama.2023.18688 -
International Orthopaedics Feb 2022International uniformity of definition and classification are crucial for diagnosis and management of cauda equina syndrome (CES). They are also useful for clinicians... (Review)
Review
PURPOSE
International uniformity of definition and classification are crucial for diagnosis and management of cauda equina syndrome (CES). They are also useful for clinicians when discussing CES with patients and relatives, and for medicolegal purposes.
METHODS
We reviewed published literature using PubMed on definition and classification of cauda equina syndrome since 2000 (21 years). Using the search terms 'cauda equina' and 'definition' or 'classification', we found and reviewed 212 papers.
RESULTS
There were 17 different definitions of CES used in the literature. There were three well-defined methods of classification of CES. The two-stage system of incomplete CES (CESI) versus CES with retention (CESR) is the most commonly used classification, and has prognostic value although the details of this continue to be debated.
CONCLUSION
We used the existing literature to propose a clear definition of CES. We also drew on peer-reviewed published literature that has helped to amplify and expand the CESI/CESR dichotomy, adding categories that are both less severe than CESI, and more severe than CESR, and we propose clear definitions in a table form to assist current and future discussion and management of CES.
Topics: Cauda Equina Syndrome; Humans; Polyradiculopathy; Prognosis
PubMed: 34862914
DOI: 10.1007/s00264-021-05273-1 -
Journal of Applied Physiology... May 2021Critical illness-associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into...
Critical illness-associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into three major classifications based on the component of the neuromuscular system (i.e. peripheral nerves or skeletal muscle or both) that are affected. This includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and an overlap syndrome, critical illness polyneuromyopathy (CIPNM). It is a common complication observed in people with critical illness requiring intensive care unit (ICU) admission. Given CIAW is found in individuals experiencing grave illness, it can be challenging to study from a practical standpoint. However, over the past 2 decades, many insights into the pathophysiology of this condition have been made. Results from studies in both humans and animal models have found that a profound systemic inflammatory response and factors related to bioenergetic failure as well as microvascular, metabolic, and electrophysiological alterations underlie the development of CIAW. Current management strategies focus on early mobilization, achieving euglycemia, and nutritional optimization. Other interventions lack sufficient evidence, mainly due to a dearth of large trials. The goal of this Physiology in Medicine article is to highlight important aspects of the pathophysiology of these enigmatic conditions. It is hoped that improved understanding of the mechanisms underlying these disorders will lead to further study and new investigations for novel pharmacologic, nutritional, and exercise-based interventions to optimize patient outcomes.
Topics: Critical Care; Critical Illness; Humans; Intensive Care Units; Muscular Diseases; Neuromuscular Diseases; Polyneuropathies
PubMed: 33734888
DOI: 10.1152/japplphysiol.00019.2021 -
Journal of Neurology Jun 2021Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form... (Review)
Review
Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.
Topics: Adult; Amyloid Neuropathies, Familial; Brazil; Consensus; Humans; Japan; Polyneuropathies; Portugal; Prealbumin; Sweden
PubMed: 31907599
DOI: 10.1007/s00415-019-09688-0 -
Diabetes Research and Clinical Practice Apr 2022Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality,... (Review)
Review
Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life.
Topics: Consensus; Diabetes Mellitus; Diabetic Neuropathies; Humans; Neuralgia; Polyneuropathies; Quality of Life
PubMed: 34547367
DOI: 10.1016/j.diabres.2021.109063 -
International Journal of Molecular... Apr 2023Dysfunction of the immune system can result in damage of the peripheral nervous system. The immunological mechanisms, which include macrophage infiltration, inflammation... (Review)
Review
Dysfunction of the immune system can result in damage of the peripheral nervous system. The immunological mechanisms, which include macrophage infiltration, inflammation and proliferation of Schwann cells, result in variable degrees of demyelination and axonal degeneration. Aetiology is diverse and, in some cases, may be precipitated by infection. Various animal models have contributed and helped to elucidate the pathophysiological mechanisms in acute and chronic inflammatory polyradiculoneuropathies (Guillain-Barre Syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, respectively). The presence of specific anti-glycoconjugate antibodies indicates an underlying process of molecular mimicry and sometimes assists in the classification of these disorders, which often merely supports the clinical diagnosis. Now, the electrophysiological presence of conduction blocks is another important factor in characterizing another subgroup of treatable motor neuropathies (multifocal motor neuropathy with conduction block), which is distinct from Lewis-Sumner syndrome (multifocal acquired demyelinating sensory and motor neuropathy) in its response to treatment modalities as well as electrophysiological features. Furthermore, paraneoplastic neuropathies are also immune-mediated and are the result of an immune reaction to tumour cells that express onconeural antigens and mimic molecules expressed on the surface of neurons. The detection of specific paraneoplastic antibodies often assists the clinician in the investigation of an underlying, sometimes specific, malignancy. This review aims to discuss the immunological and pathophysiological mechanisms that are thought to be crucial in the aetiology of dysimmune neuropathies as well as their individual electrophysiological characteristics, their laboratory features and existing treatment options. Here, we aim to present a balance of discussion from these diverse angles that may be helpful in categorizing disease and establishing prognosis.
