Risdiplam for the treatment of adults with spinal muscular atrophy: Experience of the Northern Ireland neuromuscular service.

INTRODUCTION/AIMS: Risdiplam is the newest available treatment for patients with spinal muscular atrophy (SMA). There is little information on its use in adults. We present the clinical experience of adults with SMA treated with risdiplam through the Early Access to Medicines Scheme (EAMS) in Northern Ireland. METHODS: All adults with Type 2 SMA attending the regional neuromuscular clinic were offered risdiplam treatment. Patients had assessments of respiratory function, the Epworth Sleepiness Scale (ESS), Quality of Life Measure for People with Slowly Progressive and Genetic Neuromuscular Disease (QOLM), and Egen Klassifikation 2 (EK2) every 3 mo and the Revised Upper Limb Module for SMA (RULM) at baseline and 6 mo. All assessments other than the RULM were carried out virtually. RESULTS: Six of seven patients who were offered risdiplam consented to treatment through the EAMS (five female, one male, mean age 33.7 y). It was generally well tolerated other than skin photosensitivity in all patients. All patients remained on therapy at 9 mo. All reported meaningful improvements in overall strength, sense of wellbeing, and speech quality. There was no change in respiratory function, daytime hypersomnolence, or upper limb function (all p > .05). There was improvement in the QOLM (p = .027) and EK2 (p = .009). DISCUSSION: Our study raises hopes that risdiplam may be efficacious in adults; however, more systematic studies in larger cohorts are needed before drawing any definitive conclusions. This study also demonstrated the feasibility of virtual assessments.

Temporal evolution of diaphragm thickness and diaphragm excursion among subjects hospitalized with COVID-19: A prospective observational study.

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has an affinity for the angiotensin-converting enzyme 2 (ACE2) receptors, which are present abundantly on the diaphragm. This study aims to describe temporal changes in diaphragmatic thickness and excursion using ultrasonography in subjects with acute COVID-19. METHODS: This prospective observational study included adults hospitalized with COVID-19 in the past 48 hours. The diaphragm thickness at end-expiration (DTE), diaphragm thickening fraction (DTF), and diaphragm excursion during tidal breathing (DE) and maximal inspiration (DEmax) were measured using ultrasonography daily for 5 days. The changes in DTE, DTF, DE, and Demax from day 1 to day 5 were assessed. RESULTS: This study included 64 adults (62.5% male) with a mean (SD) age of 50.2 (17.5) years. A majority (91%) of the participants had mild or moderate illness. The median (IQR) DTE, DTF (%), DE and Demax on day 1 were 2.2 (1.9, 3.0) mm, 21.5% (14.2, 31.0), 19.2 (16.5, 24.0) mm, and 26.7 (22.0, 30.2) mm, respectively. On day 5, there was a significant reduction in the DTE (p=0.002) with a median (IQR) percentage change of -15.7% (-21.0, 0.0). The DTF significantly increased on day 5 with a median (IQR) percentage change of 25.0% (-19.2, 98.4), p=0.03. There was no significant change in DE and Demax from day 1 to day 5, with a median (IQR) percentage change of 3.6% (-5.2, 15) and 0% (-6.7, 5.9), respectively. CONCLUSIONS: Non-intubated patients with COVID-19 exhibited a temporal decline in diaphragm thickness with increase in thickening fraction over 5 days of hospital admission. Further research is warranted to assess the impact of COVID-19 pneumonia on diaphragmatic function.

