Diagnosis and treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States: Recommendations from a panel of experts.

Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.

Early diagnosis leading to improvement of critical illness polyneuropathy associated with severe Staphylococcus aureus infection in a patient on hemodialysis.

Critical illness polyneuropathy (CIP) is a very rare complication of sepsis and multi-organ failure. Herein, we report the first case of CIP reported in a patient on maintenance hemodialysis, who improved with rehabilitation. A 55-year-old male patient was emergently admitted with fever and altered consciousness and diagnosed with bacterial meningitis based on cerebral spinal fluid and cranial magnetic resonance imaging findings. Methicillin-susceptible Staphylococcus aureus was detected in blood and cerebral spinal fluid cultures. Despite treatment with appropriate antibiotics, blood cultures were positive for 9 days and serum C-reactive protein (CRP) levels were persistently elevated. Magnetic resonance imaging of hands and feet to determine infection origin revealed osteomyelitis in several fingers and toes, which required the amputation of 14 necrotic fingers and toes. Thereafter, blood cultures became negative and CRP levels declined. However, flaccid paralysis was noted in both upper and lower extremities during sepsis treatment. Nerve conduction studies showed peripheral axonal disorder in motor and sensory nerves, and CIP was determined as the cause of paralysis based on the fulfillment of all four CIP diagnostic criteria. The patient's muscle strength improved with early and appropriate medical treatment and physical therapy, and he was discharged home 147 days after admission. Prolonged high-level inflammation is a cause of CIP. Patients on hemodialysis, who are potentially immunosuppressed and vulnerable to infection, are at high risk for CIP. In patients on maintenance hemodialysis who develop flaccid paralysis during treatment for severe infection, CIP should be considered for early diagnosis and intervention.

Illness Weakness, Polyneuropathy and Myopathy: Diagnosis, treatment, and long-term outcomes.

BACKGROUND: Severe weakness associated with critical illness (CIW) is common. This narrative review summarizes the latest scientific insights and proposes a guide for clinicians to optimize the diagnosis and management of the CIW during the various stages of the disease from the ICU to the community stage. MAIN BODY: CIW arises as diffuse, symmetrical weakness after ICU admission, which is an important differentiating factor from other diseases causing non-symmetrical muscle weakness or paralysis. In patients with adequate cognitive function, CIW can be easily diagnosed at the bedside using manual muscle testing, which should be routinely conducted until ICU discharge. In patients with delirium or coma or those with prolonged, severe weakness, specific neurophysiological investigations and, in selected cases, muscle biopsy are recommended. With these exams, CIW can be differentiated into critical illness polyneuropathy or myopathy, which often coexist. On the general ward, CIW is seen in patients with prolonged previous ICU treatment, or in those developing a new sepsis. Respiratory muscle weakness can cause neuromuscular respiratory failure, which needs prompt recognition and rapid treatment to avoid life-threatening situations. Active rehabilitation should be reassessed and tailored to the new patient's condition to reduce the risk of disease progression. CIW is associated with long-term physical, cognitive and mental impairments, which emphasizes the need for a multidisciplinary model of care. Follow-up clinics for patients surviving critical illness may serve this purpose by providing direct clinical support to patients, managing referrals to other specialists and general practitioners, and serving as a platform for research to describe the natural history of post-intensive care syndrome and to identify new therapeutic interventions. This surveillance should include an assessment of the activities of daily living, mood, and functional mobility. Finally, nutritional status should be longitudinally assessed in all ICU survivors and incorporated into a patient-centered nutritional approach guided by a dietician. CONCLUSIONS: Early ICU mobilization combined with the best evidence-based ICU practices can effectively reduce short-term weakness. Multi-professional collaborations are needed to guarantee a multi-dimensional evaluation and unitary community care programs for survivors of critical illnesses.

Chronic Immune-Mediated Demyelinating Neuropathies.

OBJECTIVE: This article is an overview of chronic demyelinating neuropathies and highlights the phenotypic categorization, diagnosis, and treatment of chronic immune-mediated neuropathies. The clinical and diagnostic characteristics of other chronic demyelinating neuropathies that are common mimics of immune-mediated neuropathies are also discussed. LATEST DEVELOPMENTS: The underlying pathophysiology of chronic demyelinating neuropathies is heterogeneous, and components of both humoral and cellular immune responses are thought to play a role in the immune-mediated types of chronic demyelinating neuropathy. The role of the humoral response is highlighted with a specific focus on the relatively recent discovery of antibody-mediated antinodal and paranodal demyelinating neuropathies. Additionally, new diagnostic criteria for some of the chronic demyelinating neuropathies, as well as ways to differentiate chronic inflammatory demyelinating polyradiculoneuropathy from other chronic demyelinating polyneuropathies, are discussed. ESSENTIAL POINTS: Chronic demyelinating neuropathies can present with overlapping clinical characteristics with seemingly subtle variations. It is clinically important to differentiate these types of neuropathies because the treatment and management can vary and affect prognosis.