Topics: Animals; Guillain-Barre Syndrome; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Polyneuropathies; Autoantibodies; Inflammation; Neuritis
PubMed: 37108447
DOI: 10.3390/ijms24087288 -
Medicina Aug 2022Guillain-Barré syndrome (GBS) is characterized by rapidly progressive and generally ascending symmetrical muscle weakness, accompanied by decreased or absent...
Guillain-Barré syndrome (GBS) is characterized by rapidly progressive and generally ascending symmetrical muscle weakness, accompanied by decreased or absent osteotendinous reflexes. The inflammatory process may affect the myelin or the axon. There are 4 clinical forms of GBS: 1) acute inflammatory demyelinating polyradiculoneuropathy, 2) acute motor axonal neuropathy, 3) acute sensory and motor axonal neuropathy, and 4) the Miller-Fisher variant, which is characterized by ophthalmoplegia, ataxia and areflexia, with little muscle weakness. Diagnosis is based on the albumin-cytological dissociation observed at the end of the first week after the onset of symptoms and may persist until the third week, as well as on the specific neurophysiological alterations of each clinical form. The treatment of GBS will depend on the degree of severity, if the patient presents grade IV or less according to the Paradiso scale, it will be treated with Ig IV, if it presents grade V, the use of plasmapheresis and/or immunoadbosorption is recommended. In severe axonal cases, the use of corticosteroid bolus is recommended in initial stages. There is a clinical picture that overlaps GBS and chronic demyelinating polyneuropathy related to antibodies against neurophysin and contactin, in this case the appropriate therapy is rituximab.
Topics: Guillain-Barre Syndrome; Humans; Muscle Weakness; Plasmapheresis
PubMed: 36054864
DOI: No ID Found -
CMAJ : Canadian Medical Association... Mar 2021
Topics: Guillain-Barre Syndrome; Humans
PubMed: 33722829
DOI: 10.1503/cmaj.202710 -
Journal of Neurology Oct 2021Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder characterised by muscle weakness and impaired sensory function. The present... (Review)
Review
BACKGROUND
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder characterised by muscle weakness and impaired sensory function. The present study provides a comprehensive literature review of the burden of illness of CIDP.
METHODS
Systematic literature search of PubMed, Embase, and key conferences in May 2019. Search terms identified studies on the epidemiology, humanistic burden, current treatment, and economic burden of CIDP published since 2009 in English.
RESULTS
Forty-five full texts and nineteen conference proceedings were identified on the epidemiology (n = 9), humanistic burden (n = 7), current treatment (n = 40), and economic burden (n = 8) of CIDP. Epidemiological studies showed incidence and prevalence of 0.2-1.6 and 0.8-8.9 per 100,000, respectively, depending on geography and diagnostic criteria. Humanistic burden studies revealed that patients experienced physical and psychosocial burden, including impaired physical function, pain and depression. Publications on current treatments reported on six main types of therapy: intravenous immunoglobulins, subcutaneous immunoglobulins, corticosteroids, plasma exchange, immunosuppressants, and immunomodulators. Treatments may be burdensome, due to adverse events and reduced independence caused by treatment administration setting. In Germany, UK, France, and the US, CIDP economic burden was driven by direct costs of treatment and hospitalisation. CIDP was associated with indirect costs driven by impaired productivity.
CONCLUSIONS
This first systematic review of CIDP burden of illness demonstrates the high physical and psychosocial burden of this rare disease. Future research is required to fully characterise the burden of CIDP, and to understand how appropriate treatment can mitigate burden for patients and healthcare systems.
Topics: Adrenal Cortex Hormones; Cost of Illness; Humans; Immunoglobulins, Intravenous; Plasma Exchange; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 32583051
DOI: 10.1007/s00415-020-09998-8