Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Applications of Diffusion-Weighted MRI to the Musculoskeletal System.

Diffusion-weighted imaging (DWI) is an established MRI technique that can investigate tissue microstructure at the scale of a few micrometers. Musculoskeletal tissues typically have a highly ordered structure to fulfill their functions and therefore represent an optimal application of DWI. Even more since disruption of tissue organization affects its biomechanical properties and may indicate irreversible damage. The application of DWI to the musculoskeletal system faces application-specific challenges on data acquisition including susceptibility effects, the low T2 relaxation time of most musculoskeletal tissues (2-70 msec) and the need for sub-millimetric resolution. Thus, musculoskeletal applications have been an area of development of new DWI methods. In this review, we provide an overview of the technical aspects of DWI acquisition including diffusion-weighting, MRI pulse sequences and different diffusion regimes to study tissue microstructure. For each tissue type (growth plate, articular cartilage, muscle, bone marrow, intervertebral discs, ligaments, tendons, menisci, and synovium), the rationale for the use of DWI and clinical studies in support of its use as a biomarker are presented. The review describes studies showing that DTI of the growth plate has predictive value for child growth and that DTI of articular cartilage has potential to predict the radiographic progression of joint damage in early stages of osteoarthritis. DTI has been used extensively in skeletal muscle where it has shown potential to detect microstructural and functional changes in a wide range of muscle pathologies. DWI of bone marrow showed to be a valuable tool for the diagnosis of benign and malignant acute vertebral fractures and bone metastases. DTI and diffusion kurtosis have been investigated as markers of early intervertebral disc degeneration and lower back pain. Finally, promising new applications of DTI to anterior cruciate ligament grafts and synovium are presented. The review ends with an overview of the use of DWI in clinical routine. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

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.

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.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Familial dysautonomia.

Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful.

Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor.

BACKGROUND: Although immune-checkpoint inhibitors (ICI) are overall promissory for cancer treatment, they entail, in some cases, an undesired side-effect called hyperprogressive-cancer disease (HPD) associated with acceleration of tumor growth and shortened survival. METHODS: To understand the mechanisms of HPD we assayed the ICI therapy on two murine tumors widely different regarding immunogenicity and, subsequently, on models of local recurrences and metastases of these tumors. To potentiate the immune response (IR), we combined ICI with meta-tyrosine-that counteracts immune-suppressive signals-and a selective inhibitor of p38 pathway that proved to counteract the phenomenon of tumor-immunostimulation. RESULTS: ICI were therapeutically effective against both tumor models (proportionally to their immunogenicity) but only when they faced incipient tumors. In contrast, ICI produced acceleration of large and residual tumors. The combined treatment strongly inhibited the growth of large tumors and it managed to cure 80% of mice with local recurrences and 60% of mice bearing residual metastases. CONCLUSIONS: Tumor enhancement was paradoxically correlated to a weak increase of the antitumor IR suggesting that a weak IR - different from a strong tumor-inhibitory one-may produce stimulation of tumor growth, mimicking the HPD observed in some clinical settings.

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.

Nerve Entrapments in the Pelvis and Hip.

Clinical symptoms of pelvic entrapment neuropathies are widely variable and frequently nonspecific, thus rendering it difficult to localize and diagnose. Magnetic resonance imaging (MRI), and in particular MR neurography, has become increasingly important in the work-up of entrapment neuropathies involving the pelvic and hip nerves of the lumbosacral plexus. The major sensory and motor peripheral nerves of the pelvis and hip include the sciatic nerve, superior and inferior gluteal nerves, femoral nerve, lateral femoral cutaneous nerve, obturator nerve, and pudendal nerve. Familiarity with the anatomy and imaging appearance of normal and pathologic nerves in combination with clinical presentation is crucial in the diagnosis of entrapment neuropathies.

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.

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.

Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies.

PURPOSE OF REVIEW: Pure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons. Patients present with insidious features of autonomic failure that have a chronic course.In this review, we highlight the features of PAF, the differentiating features from other autonomic neuropathies, the diagnostic tests, and the predictors for conversion to a central synucleinopathy. RECENT FINDINGS: Natural history studies have defined the predictors for and rate of conversion to a central alpha-synucleinopathy. Skin immunohistochemistry techniques and demonstration of length-dependent neuronal loss of both somatic and autonomic small fiber nerves, and intraneural phosphorylated synuclein deposition provide diagnostic biomarkers. In the future, diagnosis maybe supported by measuring cerebrospinal fluid alpha-synuclein oligomers using techniques, such as protein misfolding cyclic amplification assay and real-time quaking-induced conversion. SUMMARY: PAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies. Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies. Novel diagnostic procedures like skin immunohistochemistry for alpha-synuclein, and protein amplification techniques are being investigated to provide an earlier and more specific diagnosis. A substantial number of PAF patients' phenoconvert to a central alpha-synucleinopathy.

Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

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.

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.

Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis.

BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke: The Global COVID-19 Stroke Registry.

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.

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).

Predictive role of ankle MRI for tendon graft choice and surgical reconstruction.

PURPOSE: Tendon transfers have become a common surgical procedure around the ankle. In this study, we sought to evaluate the existence of a correlation between specific anthropometric parameters and the size of some ankle tendons measured on MRI, in particular those mostly used as graft in ankle surgery. METHODS: We recorded gender, height, weight, and body mass index (BMI) of 113 patients (57 females; mean age: 42 ± 18) who underwent ankle MRI. MRI measurements performed by a radiologist were: axial shortest diameter of Achilles (AT), posterior tibialis (PTT), flexor digitorum longus (FDLT), flexor hallucis longus (FHLT), peroneus longus (PLT), and anterior tibialis (ATT) tendons, intermalleolar distance (ID) and talus width (TW). Mann-Whitney U test and Pearson's correlation coefficient were used. After applying the Bonferroni correction for multiple comparisons, statistical significance was set at p < 0.002. RESULTS: The mean patient height, weight and BMI were 169 ± 9.8 cm (range: 140-193), 72.4 ± 16.4 kg (range: 44-142), and 25 ± 5.7 (range: 16-50), respectively. The mean ankle measurements were: AT = 5.3 ± 1.4 mm, PTT = 3.3 ± 0.6 mm, FDLT = 2.6 ± 0.4 mm, FHLT = 2.7 ± 0.4 mm, PLT = 2.9 ± 0.5 mm, ATT = 3±0.6 mm, ID = 62.9 ± 4.5 mm, and TW = 28.8 ± 2.5 mm. A statistical difference between male and female patients was observed regarding ID (z = -6.955, p < .001), TW (z = -6.692, p < .001), AT (z = -3.587, p < .001), PTT (z = -3.783, p < .001), and FDLT (z = -3.744, p < .001). Both PTT and FDLT showed a significant correlation with ID (p < .001) and TW (p < .001). ATT size was significantly correlated with weight, ID and TW (all with p < 0.001). PLT and AT showed a significant correlation only with ID and weight (p ≤ .001), respectively. CONCLUSION: Our data might help orthopaedists in preoperative planning to identify the best graft for ankle surgical procedures including tendon transfers.