Paraproteinemic Neuropathies.

OBJECTIVE: Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical, electrophysiologic, and hematologic phenotypes of the paraproteinemic neuropathies and the diagnostic and treatment strategies for each. LATEST DEVELOPMENTS: Advances in our understanding of the underlying pathophysiology of various paraproteinemic neuropathies and their corresponding phenotypes have identified potential new therapeutic targets. Therapeutic strategies to diminish anti-myelin-associated glycoprotein (MAG) IgM antibodies have shown partial and inconsistent efficacy; however, antigen-specific immune therapy is being investigated as a novel treatment to remove the presumably pathogenic anti-MAG antibody. Advances in genetic and cell signaling studies have resulted in the approval of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Monoclonal antibodies are being investigated for the treatment of light chain amyloidosis. ESSENTIAL POINTS: Early recognition and treatment of underlying plasma cell disorders improves clinical outcomes in patients with paraproteinemic neuropathy. Despite significant progress, our knowledge regarding underlying mechanisms for paraproteinemic neuropathy is still limited. Clinicians' awareness of clinical phenotypes, electrophysiologic hallmarks, and hematologic findings of the different paraproteinemic neuropathies is crucial to promptly identify and treat patients and to avert misdiagnosis. Multidisciplinary collaboration among specialists, including neurologists and hematologists, is paramount for the optimal treatment of these patients with overlapping conditions.

Autoimmune polyneuropathies.

The autoimmune peripheral neuropathies with prominent motor manifestations are a diverse collection of unusual peripheral neuropathies that are appreciated in vast clinical settings. This chapter highlights the most common immune-mediated, motor predominant neuropathies excluding acute, and chronic inflammatory demyelinating polyradiculoneuropathy (AIDP and CIDP, respectively). Other acquired demyelinating neuropathies such as distal CIDP and multifocal motor neuropathy will be covered. Additionally, the radiculoplexus neuropathies, resulting from microvasculitis-induced injury to nerve roots, plexuses, and nerves, including diabetic and nondiabetic lumbosacral radiculoplexus neuropathy and neuralgic amyotrophy (i.e., Parsonage-Turner syndrome), will be included. Finally, the motor predominant peripheral neuropathies encountered in association with rheumatological disease, particularly Sjögren's syndrome and rheumatoid arthritis, are covered. Early recognition of these distinct motor predominant autoimmune neuropathies and initiation of immunomodulatory and immunosuppressant treatment likely result in improved outcomes.

Critical illness-associated weakness and related motor disorders.

Weakness of limb and respiratory muscles that occurs in the course of critical illness has become an increasingly common and serious complication of adult and pediatric intensive care unit patients and a cause of prolonged ventilatory support, morbidity, and prolonged hospitalization. Two motor disorders that occur singly or together, namely critical illness polyneuropathy and critical illness myopathy, cause weakness of limb and of breathing muscles, making it difficult to be weaned from ventilatory support, commencing rehabilitation, and extending the length of stay in the intensive care unit, with higher rates of morbidity and mortality. Recovery can take weeks or months and in severe cases, and may be incomplete or absent. Recent findings suggest an improved prognosis of critical illness myopathy compared to polyneuropathy. Prevention and treatment are therefore very important. Its management requires an integrated team approach commencing with neurologic consultation, creatine kinase (CK) measurement, detailed electrodiagnostic, respiratory and neuroimaging studies, and potentially muscle biopsy to elucidate the etiopathogenesis of the weakness in the peripheral and/or central nervous system, for which there may be a variety of causes. These tenets of care are being applied to new cases and survivors of the coronavirus-2 disease pandemic of 2019. This chapter provides an update to the understanding and approach to critical illness motor disorders.

Molecular, Electrophysiological, and Ultrasonographic Differences in Selected Immune-Mediated Neuropathies with Therapeutic Implications.

The spectrum of immune-mediated neuropathies is broad and the different subtypes are still being researched. With the numerous subtypes of immune-mediated neuropathies, establishing the appropriate diagnosis in normal clinical practice is challenging. The treatment of these disorders is also troublesome. The authors have undertaken a literature review of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Guillain-Barre syndrome (GBS) and multifocal motor neuropathy (MMN). The molecular, electrophysiological and ultrasound features of these autoimmune polyneuropathies are analyzed, highlighting the differences in diagnosis and ultimately treatment. The immune dysfunction can lead to damage to the peripheral nervous system. In practice, it is suspected that these disorders are caused by autoimmunity to proteins located in the node of Ranvier or myelin components of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. The electrophysiological presence of conduction blocks is another important factor characterizing separate subgroups of treatment-naive motor neuropathies, including multifocal CIDP (synonyms: multifocal demyelinating neuropathy with persistent conduction block), which differs from multifocal motor neuropathy with conduction block (MMN) in both responses to treatment modalities and electrophysiological features. Ultrasound is a reliable method for diagnosing immune-mediated neuropathies, particularly when alternative diagnostic examinations yield inconclusive results. In overall terms, the management of these disorders includes immunotherapy such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the development of more disease-specific immunotherapies should expand the therapeutic possibilities for these debilitating diseases.

