Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis.

BACKGROUND: ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. OBJECTIVES: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.

Detection of sudomotor alterations evaluated by Sudoscan in patients with recently diagnosed type 2 diabetes.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) causes morbidity and affects the quality of life. Before diabetes diagnosis, neuropathic damage may be present. Sudoscan provides accurate measurement of the sudomotor function. This study aimed to assess the abnormalities detected by Sudoscan, offered estimates of DPN prevalence, and investigated the relationship between metabolic and clinical parameters. Additionally, we evaluated the diagnostic accuracy of the Sudoscan compared with monofilament and tuning fork tests for detecting DPN. RESEARCH DESIGN AND METHODS: Cross-sectional descriptive study including patients with type 2 diabetes for <5 years since diagnosis. We investigated the presence of DPN using a 128 Hz tuning fork test, the 10 g monofilament, and the sudomotor dysfunction in feet using Sudoscan. We compared patients with and without alterations in the Sudoscan. A logistic regression model analyzed variables independently associated with sudomotor dysfunction. RESULTS: From 2013 to 2020, 2243 patients were included, 55.1% women, age 51.8 years, and 17.1% with normal weight. Monofilament tests and/or tuning fork examination were abnormal in 29% (95% CI 0.23% to 0.27%) and 619 patients (27.6%, 0.25% to 0.29%) had sudomotor alterations. In logistic regression analysis, age (ß=1.01, 0.005-1.02), diastolic blood pressure (ß=0.98, 0.96-0.99), heart rate (ß=1.01, 1.00-1.02), glucose (ß=1.00, 1.00-1.03), albuminuria (ß=1.001, 1.000-1.001), beta-blockers=1.98, 1.21-3.24) and fibrate use=0.61, 0.43-0.87) were associated with sudomotor dysfunction. The AUC (area under the curve) for Sudoscan was 0.495 (0.469-0.522), with sensitivity and specificity of 24% and 71%, respectively. CONCLUSION: The Sudoscan identified an important proportion of patients with dysfunction, allowing prompt intervention to decrease the risk for complications. TRIAL REGISTRATION NUMBER: NCT02836808.

Physiological and clinical impact in the carotid baroreceptor function following the surgical management of bilateral carotid body tumors.

OBJECTIVE: The bilateral presentation of Carotid Body Tumors (CBT) is rare; the surgical resection of these masses remains the mainstay management due to the malignant potential. We aim to describe, classify, and quantify baroreceptor failure (BRF) after the surgical management of patients with bilateral CBT to better understand the clinical consequences. METHODS: Retrospective review of patients that underwent bilateral CBT resection to assess the changes in baroreceptor function. We describe the clinical events associated to BRF after surgery, baseline patient's demographics, characteristics, comorbidities. Additionally, clinical and a quantitative evaluation of baroreceptor sensitivity were conducted using the Composite Autonomic Severity Score (CASS). RESULTS: From 1986 to 2020, a total 146 CBT resections were performed in 132 patients in our institution. Tumors were removed bilaterally in staged procedures in seven patients with a mean age of 61 years (Standard Deviation 11), six (85%) were females, and there was no family history of paragangliomas. The clinical presentation were palpable masses in 5 (71%), and odynophagia in 2 (29%) cases; malignant histopathology following surgery was found in one case. BRF occurred in one patient after unilateral CBT resection, consisting of bradycardia and a 40 s asystole that was not previously associated to BR sensitivity. Three (43%) patients presented BRF in the immediate postoperative period of the contralateral CBT excision, consisting of volatile hypertensive crisis in two cases, and supraventricular tachycardia in one. All the patients developed (100%) chronic baroreceptor sensitivity symptoms consisting in syncope, vertigo and fatigue in 4 (57%), tachycardia in 2 (28%), and orthostatic headache in one (14%). Autonomic testing showed mixed sympathetic and parasympathetic failure in five (71%), severe sympathetic failure in 1 (14%), and parasympathetic dysfunction in one patient (14%). CONCLUSIONS: Postoperative autonomic assessment confirmed BRF in all studied patients that underwent staged bilateral CBT resection with mixed, sympathetic, and parasympathetic dysfunction. Further studies are necessary to evaluate the incidence and physiological mechanisms of these sequelae to anticipate possible complications and offer the appropriate perioperative management.

Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS).

