Canadian guidance for diagnosis and management of acute hepatic porphyrias.

Acute hepatic porphyrias (AHP) comprise four rare monogenic autosomal conditions. Each is linked to a deficiency of heme metabolizing enzymes. Common manifestations include severe abdominal pain, nausea, confusion, hyponatremia, hypertension, tachycardia, and neuropathy. Diagnosis is challenging due to a non-specific, variable presentation with symptoms mimicking other common conditions. Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, δ-aminolevulinic acid and porphyrins using a single random (spot) sample. However, many patients have complications due to delays in diagnosis and management. A novel small interfering RNA-based agent, givosiran, has demonstrated efficacy in reducing acute attacks in a recent Phase III trial, leading to its approval for the management of AHP. Early diagnosis is crucial for the timely introduction of disease-modifying treatments that reduce impairments, enhance quality of life, and extend survival. In this guidance, we aim to improve awareness and outcomes of AHP by making recommendations about diagnosis, monitoring, and treatment in Canada.

Reliability of confocal corneal microscopy for measurement of dendritic cell density in suspected small fiber neuropathy.

INTRODUCTION/AIMS: Dendritic cells (DCs) and their contacts with corneal nerves are described in animal models of nerve damage. Dendritic cell density (DCD) is a potential marker of immune activity in suspected small-fiber neuropathy (SFN). Here, we aim to evaluate the intra- and inter-rater reliability of DCD measurements in suspected SFN. METHODS: This retrospective study collected DCD from confocal microscopy images from the corneal sub-basal epithelium of the eye from 48 patients (mean age 49.6 ± 12.1 y, 61% female). Two examiners, each blinded to the other's examinations and measurements, assessed DCD to evaluate inter-rater reliability. For intra-rater reliability, the first examiner performed a second measurement after 14 days. DCs were classified into two cell morphological subtypes: mature and immature. RESULTS: Test-retest reliability for total DCD showed excellent agreement, with an intraclass correlation coefficient of 0.96 and inter-rater reliability intraclass correlation coefficient of 0.77. The immature cell subtype showed excellent intra-rater reliability but lower inter-rater reliability. DISCUSSION: We found that DCD measurements in the corneal sub-basal epithelium are sufficiently reliable for consideration in clinical studies of patients with suspected SFN.

Optimal cut-off value of the modified Toronto Clinical Neuropathy Score in the diagnosis of polyneuropathy.

BACKGROUND AND PURPOSE: The modified Toronto Clinical Neuropathy Score (mTCNS) is a valid and reliable scale for the diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). The aim of this study was to determine the optimal diagnostic cut-off value of the mTCNS in diverse polyneuropathies (PNPs). METHODS: Demographics and mTCNS values were retrospectively extracted from an electronic database of 190 patients with PNP and 20 normal controls. Sensitivity, specificity, and likelihood ratios and area under the receiver-operating characteristic (ROC) curve were determined for each diagnosis and different cut-off values of the mTCNS. Patients underwent clinical, electrophysiological and functional assessments of their PNP. RESULTS: Forty-three percent of PNP was related to diabetes or impaired glucose tolerance. mTCNS was significantly higher in patients with PNP than in those without (15.27 ± 8 vs. 0.79 ± 1.4; p = 0.001). The cut-off value for diagnosing PNP was ≥3 (sensitivity 98.4%, specificity 85.7%, positive likelihood ratio 6.88). The area under the ROC curve was 0.987. CONCLUSION: A value of 3 or more on the mTCNS is recommended for the diagnosis of PNP.

Sympathetic and electrochemical skin responses in the assessment of sudomotor function: a comparative study.