Paediatric Aps - Children Are Not Just Small Adults

Introduction/Background: Antiphospholipid syndrome (APS) is a rare autoimmune multisystem disease characterised by thrombosis and pregnancy morbidity in the presence of persistently elevated titres of: lupus anticoagulant, anticardiolipin and/or anti-glycoprotein 1. It may be primary (occurring alone) or secondary (in combination with another disease, most commonly systemic lupus erythematosus (SLE)). Recent publications highlighted clinical criteria limitations for children and raised awareness of the burden and prevalence of non-criteria manifestations in this population. This case report adds further weight to the need to raise multi-specialty awareness of non-criteria manifestations to aid recognition and treatment of this rare condition with potentially severe sequelae. Description/Method: 13-year-old female with SLE diagnosed aged 8 in India with bilateral optic neuritis occurring two months later. ANA positive at diagnosis with low complement and thrombocytopenia. Treated with prednisolone and hydroxychloroquine. Patient moved to the UK aged 9;initial abnormal bloods: mildly positive ANA (ENA negative), thrombocytopenia, strong lupus anticoagulant. As serology not strongly suggestive and optic neuritis rare in lupus diagnosis questioned. Ophthalmology review confirmed bilateral optic atrophy without evidence of previous vasculitis. There was debate whether the postretinal demyelination was due to antiphospholipid syndrome or a primary demyelinating condition. Hydroxychloroquine stopped and azathioprine started. Following normal neurology investigations (brain, spine MRI/MRV/MRA) concluded if patient developed new APSrelated symptoms or worsening visual evoked potentials anticoagulation would be discussed. Patient remained stable over four years with chronic thrombocytopenia and ESR persistently elevated. Azathioprine changed to Mycophenolate mofetil (MMF) due to side effects. Routine medication monitoring bloods in 2022 showed ESR 97, CRP 78, Platelets 61. Review identified vasculitic rash on soles of both feet with palpable nodules and normal pulses. Further investigation confirmed antiphospholipid antibody triple positivity. Aspirin commenced, hydroxychloroquine restarted, MMF dose increased and rituximab administered. Left foot rash settled but right progressed with toe discolouration and numbness. Skin biopsy considered but not performed due to skin integrity concerns. Foot pulses remained present and normal. Bilateral lower limb doppler reported as normal;increased symptoms resulted in CT angiogram which revealed bilateral non-occlusive popliteal thrombus and left pulmonary embolus. Subsequent echocardiogram was normal. Patient was anticoagulated with low molecular weight heparin followed by warfarin. Vascular surgical team advocated medical management and patient received seven infusions of Iloprost followed by Sildenafil. She achieved near total resolution of skin changes to toes with only minimal loss of skin over tip of right great toe. Patient will now require long-termanticoagulation. Discussion/Results: APS was considered in initial differential diagnosis but patient did not meet current clinical criteria as no past evidence of thrombosis. Lupus anticoagulant was consistently strongly positive and anticardiolipin repeatedly negative. As anti-B2 glycoprotein 1 antibody is not routinely tested and must be verbally requested, it was only checked once (negative) prior to discovery of triple positivity. ANA reported as strongly positive at time of SLE diagnosis but reviewing original notes from India titre was 1:100 and therefore not highly convincing. ENA negative and complement and white cell count normal on repeat testing since. Therefore, it is probable that this patient has primary APS as opposed to secondary APS in association with SLE. However, it is possible that this patient may develop more symptoms of SLE over time. When this patient presented with foot rash there were high numbers of children presenting with varying severity of painful, itchy toes coined 'covid toes' due to suspected lin to SARS-CoV-2 infection. Patient had exposure history, and COVID antibody serology was difficult to interpret due to recent vaccination. Dermatology found appearance to be consistent with 'covid toes' and advised supportive treatment. The triple APS antibody positivity result provided probable aetiology. Providing evidence of thrombus was problematic with false reassurance from apparently normal lower limb arterial doppler when actually popliteal arteries were not checked in view of the presence of normal flow proximally at the groin and distally in the feet. This case highlights the need to continue to search for thrombus in presence of high titres antiphospholipid antibodies and particularly in the case of triple positivity as although patient presented with colour change to toes, she was entirely asymptomatic from her PE and her left foot improved spontaneously despite a left popliteal thrombus also being present. Key learning points/Conclusion: Non-criteria manifestation of thrombocytopenia (occurs in 25% paediatric APS patients) was present throughout and patient had past history of haematuria (a recognised renal non-criteria manifestation). A paediatric specific APS criteria including these may have resulted in earlier detection of triple antiphospholipid antibody positivity and thus earlier treatment escalation and possible avoidance of thrombus. It has been reported that a high proportion of children with positive antiphospholipid antibodies don't develop a thrombus. However, it is interesting that our patient was entirely asymptomatic from her pulmonary embolus which was an incidental finding on her CT angiogram. This prompts a discussion about how much imaging should be performed in those with high levels of persistent positive antiphospholipid antibodies. Rituximab resulted in normalisation of platelet count and ESR for the first time since initial presentation. Anticardiolipin antibodies normalised, lupus anticoagulant decreased from strong to moderate and anti- B2 glycoprotein levels decreased but remained positive. Rituximab is a recognised treatment for catastrophic antiphospholipid syndrome (CAPS) but not routinely used in APS. The consistently raised ESR in an apparently clinically well patient is a reminder to continue to search for causes of inflammation. As the CRP was largely in normal range, this demonstrates the unique value of the ESR. In view of anti-B2 glycoprotein 1 antibody requiring to be verbally requested, discussions are ongoing with the laboratory department regarding the possibility of electronic request and a comment with recommendation to check other two antiphospholipid antibodies following one positive antibody result. As a result of this case, a plan will be put in place to ensure annual screening of antiphospholipid antibodies in all juvenile SLE patients in our care. It is hoped that this case report promotes discussion amongst the paediatric rheumatology community regarding further research required for development of paediatric specific APS criteria and management.

Acute motor and sensory axonal neuropathy in a patient with undiagnosed mixed connective tissue disease