BACKGROUND: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. METHODS: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). RESULTS: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). CONCLUSIONS: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

COVID-19-related diffuse posthypoxic leukoencephalopathy and microbleeds masquerades as acute necrotizing encephalopathy.

BACKGROUND: The complications of coronavirus disease 2019 (COVID-19), the clinical entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are not limited to the respiratory system. Leukoencephalopathy with microbleeds is increasingly seen in patients with COVID-19. New information is needed to delineate better the clinical implications of this infectious disease. CASE REPORT: A 46-year-old man with confirmed SARS-CoV-2 infection was admitted to the intensive care unit (ICU) with severe COVID-19. After transfer to the general wards, the patient was noted drowsy, disorientated, with slow thinking and speech. A brain MRI showed bilateral symmetrical hyperintense lesions in the deep and subcortical whiter matter, involving the splenium of the corpus callosum, as well as multiple microhemorrhages implicating the splenium and subcortical white matter. No contrast-enhanced lesions were observed in brain CT or MRI. CSF analysis showed no abnormalities, including a negative rtRT-PCR for SARS-CoV-2. An outpatient follow-up visit showed near-complete clinical recovery and resolution of the hyperintense lesions on MRI, without microbleeds change. CONCLUSION: We present the case of a survivor of severe COVID-19 who presented diffuse posthypoxic leukoencephalopathy, and microbleeds masquerading as acute necrotizing encephalopathy. We postulate that this kind of cerebral vasogenic edema with microbleeds could be the consequence of hypoxia, inflammation, the prothrombotic state and medical interventions such as mechanical ventilation and anticoagulation.

Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review.

BACKGROUND: Tuberculous meningitis (TBM) is the most frequent, severe, and disabling form of central nervous system (CNS) tuberculosis (TB). TBM paradoxical manifestations are characterized by clinical or paraclinical worsening after 1 month of effective anti-TB treatment in patients who initially responded to treatment despite the use of adjunctive corticosteroids. METHODS: Retrospective descriptive study of consecutive HIV-negative adult patients (≥ 18 years) with definitive TBM who developed a paradoxical manifestation following anti-TB in a tertiary-care hospital in Mexico from 2009 to 2019; we also conducted a literature review of published cases/series of paradoxical manifestations in HIV-negative patients from 1980 to 2020. RESULTS: We detected 84 cases of definitive TBM; 55 (68.7%) HIV-negative patients and 29 (36.3%) HIV-infected patients. Among HIV-negative patients, four (7.3%), three female and one male (19-49 years old), developed a paradoxical manifestation within 4-14 weeks following treatment initiation despite receiving adequate corticosteroid doses; Mycobacterium bovis was isolated from the cerebrospinal fluid of three cases and Mycobacterium tuberculosis in one more. Two patients developed vasculopathy-related cerebral infarctions, one severe basilar meningitis, and hydrocephalus, one more a tuberculoma. Two were treated with intravenous cyclophosphamide, and two with steroids. One of the patients treated with steroids died; patients who received cyclophosphamide had a good clinical response. CONCLUSIONS: This case series illustrates the diverse clinical/radiologic paradoxical manifestations of TBM in HIV-negative patients. Cyclophosphamide may be safe and effective in treating TBM-associated paradoxical manifestations. Specific diagnostic and care protocols for these patients are needed.

A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis).

Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes leading to amyloidosis may differ between the different variants. In addition, fibril accumulation and toxicity vary between different mutations. Structural changes in amyloidogenic TTR have been difficult to identify through X-ray crystallography; but nuclear magnetic resonance spectroscopy has revealed different chemical shifts in the backbone structure of mutated and wild-type TTR, resulting in diverse responses to the cellular conditions or proteolytic stress. Toxic mechanisms of TTR amyloidosis have different effects on different tissues. Therapeutic approaches have evolved from orthotopic liver transplants to novel disease-modifying therapies that stabilize TTR tetramers and gene-silencing agents like small interfering RNA and antisense oligonucleotide therapies. The underlying molecular mechanisms of the different TTR variants could be responsible for the tropisms to specific organs, the age at onset, treatment responses, or disparities in the prognosis.

TRANSTHYRETIN AMYLOIDOSIS THERAPIES: GUIDING THE FUTURE.

