Immunotherapy with subcutaneous immunoglobulin or plasmapheresis in patients with postural orthostatic tachycardia syndrome (POTS).

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS), one of the most common autonomic disorders, is associated with significant morbidity and functional impairment. Although several possible etiologies have been proposed, autoimmunity has emerged as one of the leading causes with various specific and non-specific antibodies identified in patients with POTS. Treatment with intravenous immunoglobulin has been previously described. We present a case series of patients with severe POTS refractory to the standard pharmacologic and non-pharmacologic therapies treated with immunotherapy consisting of either subcutaneous immunoglobulin (SCIG) therapy or plasmapheresis (PLEX) and report their treatment outcomes. METHODS: Clinical history of 7 patients with POTS who were treated with SCIG or PLEX was reviewed. Response to treatment was assessed using COMPASS 31 and functional ability scale (FAS), completed by patients retrospectively, pre- and 3-12 months post-treatment with SCIG or PLEX. RESULTS: All patients improved following SCIG or PLEX with an average 50% reduction in COMPASS 31 score and 217% increase in FAS scores. Six out of seven patients were able to reduce or discontinue oral medications for POTS, and five patients were able to return to work or school. Four patients had skin biopsy or quantitative sudomotor axon reflex test (QSART)-proven small fiber neuropathy, and five had various positive antibodies at low titers. CONCLUSION: Patients with severe, treatment-refractory POTS experienced significant functional improvement with reduction in the autonomic symptoms following immunotherapy with SCIG or PLEX. Randomized controlled trials of SCIG and/or PLEX are needed to determine the efficacy and safety of these long-term therapies in patients with POTS.

Persistent Antiphospholipid Antibodies, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome and Post-COVID Syndrome: 1 Year On.

This is the first case report of a patient with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) with multiple persistent antiphospholipid antibody (aPL)-positivity more than a year after illness onset who also meets Global Consensus-2 criteria for mast cell activation syndrome (MCAS), suggesting pathological activation of the acquired and innate immune systems by SARS-CoV-2. While the patient continues to meet criteria for POTS 1 year on, her functional ability has improved significantly with therapy directed at MCAS, POTS and aPL-positivity. LEARNING POINTS: A subset of long-haul COVID-19 patients have postural orthostatic tachycardia syndrome (POTS), which can be diagnosed by a 10-minute in-office stand test.Antiphospholipid antibodies may be associated with POTS in patients with long-haul COVID-19 and have important clinical implications.Mast cell activation syndrome (MCAS) may be associated with long-haul COVID-19 (with or without POTS) and can often be easily treated, including with over-the-counter medications, supplements and dietary changes.

A trial of antithrombotic therapy in patients with refractory migraine and antiphospholipid antibodies: A retrospective study of 75 patients.

OBJECTIVE: It has been reported that patients with antiphospholipid antibodies (aPL) and refractory migraine may experience symptomatic improvement with antithrombotic therapy, but this phenomenon has not been well studied. This study was undertaken to detail the response to trials of antithrombotic therapy in these patients. METHODS: This is a retrospective study of 75 patients with refractory migraine and aPL who were given a 2-4 week trial of aspirin, clopidogrel and/or anticoagulation. Major response was defined as 50-100% improvement in frequency and/or severity of migraine; minor response: 25-49% improvement; no response: <25% improvement. RESULTS: 66 patients were given a trial of aspirin: 47% responded (21% major); 60 patients were given a trial of clopidogrel: 83% responded (67% major); and 34 patients were given a trial of anticoagulation (usually apixaban): 94% responded (85% major). The response rate to any anti-thrombotic therapy was 89% (83% major). Many patients also noted improvement in non-headache symptoms. No patient experienced stroke. There was no major bleeding during any 2-4 week treatment trial and only 3 of 69 patients maintained on an antithrombotic regimen for a median follow up of 29.9 months (5-100) experienced major bleeding. CONCLUSIONS: There was a high rate of symptomatic response to antithrombotic therapy in this context and long-term follow up suggested an individualized symptom-derived antithrombotic regimen may be associated with a low bleeding risk. Our data support consideration of a 2-4 week trial of antithrombotic therapy, usually starting with antiplatelet therapy, in aPL-positive patients with refractory migraine, particularly if other treatment options have been exhausted. As a retrospective study, our data provide only Class IV level of evidence, but they suggest randomized controlled trials are warranted to validate these encouraging findings.