Case Report: Acute motor and sensory axonal neuropathy (AMSAN) syndrome is a rare subtype of Guillain-Barre syndrome (GBS) with poor recovery [1]. While respiratory and gastrointestinal infections may precipitate AMSAN, an underlying autoimmune disorder is seldom reported in literature. We herein report the complex case of a patient with undiagnosed, asymptomatic mixed connective tissue disease (MCTD) who developed AMSAN syndrome. Case: A 44-year-old Asian male without medical history presented with progressively worsening weakness of both upper and lower extremities and inability to perform daily activities. His symptoms started 12 weeks prior with difficulty standing from a seated position. He felt subjectively better for some time until a week prior, when he became bedbound. He had diarrhea 6 months ago, with 5-6 loose bowel movements a day for a few weeks. Vital signs on admission was normal. On neurological examination, he was alert and oriented, with bilateral upper and lower extremity flaccid paralysis, diffuse muscle atrophy, bilateral hand and foot drop, negative Hoover sign, diffuse areflexia, and intact sensation. Cerebrospinal fluid (CSF) analysis showed WBC 0 and protein level 136. MRI cervical, thoracic, and lumbar spine were normal. EMG revealed sensory involvement with positive sharp waves in proximal muscles along with fibrillations. Intravenous immunoglobulin (IVIG) was initiated at 0.4 mg/kg for 5 days. Infectious workup for COVID-19, stool culture, HIV, TB, RPR and campylobacter jejuni antibody (Ab), was negative. ANA was positive in a speckled pattern with titres 1:1280, with a positive RNP Ab, SS-A, and RF IgM, IgG and IgA. Rest of the autoimmune workup (anti-dsDNA, anti-CCP, SS-B, aldolase, anti-Jo-1, anti-Scl-70, p-ANCA, c-ANCA, anti-GM1, anti-GQ1b, and anti-GD1a ganglioside Ab) was negative. The myositis specific 11 Ab panel was negative. Despite IVIG therapy, he developed dysphagia, respiratory distress, with a negative inspiratory force of -0, requiring intubation. He had a tracheostomy and PEG tube placed and remains quadraplegic nearly 120 days later. Discussion(s): The authors report a unique case of a patient who became progressively weak over 3 months, leading to complete quadriplegia. Interestingly, this is more consistent with chronic inflammatory demyelinating poly-neuropathy (CIDP), as AMSAN typically develops over a short period of 2 to 4 weeks [2]. Despite having negative anti-GM1 and anti-GD1a Ab (in which positive Ab are pathognomonic but not always present in AMSAN syndrome), the patient had weakness that began in the lower extremities, progressing to paralysis, along with albuminocytological dissociation on CSF analysis, pointing to a GBS diagnosis [3]. He had sensory involvement in the EMG, thus making the diagnosis as AMSAN. He had an undiagnosed, asymptomatic autoimmune process most consistent with MCTD. Whether the two disease processes are related to each other is a concept that has not yet been investigated. Pediatric Clinical Case Reports Concurrent Session Saturday February 4, 2023 1:00 PM Copyright © 2023 Southern Society for Clinical Investigation.

An occurrence of immune-mediated necrotizing myopathy following treatment of polymyositis in a Filipino female: A case report

Background: Necrotizing myopathy has been previously described but was not included in the Peter and Bohan criteria until 2004, when immune-mediated necrotizing myopathy (IMNM) was distinguished from polymyositis (PM) based on immunologic and histopathologic differences. IMNM is currently a well-recognized autoimmune myopathy and represents up to 20% of these cases. Case: A 60-year- old female with biopsy-proven PM achieved sustained clinical remission with Rituximab. Her co-morbid conditions include hypertension, diabetes mellitus, and dyslipidemia. The patient noted a recurrence of gradual progressive, proximal muscle weakness and easy fatigability after receiving her first mRNA Covid-19 vaccine. Four months after onset of symptoms, CK Total was 9600 U/L. Rituximab was administered and muscle weakness and total CK levels (1247 U/L) improved within 10 days. She was prescribed rosuvastatin and fenofibrate for dyslipidemia within 7 days of completing the rituximab course. Two weeks later, proximal muscle weakness recurred. She became wheelchair-bound and experienced dysphonia. MMT score was 2/5 in proximal muscles and total CK total increased to 19,935 U/L. The patient received Methylprednisolone 500 mg IV once a day for 3 days. She had a good response with resolution of dysphonia and improvement of MMT to 4/5 on shoulder abduction and hip flexion on the 6th hospital day. She was discharged on oral methylprednisolone at 1 mg/kg/day. Muscle biopsy was consistent with an immune-mediated necrotizing myopathy, revealing necrotic fibers, intracellular macrophages, fatty infiltrates, irregular staining patterns on NADH stain with no evidence of endomysial inflammation, perifascicular atrophy, ragged red fibers, or rimmed vacuoles. Antibodiy against 3-hydoxy- 3- methylglutarylcoenzymeA reductase (HMGCR) result is pending but the other myositis-specific antibodies are negative.(including anti-SRP). Conclusion(s): IMNM is an autoimmune myopathy associated with anti-HMGCR and anti-SRP antibodies that clinically present similarly to polymyositis. The temporal occurrence of worsening muscle weakness with initiation of statin therapy make statin toxic myopathy or immune mediated necrotizing myopathy as diagnostic considerations. This case emphasizes the need to re-evaluate the etiology of new onset muscle weakness in patients with idiopathic inflammatory myopathy and highlights the role of myositis-specific antibodies and muscle biopsy in confirming the diagnosis.