Transthyretin (TTR) amyloidosis (ATTR) is a progressive condition characterized by multiorgan accumulation of amyloid deposits composed of transthyretin (TTR) fibrils. Over the past decades, despite being a rare disease, ATTR amyloidosis has enabled top-tier therapeutics. In the 90s, organ transplantation was the mainstream therapeutic option and fostered distinct approaches, such as combined liver-heart transplant and domino (sequential) liver transplantation. Likewise, several TTR molecule stabilizers were developed successfully. Over the past decade, oriented genetic therapies emerged to prevent, control, and, surprisingly, reverse amyloid deposition. Silencing the TTR gene using different strategies is flourishing, and ongoing trials continue to evaluate diverse approaches to optimize their application. The following perspective describes the currently available treatments for ATTR amyloidosis and the prospects on the potential application of these strategies in other medical fields.

Characteristics and predictors for silent hypoxemia in a cohort of hospitalized COVID-19 patients.

BACKGROUND: An intriguing feature recently unveiled in some COVID-19 patients is the "silent hypoxemia" phenomenon, which refers to the discrepancy of subjective well-being sensation while suffering hypoxia, manifested as the absence of dyspnea. OBJECTIVE: To describe the clinical characteristics and predictors of silent hypoxemia in hospitalized COVID-19 patients. METHODS: We conducted a prospective cohort study including consecutive hospitalized adult (≥ 18 years) patients with confirmed COVID-19 presenting to the emergency department with oxygen saturation (SpO2) ≤ 80% on room air from March 15 to June 30, 2020. We analyzed the characteristics, disease severity, and in-hospital outcomes of patients presenting with dyspnea and those without dyspnea (silent hypoxemia). RESULTS: We studied 470 cases (64.4% men; median age 55 years, interquartile range 46-64). There were 447 (95.1%) patients with dyspnea and 23 (4.9%) with silent hypoxemia. The demographic and clinical characteristics, comorbidities, laboratory and imaging findings, disease severity, and outcomes were similar between groups. Higher breathing and heart rates correlated significantly with lower SpO2 in patients with dyspnea but not in those with silent hypoxemia. Independent predictors of silent hypoxemia were the presence of new-onset headache (OR 2.919, 95% CI 1.101-7.742; P = 0.031) and presenting to the emergency department within the first eight days after symptoms onset (OR 3.183, 95% CI 1.024-9.89; P = 0.045). CONCLUSIONS: Patients with silent hypoxemia sought medical attention earlier and had new-onset headache more often. They were also likely to display lower hemodynamic compensatory responses to hypoxemia, which may underestimate the disease severity.

Neurologic manifestations in hospitalized patients with COVID-19 in Mexico City.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is a systemic entity that frequently implies neurologic features at presentation and complications during the disease course. We aimed to describe the characteristics and predictors for developing in-hospital neurologic manifestations in a large cohort of hospitalized patients with COVID-19 in Mexico City. METHODS: We analyzed records from consecutive adult patients hospitalized from March 15 to June 30, 2020, with moderate to severe COVID-19 confirmed by reverse transcription real-time polymerase chain reaction (rtRT-PCR) for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neurologic syndromes were actively searched by a standardized structured questionnaire and physical examination, confirmed by neuroimaging, neurophysiology of laboratory analyses, as applicable. RESULTS: We studied 1,072 cases (65% men, mean age 53.2±13 years), 71 patients had pre-existing neurologic diseases (diabetic neuropathy: 17, epilepsy: 15, history of ischemic stroke: eight, migraine: six, multiple sclerosis: one, Parkinson disease: one), and 163 (15.2%) developed a new neurologic complication. Headache (41.7%), myalgia (38.5%), dysgeusia (8%), and anosmia (7%) were the most common neurologic symptoms at hospital presentation. Delirium (13.1%), objective limb weakness (5.1%), and delayed recovery of mental status after sedation withdrawal (2.5%), were the most common new neurologic syndromes. Age, headache at presentation, preexisting neurologic disease, invasive mechanical ventilation, and neutrophil/lymphocyte ratio ≥9 were independent predictors of new in-hospital neurologic complications. CONCLUSIONS: Even after excluding initial clinical features and pre-existing comorbidities, new neurologic complications in hospitalized patients with COVID-19 are frequent and can be predicted from clinical information at hospital admission.