Diagnosis of mast cell activation syndrome: a global "consensus-2".

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Reading and numeracy attainment of children reported to child protection services: A population record linkage study controlling for other adversities.

BACKGROUND: Maltreated children are at risk of poor educational outcomes, but also experience greater individual, family, and neighbourhood adversities that may obscure an understanding of relationships between child protection involvement and educational attainment. OBJECTIVE: To examine associations between child protection involvement and 3rd- and 5th-grade reading and numeracy attainment, while controlling multiple other adversities. PARTICIPANTS AND SETTING: Participants were 56,860 Australian children and their parents from the New South Wales Child Development Study with linked multi-agency records. METHODS: Multinomial logistic regressions examined associations between level of child protection involvement (Out-Of-Home Care [OOHC] placement; substantiated Risk Of Significant Harm [ROSH]; unsubstantiated ROSH; non-ROSH; and no child protection report) and standardised tests of 3rd- and 5th-grade reading and numeracy. Fully adjusted models controlled demographic, pregnancy, birth, and parental factors, and early (kindergarten) developmental vulnerabilities on literacy and numeracy, and other developmental domains (social, emotional, physical, communication). RESULTS: All children with child protection reports were more likely to attain below average, and less likely to attain above average, 3rd- and 5th-grade reading and numeracy, including children with reports below the ROSH threshold. Children with substantiated ROSH reports who were not removed into care demonstrated the worst educational attainment, with some evidence of protective effects for children in OOHC. CONCLUSIONS: A cross-agency response to supporting educational attainment for all children reported to child protection services is required, including targeted services for children in OOHC or with substantiated ROSH reports, and referral of vulnerable families (unsubstantiated and non-ROSH cases) to secondary service organisations (intermediate intervention).

Chronic Physical Health Conditions, Mental Health, and Sources of Support in a Longitudinal Australian Child Population Cohort.

OBJECTIVE: This study examined associations between chronic physical health conditions (identified from hospital records) that are subject to school health care plans, and children's emotional, behavioral, and social functioning during early (∼5 years of age) and middle childhood (∼11 years). METHODS: Participants were 21,304 Australian children from a representative longitudinal population cohort derived by multi-agency record linkage. Hospital presentations (admitted patients and emergency department) identified children with asthma (n = 1,573), allergies and anaphylaxis (n = 738), type 1 diabetes (n = 59), epilepsy (n = 87), and any of these conditions (n = 2,275), relative to 19,029 children without these presentations. Logistic regression analyses determined associations between these exposures and (i) emotional, behavioral, social, and overall vulnerabilities reported by teachers (early childhood) and children (middle childhood), and (ii) self-reported lack of sources of support (middle childhood). RESULTS: Prevalence of any condition in hospital records was 7.5% by early childhood, and 10.7% by middle childhood. Relative to peers without these presentations, small increases in risk of overall problems, and selected emotional, behavioral, and social problems, were apparent for children with any condition, and asthma specifically, in early and middle childhood. Large and pervasive effects were apparent for epilepsy, limited small effects in middle childhood only for allergies and anaphylaxis, and no increases in risk associated with type 1 diabetes examined in middle childhood. No condition was associated with increased risk of lacking supports. CONCLUSIONS: Children with hospital records of chronic conditions, particularly epilepsy and asthma, might benefit from school-based care plans that integrate their physical and mental health support needs.

Recognition and Management of Medication Excipient Reactivity in Patients With Mast Cell Activation Syndrome.