Steroids - Exploitation

Corticosteroids, more specifically glucocorticoids are one of the most prescribed drugs. Corticosteroids are adrenal hormones that serve significant physiologic activities such as modulating glucose metabolism, protein catabolism, calcium metabolism, bone turnover control, immunosuppression, and down-regulation of inflammatory cascade. Corticosteroids are regarded life-saving due to their various effects and have been used therapeutically to treat broad range of auto-immune, rheumatologic, inflammatory, neoplastic, and viral illnesses.However, the therapeutic benefits of glucocorticoids are restricted by the adverse effects. The most serious side effects of corticosteroids are associated with the use of higher doses for longer periods and OTC availability in specific pharmacies, which leads to dependency, as well as its usage in mild and moderate server instances, which is contrary to guidelines. In the recent times the use of corticosteroids has been multiplied with the emergence of the Covid -19 pandemic. WHO and the standard guidelines has recommended the usage of corticosteroids in critically ill covid-19 patients but their usage in mild and moderate cases caused more harm than benefit. This illicit usage has resulted in the development of opportunistic fungal illnesses such as mucormycosis, posing an extra risk to patients in terms of quality of life and finances. Other adverse effects of systemic corticosteroids include morphological changes, increased blood sugar levels, delayed wound healing, infections, decreased bone density, truncal obesity, cataracts, glaucoma, blood pressure abnormalities, and muscle fibre atrophy.In this review we want to discuss the significance and detrimental effects of corticosteroids emphasizing on the recent times i.e., COVID-19.

A paralysis poser: a growing COVID concern

Purpose of Study: Report a rare case of onset of seronegative, juvenile dermatomyositis likely potentiated by Covid-19 infection Methods Used: Case analysis and literature research Summary of Results: A 7 year-old previously healthy male presented with 3 weeks of progressive, bilateral upper and lower extremity weakness, difficulty swallowing, voice changes, periorbital edema, and rash. Recent history was notable for diagnoses of COVID-19 one month prior to presentation and streptococcal pharyngitis 2 months prior to presentation. Notably, there is a family history of systemic lupus erythematosus. On examination, the patient demonstrated bilateral periorbital swelling with purple discoloration of the upper eyelids, a violaceous, pruritic, macular rash on his upper extremities and on his abdomen. Musculoskeletal exam was significant for severe axial (strength 2/5) and proximal (strength 3/5) muscleweakness with notable inability to sit unsupported or maintain head control. His neurologic exam was nonfocal;however, diffuse hyporeflexia in both upper and lower extremities were elicited. Initial screening labs were notable for mild transaminitis;positive ANA (1:80 in speckled pattern), negative ANCA, negative dsDNA/Anti- Sm, elevated aldolase of 10.3, CK 464, and LDH 665;normal thyroid studies and normal inflammatory markers. MRI with and without contrast of the spine indicated diffuse myositis of all muscle groups. Due to concern for autoimmune mediated myositis, Rheumatology was involved early in the patient's course. Empiric treatment was initiated early in the patient's presentation with IVIG, steroids, methotrexate, and plaquenil leading to gradual improvement in symptoms. Subsequent muscle biopsy was consistent with juvenile dermatomyositis (JDM). Conclusion(s): JDM is rare, occurring in 1 to 15 per million children. It classically presents with proximal myopathy and dermatologic findings of Gattron's papules, a heliotrope and malar rash. Its pathophysiology is not yet well defined but is thought to be a humoral mediated autoimmune disease. Muscle biopsies characteristically show perifascicular and perivascular infiltration. Early diagnosis and treatment with steroids, immune modulators, and physical therapy is critical to limit muscle atrophy. Viral infections are known triggers of rheumatologic diseases broadly;however, the more pronounced type 1 interferon response associated with COVID-19, which is known to be a driving pathway of JDM, may be a risk factor for severe, recalcitrant disease. Future research is needed to better identify involved pathophysiology and target future treatment efforts. Additionally, more education and case reports could focus on dermatologic presentations of individuals with pigmented skin. Copyright © 2023 Southern Society for Clinical Investigation.

Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2.

BACKGROUNDS: The efficacy of nusinersen and its evaluation in patients with spinal muscular atrophy (SMA) has been established in clinical trials only for pediatric patients, not for adolescent and adult patients who developed SMA in infancy or early childhood. We report a long-term follow-up in adolescent and adult patients with SMA types 1 and 2. METHODS: Nusinersen-treated patients with SMA types 1 and 2 between 2017 and 2022 were retrospectively reviewed. We compared baseline motor function tests with those after the final treatment. Physical and occupational therapists performed Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE), and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4; HFSME, 3; and RULM, 2. RESULTS: Seven patients with SMA (type 1, 1; type 2, 6) with a median age of 23 (range, 12-40)years were treated with nusinersen for 3.55 (1.78-4.53)years. Improvement was detected in CHOP-INTEND (pre, 5 [0-31]; post, 21 [0-39]; difference, 5 [0-26]; p = 0.100) without significance, although not in HFMSE (pre, 0 [0-3]; post, 0 [0-5]; difference, 0 [0-2]; p = 0.346) and RULM (pre, 1 [0-20]; post, 3 [0-21]; difference, 1 [0-2]; p = 0.089). Owing to prolonged treatment intervals with the COVID-19 pandemic, RULM worsened in two patients. CONCLUSION: Nusinersen was effective in long-term follow-up. Only CHOP-INTEND showed meaningful improvement. The interval between doses of nusinersen should not be prolonged even with the COVID-19 pandemic.