OBJECTIVES: The sympathetic skin response (SSR) is a well-established test, whereas the electrochemical skin conductance (ESC) is still under evaluation. Our aim was therefore to assess the diagnostic accuracy of ESC to detect abnormal sudomotor function, using SSR as a reference test. METHODS: A cross sectional observational study was performed of 61 neurological patients assessed for possible sudomotor dysfunction and 50 age-matched healthy controls (HC). Patients with diagnoses of vasovagal syncope (VVS, n=25), Parkinson's disease (PD, n=15), multiple system atrophy (MSA, n=11) and peripheral neuropathies (PN, n=10) were included. Sudomotor function was assessed with SSR and ESC tests in all participants. The absence of SSR in the palms or soles indicates abnormal sudomotor function. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic value of the ESC. Cardiovascular autonomic (CV-Aut) function was evaluated through the Ewing score, based on the following tests: Heart rate change with deep breathing, Valsalva ratio, 30:15 ratio, blood pressure changes on standing and during isometric exercise. A Ewing score ≥ 2 indicates the presence of CV-Aut dysfunction. RESULTS: Mean SSR amplitudes and ESC values showed differences between HC and patients with MSA or PN (p < 0.05), but not in patients with VVS or PD. Absence of SSR was associated with abnormal ESC (p < 0.05). Patients with abnormal CV-Aut dysfunction had lower ESC (p< 0.05). Palm ESC (P-ESC) and sole ESC (S-ESC) assessment had a sensitivity of 0.91 and 0.95 to predict sudomotor dysfunction, with a specificity of 0.78 and 0.85, respectively. The area under ROC curve was 0.905 and 0.98, respectively. CONCLUSIONS: ESC in palms and soles has a high diagnostic accuracy for sudomotor dysfunction as detected by absent SSR in patients with MSA and PN.

Hyperhidrosis in sleep disorders - A narrative review of mechanisms and clinical significance.

Hyperhidrosis is characterized by excessive sweating beyond thermoregulatory needs that affects patients' quality of life. It results from an excessive stimulation of eccrine sweat glands in the skin by the sympathetic nervous system. Hyperhidrosis may be primary or secondary to an underlying cause. Nocturnal hyperhidrosis is associated with different sleep disorders, such as obstructive sleep apnea, insomnia, restless legs syndrome/periodic limb movement during sleep and narcolepsy. The major cause of the hyperhidrosis is sympathetic overactivity and, in the case of narcolepsy type 1, orexin deficiency may also contribute. In this narrative review, we will provide an outline of the possible mechanisms underlying sudomotor dysfunction and the resulting nocturnal hyperhidrosis in these different sleep disorders and explore its clinical relevance.

Epidemiology of Parkinson's Disease in Chile.

INTRODUCTION: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. There is no epidemiological description of PD in Chile and not many descriptions in Latin America. This study aims to describe the incidence and prevalence of PD in Chile. METHODS: The study group was the population on the public health system in Chile between 2010 and 2018 that were registered in the GES system as having PD. Crude and standardized prevalence and incidence were calculated with a 95% confidence interval. RESULTS: 33,345 patients were found in the register as confirmed cases with PD. The crude incidence in 2018 was 23.7/100,000; the crude prevalence in 2018 was 160.7/100,000. The male-to-female ratio was 1.03. CONCLUSION: The prevalence and incidence observed in the Chilean population are consistent with studies from other countries.

Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies.

Maintenance of upright blood pressure critically depends on the autonomic nervous system and its failure leads to neurogenic orthostatic hypotension (NOH). The most severe cases are seen in neurodegenerative disorders caused by abnormal α-synuclein deposits: multiple system atrophy (MSA), Parkinson's disease, Lewy body dementia, and pure autonomic failure (PAF). The development of novel treatments for NOH derives from research in these disorders. We provide a brief review of their underlying pathophysiology relevant to understand the rationale behind treatment options for NOH. The goal of treatment is not to normalize blood pressure but rather to improve quality of life and prevent syncope and falls by reducing symptoms of cerebral hypoperfusion. Patients not able to recognize NOH symptoms are at a higher risk for falls. The first step in the management of NOH is to educate patients on how to avoid high-risk situations and providers to identify medications that trigger or worsen NOH. Conservative countermeasures, including diet and compression garments, should always precede pharmacologic therapies. Volume expanders (fludrocortisone and desmopressin) should be used with caution. Drugs that enhance residual sympathetic tone (pyridostigmine and atomoxetine) are more effective in patients with mild disease and in MSA patients with spared postganglionic fibers. Norepinephrine replacement therapy (midodrine and droxidopa) is more effective in patients with neurodegeneration of peripheral noradrenergic fibers like PAF. NOH is often associated with other cardiovascular diseases, most notably supine hypertension, and treatment should be adapted to their presence.

Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.

Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.