Mast cell activation syndrome (MCAS) is a complex disorder hallmarked by chronic multisystem inflammatory, allergic and growth dystrophic phenomena caused by inappropriate mast cell activation. MCAS has been estimated to affect as many as 17% of the population with a severity ranging from mild to life-threatening. MCAS patients are more sensitive than the average person to chemicals in the environment, including the nondrug ("inactive") ingredients (excipients) in medications and supplements. Excipient reactivity may explain unusual side effects to medications health professionals often find puzzling, such as the patient who appears intolerant of prednisone, acetaminophen, levothyroxine, or a vitamin. We present a series of patients with MCAS to illustrate important points regarding excipient reactivity which may be useful in everyday practice.

Deep capillary retinal ischemia and high-titer prothrombin-associated antiphospholipid antibodies: A case series of three patients.

PURPOSE: Acute macular neuroretinopathy has been shown to be due to ischemia of the deep capillary retinal plexus and most cases occur in young women; we hypothesized that there may be an association with antiphospholipid antibodies. OBSERVATIONS: We identified three patients who were diagnosed with deep capillary retinal ischemia after presenting with sudden onset of focal paracentral scotoma who tested persistently positive for antiphospholipid antibodies. All patients had high-titer prothrombin-associated antibodies and two of the three also had low-titer anticardiolipin antibodies. In all patients, the diagnosis was missed at the initial presentation. All patients experienced involvement of both eyes over time with permanent visual deficits and all were female with an average age at symptom onset of 34 years. All patients were using exogenous estrogen and had additional but previously undiagnosed symptoms or signs that may be seen in the antiphospholipid syndrome. One patient was ANA positive with a titer of 1:320, but none had lupus-specific antibodies or clinical features of lupus. CONCLUSIONS AND IMPORTANCE: The persistent presence of high-titer prothrombin-associated antiphospholipid antibodies in three women with deep capillary retinal ischemia suggests this may be an important association. Prothrombin-associated antibodies (anti-prothrombin IgG and anti-phosphatidylserine-prothrombin IgG and IgM) as well as the traditional antiphospholipid antibodies (anticardiolipin IgG, IgM and IgA; anti-beta 2 glycoprotein I IgG, IgM and IgA; and the lupus anticoagulant) should be included in the diagnostic work-up of patients diagnosed with deep capillary retinal ischemia. Because of the broader health and treatment implications of high-titer antiphospholipid antibodies, further investigation into this suspected association is warranted.

Intravenous Immunoglobulin Therapy in Refractory Autoimmune Dysautonomias: A Retrospective Analysis of 38 Patients.

BACKGROUND: Intravenous immunoglobulin (IVIG) has recognized efficacy in autoimmune peripheral nerve disorders, but there has been limited study of the use of IVIG in autoimmune dysautonomias. STUDY QUESTION: To determine the efficacy and safety of IVIG in patients with disabling, refractory autoimmune dysautonomias, including patients with postural tachycardia syndrome and gastrointestinal dysmotility. STUDY DESIGN: Patients with one or more autonomic disorder(s) and persistent serological evidence for autoimmunity who were unable to work or attend school despite usual treatments for dysautonomia were treated with IVIG for at least 3 months at a dose of at least 1 gm/kg monthly. MEASURES AND OUTCOMES: Outcome measures included the composite autonomic symptom scale 31 survey and a functional ability score. RESULTS: There were 38 patients, 84% female and mean age of 28.4 years. Of patients, 83.5% improved on IVIG as defined by at least 20% improvement in the composite autonomic symptom scale 31 and/or functional ability score. The mean pretreatment functional ability score was 21% (mostly bedridden), which improved to a mean of 74% (nearing able to return to work/school) for responsive patients after at least 1 year of IVIG. The mean time to the first sign of response was 5.3 weeks. There were no serious adverse events. The Mayo autoimmune dysautonomia panel antibodies and traditional Sjögren antibodies were present in only 13% and 8% of patients, respectively, but antiphospholipid antibodies and novel Sjögren antibodies were present in 76% and 42% of patients, respectively. CONCLUSIONS: There is increasing evidence that IVIG is safe and effective in a subset of patients with autonomic disorders and evidence for autoimmunity. A 4-month IVIG trial should be considered in severely affected patients who are refractory to lifestyle and pharmacological therapies. Antiphospholipid antibodies and novel Sjögren antibodies are often present in these patients and correlate with a high response rate to IVIG.