The Treatment of Postural Orthostatic Tachycardia Syndrome, Post-Covid-19 Using Aerobic and Resistance Training

BACKGROUND AND PURPOSE: Twenty-five to 50% of individuals who contract COVID-19 develop postural orthostatic tachycardia syndrome (POTS).3 The underlying etiology remains undetermined, yet there is research to support several root causes. Mechanisms such as dysautonomia, hypovolemia and prolonged bed rest leading to cardiac atrophy provide some indications.2,3,4 Recent research suggests that a structured and supervised training program that includes both aerobic and resistance components, was found to improve oxygen uptake, increase cardiac size, and increase blood volume.1,5 The purpose of this case study is to describe the successful treatment of a 13-year-old female diagnosed with POTS following COVID-19 using aerobic and resistance training. CASE DESCRIPTION: A 13-year-old female student who was being treated for hypermobility, contracted COVID-19 during her plan of care. During this time, she developed symptoms of lightheadedness, headaches, fainting episodes, dizziness and heart palpitations. Her rheumatologist performed an active head up tilt test that was negative for orthostatic hypotension but positive for tachycardia, which indicated a diagnosis of POTS. She was prescribed fluidicortisone with a dose of 1mg twice per day and returned to physical therapy. The interventions included 40 minutes of zone 2 aerobic training with a heart rate range of 151 to 171 beats per minute (BPM) on a recumbent bike and 20 minutes of resistance training of the lower extremities at rate of perceived exertion (RPE) of 7 to 8. The intensity of the aerobic training progressed to zone 3 and greater aerobic training with a heart rate of at least 171 BPM when the resting heart rate was stabilized. OUTCOME(S): The patient completed 26 visits over 4 months. Following the completion of the program, the resting heart rate of the patient returned to 76 BPM from a starting rate of 127 BPM. Heart rate response to exercise was congruent with the subjective RPE reported by the patient without any reoccurring symptoms previously experienced. An active head up tilt test was performed in the clinic without a tachycardic response indicating she was no longer positive for POTS. The patient was able to resume her previous extracurricular activities, including soccer, without symptom provocation. DISCUSSION: The physiological rationale supporting this conclusion consists of a decreased compensatory tachycardic response to upright positions, improved oxygen uptake, increased blood volume and increased cardiac size. Although there was a successful outcome to this case, there are some limitations. Psychological components should be monitored as well as a greater importance of RPE due to due to the inability to accurately detect heart intensity in the diagnosis of POTS.4,1.

An unusual recurrent case of Cryptococcal sacroilitis in an immunocompetent elderly female in Rajasthan, India

Background: Cryptococcus lives in the environment all over the globe. Although it spreads via inhalation route still most of the exposed individuals never get sick as the majority of cases are seen in immunocompromised. Objective of this clinical case report is to highlight the rare fungal etiology associated with iliac bone abscess to avoid incorrect diagnosis and prompt management of case. Case Presentation: A 70-year-old elderly female presented with hip pain for a month duration, not relieved with analgesics in September, 2021. In MRI a well-defined irregularly marginated hyperintense focal lesion was found in left iliac bone with joint effusion suggestive of infective etiology, tubercular, or less likely metastasis. CT-guided biopsy reported occasional hyphae-like fragments giving an impression of acute on chronic osteomyelitis with suspicion of fungalinfection.Culture reported Cryptococcus ne oformans.Fungal markers and Beta-dglucan were indeterminate and Galactomannan was found negative for the sample. Extrapulmonary TB was ruled out by AFB staining, MGIT Culture, and GeneXpert MTB. Bone scan, tumor markers, and PET scan ruled out osteolytic lesion secondary to metastasis. Though PET Scan and HRCT thorax confirm pulmonary involvement giving a picture of bilateral interstitial lung disease along with multiple enlarged lymph nodes. Patient serum was found negative for HIV, HBV, and HCV. Liver and renal function tests were within normal range and in hematology, ESR was raised (50;normal range:0-20). Patient is hypertensive with HbA1c of 5.3. There was no history of travel, avian exposure, weight loss, and COVID-19 infection. Patient was started on voriconazole and considering generalized lymphadenopathy, a therapeutic trial of anti-tubercular therapy was started which was stopped within a week on patient non-compliance. Abscess resolved with voriconazole and patient was discharged. In February 2022, Patient presented with similar complaints. CT scan of this fluctuant nodule depicted hypoechoic lesion which was ultrasound-guided drained.Sections show many rounds of oval fungal organism which were found PASpositive with mucicarmine and alcian blue positive capsule.Budding yeast cells were seen on KOH mount and India ink preparation demon-strated capsule which was confirmed by Cryptococcal Antigen test giving an overall impression in favor of Cryptococcosis. Patient was started on oral fluconazole and Injection liposomal amphotericin B 250 mg for 14 days. Discussion and Conclusion(s): This is the first case of skeletal Cryptococcosis at our institution which was managed by antifungals without surgical debridement resulting in resolution of abscess. Isolated focal iliac bone cryptococcosis is unusual but may occur in immunocompetent with everyday exposure to the organism. Herein, Patient had bilateral lung involvement along with multiple lymphadenopathies with no evidence of TB bacilli which inferences that the isolate most likely originated from environmental bird droppings and has disseminated from pulmonary lesion to the iliac bone. The radiological findings of iliac cryptococcosis abscess were nonspecific.A definitive diagnosis was made on histopathological and fungal examinations of ultrasound-guided drained abscess. Patient will be followed in the near future for relapse or any other medical issues related to the case.