Advances in diagnosis and management of distal sensory polyneuropathies.

Distal sensory polyneuropathy (DSP) is characterised by length-dependent, sensory-predominant symptoms and signs, including potentially disabling symmetric chronic pain, tingling and poor balance. Some patients also have or develop dysautonomia or motor involvement depending on whether large myelinated or small fibres are predominantly affected. Although highly prevalent, diagnosis and management can be challenging. While classic diabetes and toxic causes are well-recognised, there are increasingly diverse associations, including with dysimmune, rheumatological and neurodegenerative conditions. Approximately half of cases are initially considered idiopathic despite thorough evaluation, but often, the causes emerge later as new symptoms develop or testing advances, for instance with genetic approaches. Improving and standardising DSP metrics, as already accomplished for motor neuropathies, would permit in-clinic longitudinal tracking of natural history and treatment responses. Standardising phenotyping could advance research and facilitate trials of potential therapies, which lag so far. This review updates on recent advances and summarises current evidence for specific treatments.

Chemotherapy-induced polyneuropathy in cancer care-the patient perspective.

PURPOSE: Chemotherapy-related polyneuropathy (CIPN) is a very common, often dose-limiting side effect that affects the patients' quality of life. Treatment usually consists of a combination of medicinal, medical, and individualized treatment approaches, although the effectiveness of these therapies is insufficient for many patients. The aim of this article is to review and evaluate the impact of CIPN on patients' daily lives and possible effective treatment approaches. METHODS: A standardized questionnaire was developed based on ten anonymous telephone interviews with CIPN patients. The content of the questionnaire was divided into 5 categories: demographics, clinical presentation, everyday symptoms, treatment of CIPN symptoms, and medical care. Mostly closed questions were used but multiple choice and individual additions by free text answers were possible. RESULTS: CIPN limits patients' quality of life over a long period of time. In addition to diurnal and situational fluctuations, the emotional burden negatively affects patients' daily lives in many ways. From the patients' point of view, the individually implemented therapy measures were most effective in treating their complaints. But even the combination of different therapy methods insufficiently alleviates the symptoms of the patients. CONCLUSION: It is important and necessary to comprehensively inform patients about CIPN as a possible side effect, to point out prevention strategies, and to critically examine and evaluate different therapy approaches. In this way, misunderstandings of the doctor-patient relationship can be avoided. In addition, patient satisfaction and quality of life can be increased in the long term.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System.

PURPOSE OF REVIEW: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. RECENT FINDINGS: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Non-pharmacological Interventions on Pain and Quality of Life in Chemotherapy Induced Polyneuropathy: Systematic Review and Meta-Analysis.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN. MATERIALS AND METHODS: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol. RESULTS: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant. CONCLUSION: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms.

Temporary reversal of nerve and muscle dysfunction by serial electrical stimulation in critical illness neuromyopathy.

OBJECTIVE: Critical Illness Neuromyopathy (CIPNM) is a complication in sepsis patients with still enigmatic disease mechanisms. We investigated a novel electrical stimulation method to better define neuromuscular dysfunction in patients with CIPNM. METHODS: We studied 18 sepsis CIPNM patients on intensive care units, 13 at an early and 5 at a later disease stage, 7 sepsis control, and 8 neuropathy control patients. We applied slow conditioning electrical pulses at motor nerves and directly at the muscle to investigate a facilitation phenomenon (FP) of small or absent compound motor action potentials (CMAPs). RESULTS: Serial pulses induced a 2 to 490-fold increase in CMAP amplitudes in 17/18 Intensive Care Unit (ICU)-CIPNM patients (p < 0.001). These effects were short lived and reproducible. Direct muscle stimulation in the tibialis anterior muscle resulted in up to 130-fold FP in 7/9 patients tested (p < 0.01). In 4/5 post-ICU CIPNM patients FP was up to 10-fold. None of the 7 ICU sepsis control patients without CIPNM with similar disease severity and none of 8 neuropathy patients showed FP (p < 0.001). On needle EMG only 5/16 ICU patients tested revealed spontaneous activity. CONCLUSIONS: Conditioning electrical stimulation detected a functional component of the disease process showing temporary improvement in sepsis-associated CIPNM. SIGNIFICANCE: New test differentiates functional from degenerative pathology.