Neurological manifestations temporally associated with SARS-CoV-2 infection in pediatric patients in Mexico.

PURPOSE: To describe the temporal association of specific acute neurological symptoms in pediatric patients with confirmed SARS-CoV-2 infection between May and August 2020. METHODS: We performed a recollection of all the clinical and laboratory data of patients having acute neurological symptoms temporally associated with SARS-CoV-2 infection at a third-level referral hospital in Mexico City (Instituto Nacional de Pediatría). Patients in an age group of 0-17 years with acute neurological signs (including ascending weakness with areflexia, diminished visual acuity, encephalopathy, ataxia, stroke, or weakness with plasma creatinine kinase (CK) elevation) were evaluated. RESULTS: Out of 23 patients with neurological manifestations, 10 (43%) had a confirmed SARS-CoV-2 infection. Among the infected patients, 5 (50%) were males aged 2-16 years old (median age 11.8 years old). Four (40%) patients confirmed a close contact with a relative positive for SARS-CoV-2, while 6 (60%) cases had a history of SARS-CoV-2-related symptoms over the previous 2 weeks. The following diagnoses were established: 3 cases of GBS, 2 of ON, 2 of AIS, one of myositis with rhabdomyolysis, one ACA, and one of anti-NMDA-R encephalitis. CONCLUSIONS: Neurological manifestations temporally associated with SARS-CoV-2 infection were noticed in the pediatric population even without respiratory symptoms. In this study, 2 of 6 symptomatic patients had mild respiratory symptoms and 4 had unspecific symptoms. During this pandemic, SARS-CoV-2 infection should be considered as etiology in patients with acute neurological symptoms, with or without previous respiratory manifestations, particularly in teenagers.

Bioethics in medical care rationing during the coronavirus disease-19 pandemic

ABSTRACT Background: Coronavirus (CoV) disease (COVID)-19 poses difficult situations in which the ethical course of action is not clear, or choices are made between equally unacceptable responses. Methods: A web search was performed using the terms “bioethics; COVID-19; ethics; severe acute respiratory syndrome CoV-2; emergent care; pandemic; and public health emergencies.” Results: Protection from COVID-19 has resulted in the cancellation of necessary medical interventions, lengthened suffering, and potential non-COVID-19 deaths. Prolonged lockdown reduced well-being, triggering or aggravating mental illnesses and violence, and escalated medical risks. Collateral damage includes restrictions on visitations to hospitals, alienation from the deceased relative, or lack of warm caring of patients. Finally, in a public health crisis, public health interest overrides individual rights if it results in severe harm to the community. Conclusion: Balancing ethical dilemmas are one more challenge in the COVID-19 pandemic. (REV INVEST CLIN. 2021;73(1):1-5)

A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).

Bioethics in the COVID-19 Pandemic Research: Challenges and Strategies.

As all other aspects in times of the coronavirus disease (COVID)-19 pandemic, carrying-out quality clinical research has been challenging. Many well-established paradigms have shifted as a consequence of the rapid demand for new knowledge. New treatments are fast-moving, informed consent forms are difficult to obtain, a competitive invitation from researchers to participate in different studies is common, and non-COVID-19 research protocols are suffering continuity. However, these challenges should not imply taking shortcuts or accepting deficiencies in bioethical standards, but rather enhance the alertness for rigorous ethical approaches despite these less than ideal circumstances. In this manuscript, we point out some interrogates in COVID-19 research and outline possible strategies to overcome the difficult task to continue with high-quality research without violating the ethical principles.

Bioethics in the COVID-19 Pandemic Research: Challenges and Strategies

As all other aspects in times of the coronavirus disease (COVID)-19 pandemic, carrying-out quality clinical research has been challenging. Many well-established paradigms have shifted as a consequence of the rapid demand for new knowledge. New treatments are fast-moving, informed consent forms are difficult to obtain, a competitive invitation from researchers to participate in different studies is common, and non-COVID-19 research protocols are suffering continuity. However, these challenges should not imply taking shortcuts or accepting deficiencies in bioethical standards, but rather enhance the alertness for rigorous ethical approaches despite these less than ideal circumstances. In this manuscript, we point out some interrogates in COVID-19 research and outline possible strategies to overcome the difficult task to continue with high-quality research without violating the ethical principles. (REV INVEST CLIN. 2020;72(5):265-70)