Effects of COVID-19 on Synaptic and Neuronal Degeneration.

Neurons are the basic building blocks of the human body's neurological system. Atrophy is defined by the disintegration of the connections between cells that enable them to communicate. Peripheral neuropathy and demyelinating disorders, as well as cerebrovascular illnesses and central nervous system (CNS) inflammatory diseases, have all been linked to brain damage, including Parkinson's disease (PD). It turns out that these diseases have a direct impact on brain atrophy. However, it may take some time after the onset of one of these diseases for this atrophy to be clearly diagnosed. With the emergence of the Coronavirus disease 2019 (COVID-19) pandemic, there were several clinical observations of COVID-19 patients. Among those observations is that the virus can cause any of the diseases that can lead to brain atrophy. Here we shed light on the research that tracked the relationship of these diseases to the COVID-19 virus. The importance of this review is that it is the first to link the relationship between the Coronavirus and diseases that cause brain atrophy. It also indicates the indirect role of the virus in dystrophy.

Stress during the COVID-19 pandemic - impact on neuroplasticity

Introduction: The world's population has been exposed to traumatic events and high levels of stress due to the ongoing COVID-19 outbreak. Stress is known currently as a universal experience, but the concept was first defined in 1936 by Hans Selye. It has been shown that stress is associated with impairments in neuroplasticity (e.g. neuronal atrophy and synaptic loss in the hippocampus, prefrontal cortex) and has a crucial role in almost all mental disorders. Objective(s): In this paper we aim to highlight the recent theoretical and experimental advances in neuroscience regarding stress induced neuroplasticity. Method(s): We analyzed scientific literature written in English and published between 2019-2021. We used the electronic portal PubMed-NCBI. Result(s): In the last few years, molecular and cellular studies on animal models of stress related and stress-induced psychopathologies revealed alterations in gene expression, micro ARNs expression, as well as in intracellular signaling pathways that mediate the stress induced adaptations. These findings have led to new theories regarding depression and anxiety in the molecular neurobiology field. It has been shown that stress reduces BDNF expression inducing neuronal atrophy in various brain areas. Contrastingly, other studies have demonstrated that chronic antidepressant treatment increases BDNF expression. Furthermore, a crucial role has been assigned to miRNAs in the development of chronic stressinduced depression-like behavior and neuroplasticity. Conclusion(s): We hope that this paper will increase interest in the field of stress induced cellular and molecular changes. More research needs to be pursued in order to achieve a deeper understanding of the pathophysiology of stress-induced mental disorders.

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy.

INTRODUCTION: Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. METHODS: Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline. RESULTS: Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection. CONCLUSIONS: Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

A Rare Case of IgG4-Related Kidney Disease With a Rapid Growing Renal Tumor After COVID-19 Vaccination

Introduction: IgG4-related diseases (IgG4-RD) are characterized by organomegaly, high IgG4 level and marked infiltration of IgG4(+) cells in the affected organs, with renal involvement in approximately 25% of cases. The coexistence of AAV with IgG4-RD has been reported in some case, while ANCA-associated vasculitis (AAV) is often associated with autoimmune diseases. There have also been some reports of new renal lesions caused by the COVID19 vaccine, such as minimal change disease, IgA nephropathy, and vasculitis, but there are still no reports of new-onset IgG4-RD. Case Description: A 61-year-old man developed fever, malaise, thirst and polydipsia the day after a second vaccination of COVID19 (mRNA-12733, Moderna). Blood test showed kidney dysfunction, high IgG4 level, and MPO-ANCA positivity. Brain MRI showed enlargement of pituitary gland. Salivary gland scintigraphy showed secretory impairment in the submandibular and parotid glands. CT scan revealed a rapid growing left renal tumor and CT-guided needle biopsy was performed. Renal specimens showed diffuse infiltrates of CD138(+) plasma cells in the interstitium. More than 40% of IgG(+) cells were IgG4-positive, accompanied by interstitial fibrosis with a "striform" pattern. Focal necrotic and granulomatous lesions were detected with tubular atrophy and tubulitis. Bowman's capsules were disrupted by massive interstitial inflammation in some glomeruli, but no obvious proliferative lesions. Finally, he was diagnosed as IgG4-RD and steroid therapy was started. Desmopressin was administered for central enuresis. The systemic symptoms were improved gradually and the renal tumor was reduced. Discussion(s): In this case, it is suggested that immunological changes caused by the vaccine or allergic reaction to the vaccine may trigger the onset of the disease. Elevated MPO-ANCA titer and tubulointerstitial nephritis with necrotic and granulomatous lesions may have been associated with AAV. However, the patient had renal tumor with characteristic pathological findings of IgG4-RD, accompanied by hypophysitis and sialadenitis. We concluded that the main condition in our case is IgG4-RD. IgG4-related kidney disease after COVID-19 vaccination is extremely rare. Careful monitoring after the COVID19 vaccine is important with immunological abnormalities.