How We Treat Autoimmune Small Fiber Polyneuropathy with Immunoglobulin Therapy.

Intravenous immunoglobulin therapy is FDA approved for the immune-mediated peripheral nerve disorders Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. Immunoglobulin therapy has been used increasingly with significant efficacy in the treatment of patients with disabling autoimmune forms of dysautonomia, which are most often small fiber (autonomic and/or sensory) polyneuropathies. It is recognized by most who treat these disorders, however, that patients with autonomic dysfunction treated with intravenous immunoglobulin therapy develop aseptic meningitis or severe lingering headache more frequently than other patient populations when this therapy is dosed in the traditional fashion. We discuss our combined 27 years of experience with the use of immunoglobulin and other immune modulatory therapy in patients with autoimmune small fiber polyneuropathy.

Autonomic neuropathy-in its many guises-as the initial manifestation of the antiphospholipid syndrome.

Autonomic disorders have previously been described in association with the antiphospholipid syndrome. The present study aimed to determine the clinical phenotype of patients in whom autonomic dysfunction was the initial manifestation of the antiphospholipid syndrome and to evaluate for autonomic neuropathy in these patients. This was a retrospective study of 22 patients evaluated at the University of Colorado who were found to have a disorder of the autonomic nervous system as the initial manifestation of antiphospholipid syndrome. All patients had persistent antiphospholipid antibody positivity and all patients who underwent skin biopsy were found to have reduced sweat gland nerve fiber density suggestive of an autonomic neuropathy. All patients underwent an extensive evaluation to rule out other causes for their autonomic dysfunction. Patients presented with multiple different autonomic disorders, including postural tachycardia syndrome, gastrointestinal dysmotility, and complex regional pain syndrome. Despite most having low-titer IgM antiphospholipid antibodies, 13 of the 22 patients (59%) suffered one or more thrombotic event, but pregnancy morbidity was minimal. Prothrombin-associated antibodies were helpful in confirming the diagnosis of antiphospholipid syndrome. We conclude that autonomic neuropathy may occur in association with antiphospholipid antibodies and may be the initial manifestation of the syndrome. Increased awareness of this association is important, because it is associated with a significant thrombotic risk and a high degree of disability. In addition, anecdotal experience has suggested that antithrombotic therapy and intravenous immunoglobulin therapy may result in significant clinical improvement in these patients.

Network resilience in the face of health system reform.

Many health systems now use networks as governance structures. Network 'macroculture' is the complex of artefacts, espoused values and unarticulated assumptions through which network members coordinate network activities. Knowledge of how network macroculture during 2006-2008 develops is therefore of value for understanding how health networks operate, how health system reforms affect them, and how networks function (and can be used) as governance structures. To examine how quasi-market reforms impact upon health networks' macrocultures we systematically compared longitudinal case studies of these impacts across two care networks, a programme network and a user-experience network in the English NHS. We conducted interviews with key informants, focus groups, non-participant observations of meetings and analyses of key documents. We found that in these networks, artefacts adapted to health system reform faster than espoused values did, and the latter adapted faster than basic underlying assumptions. These findings contribute to knowledge by providing empirical support for theories which hold that changes in networks' core practical activity are what stimulate changes in other aspects of network macroculture. The most powerful way of using network macroculture to manage the formation and operation of health networks therefore appears to be by focusing managerial activity on the ways in which networks produce their core artefacts.