Epidemiology of chronic inflammatory demyelinating polyneuropathy in the South-Eastern area of Santiago, Chile.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated polyneuropathy. It usually has an insidious onset, progressive course and heterogeneous clinical features. As far as we know, there is no epidemiological information on CIDP in South America and the Caribbean. Our aim was to estimate the frequency of CIDP in the South-Eastern region of Santiago, where our hospital is based and the population number assigned is officially reported every year by the health authorities. Records of 581 patients registered with the diagnosis of neuropathy were found and all patients meeting the diagnostic criteria of the EFNS/PNS for definitive and possible CIDP were included. Data were collected using a data extraction protocol designed by the authors and which included demographic, clinical, laboratory and electrophysiological information. The estimated prevalence and incidence of CIDP were 2.95/100,000 and 0.46/100,000 respectively. Fifteen patients (8 men, 7 women) were classified as definitive or possible CIDP. Nine patients had typical CIDP and three also had diabetes mellitus. The prevalence and incidence rates were similar to those reported in other regions of the world.

Cardiovascular responses to isometric handgrip exercise in young patients with recurrent vasovagal syncope.

OBJECTIVE: Arterial blood pressure (BP) increased in healthy humans in response to isometric handgrip (IHG), but the pattern of the relative contribution of cardiac output (CO) and total peripheral resistance (TPR) changes to the pressor response is different among individuals. We investigated weather patients with recurrent vasovagal syncope (VVS) have a similar pattern of individual CO, TPR and pressor responses to IHG, as healthy subjects. METHODS: 32 patients (27.5 ±â€¯2.6 years), and 30 age-matched controls. Autonomic function was evaluated using finger-photoplethysmography to measure BP and heart rate (HR) response to gravitational stress (ΔBP, ΔHR), Valsalva maneuver (VM) and baroreflex sensitivity (BRS), and BP HR and CO changes during IHG. RESULTS: ΔBP, ΔHR, VM and IHG tests did not show significant difference between VVS patients and controls, although BRS was lower in VVS group (p < 0.05). Pattern of individual pressor, CO and TPR responses to IHG was significantly different between VVS patients and healthy subjects (Chi square, p = 0.0246). In 100% of the healthy subjects BP increased during IHG, but in a 19% of the patients BP (CO and TPR) did not increased during IHG. In VVS patients, the autonomic tests (ΔBP, ΔHR, VM and BRS) showed no significant differences between the group with BP increase and the group without pressor response. CONCLUSION: In VVS patients, the pattern of individual CO and TPR changes to IGH is different from healthy subjects. VVS patients may present an abnormal regulation of cardiovascular responses to IHG, with preserved cardiovagal and cardiac sympathetic function.

Adhesión al tratamiento farmacológico y descripción de sus factores asociados en pacientes con miastenia grave / Pharmacological treatment compliance and a description of its associated factors in patients with myasthenia gravis

Introducción. La adhesión al tratamiento farmacológico es un problema de salud pública, pero no se ha estudiado en pacientes con miastenia grave. Objetivo. Determinar la adhesión al tratamiento farmacológico en pacientes con miastenia grave y describir al grupo de pacientes no adherentes al tratamiento. Pacientes y métodos. Estudio de corte transversal, en pacientes con miastenia grave, en control y abandono del tratamiento farmacológico en el Hospital Padre Hurtado, Santiago de Chile. Los pacientes fueron invitados a participar de forma voluntaria y anónima. Se evaluó la adhesión al tratamiento con la escala Morisky-Green-Levine de cuatro ítems. Además, se evaluó la gravedad de la miastenia grave con el test manual de fuerza muscular (MMT); la calidad de vida asociada a la miastenia grave, con el 15-Item Quality Of Life Instrument for Myasthenia Gravis (MG-QOL15), y el riesgo de depresión, con el cuestionario de salud general de 12 ítems (GHQ-12). Resultados. Participaron 26 pacientes, de los cuales 15 (57,7%) eran mujeres. Sólo 10 (38,5%) mostraron adhesión al tratamiento. Los no adherentes presentaron mayor debilidad (MMT; p = 0,06) y peor calidad de vida (MG-QOL15; p = 0,008), y tomaban más fármacos para la miastenia grave (p = 0,003). Además, presentaron mayor riesgo de depresión (GHQ-12; p = 0,03) comparados con el grupo de adhesión al tratamiento. Conclusión. Tres de cada cinco pacientes con miastenia grave abandonaron el tratamiento, lo que se asoció con mayor debilidad, peor calidad de vida y mayor riesgo de depresión. Por lo tanto, debería evaluarse la adhesión al tratamiento en los pacientes con miastenia grave (AU)