Probenecid-Induced IgA Nephropathy Is Reversible

Introduction: IgA nephropathy is usually idiopathic in nature but can have a genetic predisposition & it can also be secondary to autoimmune diseases, vasculitis, infections, liver disease, or anti-VEGFdrugs like bevacizumab, & covid vaccine. We present a case of probenecid-induced IgA nephropathy. Case Description: A 65-year-old male with chronic gout developed progressive chronic kidney disease over a 3-year period. He had been on probenecid 1 g twice daily for his gout for 15 yrs. His sodium iothalamate clearance deteriorated to 58 mL/min, with a serum creatinine of 1.5 mg/dL. All other serologic tests were negative. His 72-hour lead level was also normal. He did not have SLE, granulomatous disease, or systemic rheumatic disorders. Suprisingly he did not have proteinuria or hematuria. Renal biopsy revealed IgA nephropathy, with segmental mesangial hypercellularity, mild arterial sclerosis, & tubular atrophy. Cytoplasmic lipofuscin pigment was noted on PAS stain capillary loops with focal thickening of the glomerular basement membrane, engorged capillary loops, & thickened tubular basement membrane. Immunofluorescence studies showed diffuse segmental paramesangial granules of IgA [3+] & fibrinogen as well as paramesangial granules of IgG [2+], Kappa & lambda. Electron microscopy showed swollen podocytes with increased cytoplasmic organelles and vacuolization, focal foot process effacement, & electron-dense deposits in the paramesangium & mesangium. His MEST score was zero. 6 months after discontinuation of probenecid, the patient's iothalamate GFR significantly improved to 79 mL/min, followed by 82 mL/min 6 months later. He never had proteinuria, hematuria, or casts throughout his disease course. Five years later his GFR was 88 ml/min with a serum creatinine of 1.1 mg/dl. Discussion(s): Probenecid has pleiotropic effects on the human immune system. It inhibits Pannexin-1 channels which are known to modulate T-cell function. Probenecid also regulates TRPV -2 channels as an agonist. These channels are also present on human immune B and T cell lymphocytes. Probenecid inhibits VEGF in retinal endothelial cells, & bevacizumab, an anti-VEGF monoclonal antibody, has been shown to cause IgA nephropathy. We conclude that probenecid can be a cause of IgA nephropathy which is reversible upon drug discontinuation.

Guillain-Barre Syndrome and Parsonage-Turner Syndrome Following COVID-19 Viral Vector Vaccination

Case Diagnosis: Patient is a 63-year-old male with Guillain-Barre Syndrome and Parsonage-Turner Syndrome following COVID-19 Vaccination Case Description or Program Description: Eight days after receiving a viral vector COVID-19 vaccination, the patient developed low back and left thigh pain with severe right shoulder pain developing the following day. He denied recent viral illnesses, gastrointestinal symptoms, or prior right shoulder pain. Pain, weakness, and sensory changes gradually involved all four extremities. He was hospitalized and Guillain-Barre Syndrome (GBS) was confirmed by lumbar puncture. He tested negative for Campylobacter jejuni. Cervical and lumbar spine MRIs showed mild degenerative changes without stenosis or neuroforaminal impingement. Right shoulder MRI showed no abnormality. He responded to a 5-day course of IVIG. His extremity pain gradually resolved but right shoulder weakness remained. Electrodiagnostic testing six months after symptom onset showed evidence of GBS in recovery. Right shoulder girdle muscles were not tested during the first EMG. After stays at an LTAC and SNF, the patient was admitted to IPR. While at IPR, he reported debilitating right shoulder weakness and limited ROM. On exam, significant atrophy of the right deltoid, infraspinatus, and supraspinatus muscles was observed. A repeat electrodiagnostic study showed evidence of a right Parsonage-Turner syndrome (PTS) in addition to the GBS in recovery. Setting(s): Inpatient Rehabilitation (IPR) Assessment/Results: Patient's presentation and EMG findings pointed to a concurrent occurrence of PTS and GBS after his COVID-19 vaccination. A right shoulder ultrasound-guided glenohumeral joint corticosteroid injection improved his shoulder ROM. The patient was discharged home with outpatient therapy after four weeks of IPR. Discussion (relevance): Rare instances of GBS and Parsonage-Turner Syndrome have been reported after a COVID-19 vaccination. This appears to be the first reported case where GBS and PTS have both occurred in a patient soon after receiving a COVID-19 vaccination. Conclusion(s): Concurrent PTS and GBS can develop after COVID-19 vaccine administration.