Successful utilization of high frequency spinal cord stimulation for HIV and chemotherapy induced polyneuropathy.

We present a case of a 53-year-old male who presented with functionally limiting bilateral lower extremity neuropathic pain secondary to multiple subtypes of small fiber neuropathy. He had failed management with multiple conservative measures including oral medications, physical therapy and desensitization techniques. He ultimately underwent placement of a spinal cord stimulator and continued to experience 80% improvement of his pain, as well as improved function and quality of life at 5 month follow-up. To our knowledge, this is the first reported case of successful treatment of multiple subtypes of small fiber neuropathy with spinal cord stimulator.

We report a case of a 53-year-old male who presented with multiple subtypes of small fiber neuropathy, characterized by abnormal sensation and nerve pain in his distal lower extremities, which was making performing his activities of daily living challenging. He had failed multiple conservative measures including oral medications, physical therapy and desensitization techniques. The patient then underwent a trial with a spinal cord stimulator, which includes placing a device in the spinal canal that can alleviate pain by providing low levels of electrical current. At the 5 month follow-up, he continued to report 80% improvement of his pain as well as improved function and quality of life. This is the first reported use of spinal cord stimulator in a patient with multiple subtypes of small fiber neuropathy.

Rituximab in chronic immune mediated neuropathies: a systematic review.

Chronic immune mediated neuropathy is a heterogenous group of peripheral nerve diseases, encompassing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), autoimmune nodopathy, multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) neuropathy. Rituximab (RTX) is a chimeric monoclonal antibody targeting the CD20 antigen, which has been used in the treatment of autoimmune neuropathies, although the efficacy of RTX remains unclear. A literature search was performed using Medline, Embase and Cochrane Register for studies between 2000 and 2021 using the search terms "Chronic inflammatory demyelinating polyneuropathy" OR "Multifocal motor neuropathy" OR "Myelin associated glycoprotein" OR "Distal acquired demyelinating neuropathy" OR "Multifocal acquired demyelinating sensory and motor neuropathy" OR "demyelinating neuropathy" AND "Rituximab". Twenty-three studies were included, of which two were randomised controlled trials, 6 prospective studies and 15 retrospective studies. RTX was effective in 63% of CIDP patients, 48% of anti-MAG neuropathy, and 96% of patients with autoimmune nodopathy. Neurophysiological improvement was evident in 58% of CIDP and 40% of anti-MAG neuropathy patients. Low rates of serious adverse events (2.6%) were observed. These results indicate that RTX has potential as a treatment in immune mediated polyneuropathy, although the quality of evidence supporting its use it poor. Randomized controlled trials are required to reliably establish the efficacy and safety of RTX. Trial registration number: CRD42020179666.

TTR exon-humanized mouse optimal for verifying new therapies for FAP.

Familial amyloidotic polyneuropathy (FAP) is caused by a mutation in the transthyretin (TTR) gene. In addition, deposition of wild-type TTR can cause senile systemic amyloidosis (SSA). To date, we have produced several transgenic mouse models for FAP and SSA by introducing TTR genes with different promoters or mutations. However, mouse TTR can associate with human TTR to produce hybrid tetramers in transgenic mice. Thus, these transgenic mice cannot be used to test the efficacy of a new therapy. In this study, we attempted to construct an optimized mouse model to verify a new therapy. The TTR gene consists of 4 exons and 3 introns. We prepared two gRNAs, one for the exon 1 and the other for exon 4, and a single donor vector carrying the whole TTR gene in which mouse exons were replaced with human exons. Using these vectors, we produced a TTR exon-humanized mouse with human exons and mouse introns using genome editing technology. These TTR exon-humanized mice showed normal TTR expression patterns in terms of serum TTR level and spatial specificity. These TTR exon-humanized mice will be useful for devising new treatment methods for FAP, including gene therapy.

Evidence base for investigative and therapeutic modalities in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy.

Chronic inflammatory demyelinating polyneuropathy, its variants and multifocal motor neuropathy belong to a spectrum of peripheral nerve disorders with complex dysimmune disease mechanisms. Awareness of the unique clinical phenotypes but also heterogeneity between patients is vital to arrive at early suspicion and ordering appropriate tests. This includes requirements for optimal electrodiagnostic protocol, aimed to capture sufficient electrophysiologic evidence for relevant abnormalities, a case-based approach on the eventual need to further expand the diagnostic armamentarium and correct reading of their results. Considerable phenotypical variation, diverse combinations of abnormalities found on diagnostic tests and heterogeneity in disease course and treatment response, all contribute to widespread differences in success rates on timely diagnosis and optimal treatment. We aim to provide a practical overview and guidance on relevant diagnostic and management strategies, including pitfalls and present a summary of the relevant novel developments in this field.