Introduction. Medication adherence is a public health problem and this has not been previously studied in myasthenia gravis patients. Aim. To determine if patients with myasthenia gravis are adherent to treatment and to describe the clinical factors of patients who are non-adherent to treatment. Patients and methods. Cross-sectional study of patients with myasthenia gravis followed at Padre Hurtado Hospital, Santiago de Chile, who received their medication through the hospital and therefore were on the pharmacy's list. Patients'. participation was voluntary and anonymous. Medication adherence was assessed with the Morisky-Green-Levine survey (4 items). Patients were assessed for myasthenia gravis severity with the Manual Muscle Test, and myasthenia gravisrelated quality of life with the MG-QOL15. Finally, patients were screened for depression with the 12-Item General Health Questionnaire. Results. 26 patients were enrolled and 15 (57.7%) were women. Only 10 (38.5%) of patients were adherent to treatment. Patients who were not adherent to medication had more weakness (p = 0.06), worse quality of life (p = 0.008), were taking a greater number of myasthenia gravis drugs (p = 0.003) and had a higher risk of depression (p = 0.03). Conclusions. In this cohort of myasthenia gravis patients, three out of five patients were not adherent to treatment. These patients tended to have more weakness, worse quality of life and higher risk of depression. Medication adherence should be assessed routinely in patients with myasthenia gravis (AU)

Descripción electrofisiològica del síndrome de túnel carpiano según edad en pacientes adultos / Electrophysiological severity of carpal tunnel syndrome according to age in adult patients

Background: Carpal tunnel syndrome (CTS) represents 90% of entrapment neuropathies. Severity may be greater in older patients. Aim: To describe the electrophysiological findings in adult patients with CTS and determine if severity is related to age. Material and Methods: Descriptive and retrospective study of electrophysiological findings in patients over 18 years of age with clinical suspicion of CTS, studied between January 2011 and December 2015. Neurophysiological severity was classified in 3 grades, comparing them by age, gender and laterality. Results: Of 1156 patients subjected to electrophysiological studies due to a clinical suspicion of CTS, 690 (60%) had electrophysiological features of the disease. In 274 patients (24%) the compromise was mild, in 162 (14%) it was moderate and in 254 (22%) it was severe. There was a positive association between age and CTS severity (p < 0.01). Severity was significantly greater in males than females (p < 0.01). Bilateral CTS was present in 471 patients (68%), which was associated with increased age and severity (p < 0.01). Conclusions: Electrophysiological severity in CTS increases with age. Other factors associated with higher severity are male gender and bilateral disease.

[Usefulness of the activities of daily living questionnaire (T-ADLQ) in patients with minor stroke]. / Cuestionario de actividades de la vida diaria (T-ADLQ): utilidad en pacientes con accidente cerebrovascular menor.

BACKGROUND: The inability to carry out activities of daily living (ADL) is prevalent in elderly people and it is associated with hypertension and stroke. AIM: To evaluate ADLs using the T-ADLQ in hypertensive patients with minor stroke. SUBJECTS AND METHODS: T-ADLQ, Cognitive tests (Minimental and Addenbrooke), and Hamilton depression test were applied to 100 hypertensive ambulatory patients (55 without symptomatic stroke and 45 with ischemic stroke, Rankin ≤ 2). RESULTS: In stroke patients the ability to perform ADL was significantly reduced compared with hypertensive patients without stroke. Cognitive dysfunction and depressive symptoms were associated with a lower ADL performance. CONCLUSIONS: The T-ADLQ is useful to evaluate ADL in hypertensive ambulatory patients with ischemic stroke.

Recessive dystrophic epidermolysis bullosa results in painful small fibre neuropathy.

Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.

Cuestionario de actividades de la vida diaria (T-ADLQ): utilidad en pacientes con accidente cerebrovascular menor / Usefulness of the activities of daily living questionnaire (T-ADLQ) in patients with minor stroke

Background: The inability to carry out activities of daily living (ADL) is prevalent in elderly people and it is associated with hypertension and stroke. Aim: To evaluate ADLs using the T-ADLQ in hypertensive patients with minor stroke. Subjects and Methods: T-ADLQ, Cognitive tests (Minimental and Addenbrooke), and Hamilton depression test were applied to 100 hypertensive ambulatory patients (55 without symptomatic stroke and 45 with ischemic stroke, Rankin ≤ 2). Results: In stroke patients the ability to perform ADL was significantly reduced compared with hypertensive patients without stroke. Cognitive dysfunction and depressive symptoms were associated with a lower ADL performance. Conclusions: The T-ADLQ is useful to evaluate ADL in hypertensive ambulatory patients with ischemic stroke.

Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease.

The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.