Parsonage-Turner Syndrome Resulting in Spinal Accessory Nerve Lesion After COVID-19 Vaccine: A Case Report

Case Diagnosis: A patient presenting with right shoulder pain and weakness after COVID-19 vaccination is found to have Parsonage-Turner syndrome (PTS) of the spinal accessory nerve. Case Description or Program Description: An 18-year-old male patient with no significant medical history presented to the Physiatry clinic for evaluation of right shoulder pain and protrusion of his right scapula. He denied any trauma or known inciting events. He received his two doses of the COVID-19 vaccine on the contralateral deltoid one month and one week prior. Two days after the 2nd dose, he woke up with 8/10 pain in his right shoulder and displayed right scapular protrusion. He also had self-limiting chills and myalgia. His pain improved, but the scapular protrusion persisted. On examination, there was right trapezius atrophy, right scapula lateral winging, and dyskinesis of right scapulothoracic motion. Right shoulder shrug strength was 4/5, but upper extremity strength otherwise remained 5/5 bilaterally. Electrodiagnostic studies approximately 1 month after symptom onset revealed an acute spinal accessory nerve lesion with ongoing denervation potentials in the superior portion of the mid trapezius muscle. Setting(s): Outpatient Physiatry clinic in Northeast health system. Assessment/Results: The patient's clinical presentation, history, and electrodiagnostic findings were consistent with Parsonage-Turner syndrome of the right spinal accessory nerve. One month after onset, his pain resolved, but he had residual right shoulder shrug weakness and right trapezius atrophy. He had not yet started physical therapy at the time of follow-up. Discussion (relevance): This is the first reported case, to our knowledge, of Parsonage-Turner syndrome resulting in spinal accessory nerve palsy from COVID- 19 vaccination. Conclusion(s): While the risk of complications, such as Parsonage-Turner syndrome, remains rare with COVID-19 vaccination, it is important to be mindful of vaccination history in patients with unexplained neurological injuries. However, data continues to show that the risk of complications of COVID-19 infection greatly exceed those of the vaccine.

Two Case Reports of Cytomegalovirus Induced Collapsing Focal Segmental Glomerulosclerosis in Immunocompetent Hosts

Introduction: Collapsing focal segmental glomerulosclerosis (cFSGS) refers to a distinct pattern of glomerulopathy characterized by a glomerular capillary collapse in a segmental global manner, podocyte proliferation, and tubulointerstitial injury. Viral infections like HIV, Parvovirus B19, and CMV seem to be prominent triggers for the development of a conventional histological pattern of FSGS. CMV-associated renal disease has been described only in transplant and immunocompromised patients. Case Description: Case 1 18-year-old female with history of asthma and HbSS disease presented with fever, nausea, vomiting, and neck pain Physical examination revealed a temperature of 102 F, icterus, negative meningeal signs, no rales, rhonchi or wheezing. Initial creatinine 0.2 mg/dL. COVID-19 PCR was negative but IgG antibodies positive. Patient developed non-oliguric AKI with fluid overload requiring hemodialysis. CMV IgM and CMV PCR were positive. She recieved antibiotic therapy and also ganciclovir. Biopsy revealed collapsing FSGS with acute tubular injury. A week after completion of ganciclovir therapy creatinine returned to baseline of 1.7 mg/dL. Case 2 40-year-old African American male with history of diabetes and asthma presented with fever, fatigue, epigastric pain and chest pain. Initial creatinine 1.2 mg/dl, hepatic function (AST 333 U/L, ALT 265 U/L, ALK 207 U/L), ferritin (13682 ng/ml), triglycerides (276 mg/dl) and proteinuria (urine protein /creatinine ratio: 2, urine albumin/creatinine:1016 mg/gm). Patient developed anuric renal failure which required hemodialysis. Biopsy revealed collapsing FSGS with diffuse podocyte effacement, moderate tubular atrophy, and interstitial fibrosis. CMV DNA antibodies were positive. Methylprednisolone and valganciclovir were started with patient creatinine trending down to 3.7 mg/dL. Three weeks following discharge, creatinine levels were 1.5 mg/dL with decreased proteinuria. Discussion(s): Collapsing FSGS in immunocompetent patients is uncommon. Reports mention benefits of ganciclovir and steroid therapy for CMV infection in immunocompromised patients. CMV infection should be considered in patients with systemic inflammatory disease and severe renal failure, as early treatment with steroids and antivirals helps preserve renal function.

Clinical application of prion-like seeding in α-synucleinopathies: Early and non-invasive diagnosis and therapeutic development.

The accumulation and deposition of misfolded α-synuclein (α-Syn) aggregates in the brain is the central event in the pathogenesis of α-synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. Currently, the diagnosis of these diseases mainly relies on the recognition of advanced clinical manifestations. Differential diagnosis among the various α-synucleinopathies subtypes remains challenging. Misfolded α-Syn can template its native counterpart into the same misfolded one within or between cells, behaving as a prion-like seeding. Protein-misfolding cyclic amplification and real-time quaking-induced conversion are ultrasensitive protein amplification assays initially used for the detection of prion diseases. Both assays showed high sensitivity and specificity in detection of α-synucleinopathies even in the pre-clinical stage recently. Herein, we collectively reviewed the prion-like properties of α-Syn and critically assessed the detection techniques of α-Syn-seeding activity. The progress of test tissues, which tend to be less invasive, is presented, particularly nasal swab, which is now widely known owing to the global fight against coronavirus disease 2019. We highlight the clinical application of α-Syn seeding in early and non-invasive diagnosis. Moreover, some promising therapeutic perspectives and clinical trials targeting α-Syn-seeding mechanisms are presented.