Craniocervical instability in patients with Ehlers-Danlos syndromes: outcomes analysis following occipito-cervical fusion.

Craniocervical instability (CCI) is increasingly recognized in hereditary disorders of connective tissue and in some patients following suboccipital decompression for Chiari malformation (CMI) or low-lying cerebellar tonsils (LLCT). CCI is characterized by severe headache and neck pain, cervical medullary syndrome, lower cranial nerve deficits, myelopathy, and radiological metrics, for which occipital cervical fusion (OCF) has been advocated. We conducted a retrospective analysis of patients with CCI and Ehlers-Danlos syndrome (EDS) to determine whether the surgical outcomes supported the criteria by which patients were selected for OCF. Fifty-three consecutive subjects diagnosed with EDS, who presented with severe head and neck pain, lower cranial nerve deficits, cervical medullary syndrome, myelopathy, and radiologic findings of CCI, underwent open reduction, stabilization, and OCF. Thirty-two of these patients underwent suboccipital decompression for obstruction of cerebral spinal fluid flow. Questionnaire data and clinical findings were abstracted by a research nurse. Follow-up questionnaires were administered at 5-28 months (mean 15.1). The study group demonstrated significant improvement in headache and neck pain (p < 0.001), decreased use of pain medication (p < 0.0001), and improved Karnofsky Performance Status score (p < 0.001). Statistically significant improvement was also demonstrated for nausea, syncope (p < 0.001), speech difficulties, concentration, vertigo, dizziness, numbness, arm weakness, and fatigue (p = 0.001). The mental fatigue score and orthostatic grading score were improved (p < 0.01). There was no difference in pain improvement between patients with CMI/LLCT and those without. This outcomes analysis of patients with disabling CCI in the setting of EDS demonstrated significant benefits of OCF. The results support the reasonableness of the selection criteria for OCF. We advocate for a multi-center, prospective clinical trial of OCF in this population.

Diagnostic test accuracy study of a commercially available deep learning algorithm for ischemic lesion detection on brain MRIs in suspected stroke patients from a non-comprehensive stroke center.

PURPOSE: To estimate the ability of a commercially available artificial intelligence (AI) tool to detect acute brain ischemia on Magnetic Resonance Imaging (MRI), compared to an experienced neuroradiologist. METHODS: We retrospectively included 1030 patients with brain MRI, suspected of stroke from January 6th, 2020 to 1st of April 2022, based on these criteria: Age ≥ 18 years, symptoms within four weeks before the scan. The neuroradiologist reinterpreted the MRI scans and subclassified ischemic lesions for reference. We excluded scans with interpretation difficulties due to artifacts or missing sequences. Four MRI scanner models from the same vendor were used. The first 800 patients were included consecutively, remaining enriched for less frequent lesions. The index test was a CE-approved AI tool (Apollo version 2.1.1 by Cerebriu). RESULTS: The final analysis cohort comprised 995 patients (mean age 69 years, 53 % female). A case-based analysis for detecting acute ischemic lesions showed a sensitivity of 89 % (95 % CI: 85 %-91 %) and specificity of 90 % (95 % CI: 87 %-92 %). We found no significant difference in sensitivity or specificity based on sex, age, or comorbidities. Specificity was reduced in cases with DWI artifacts. Multivariate analysis showed that increasing ischemic lesion size and fragmented lesions were independently associated with higher sensitivity, while non-acute lesion ages lowered sensitivity. CONCLUSIONS: The AI tool exhibits high sensitivity and specificity in detecting acute ischemic lesions on MRI compared to an experienced neuroradiologist. While sensitivity depends on the ischemic lesions' characteristics, specificity depends on the image quality.

A 48-YEAR-OLD CAUCASIAN MAN WITH UNILATERAL "SMUDGE" IN INFERIOR VISUAL FIELD.

PURPOSE: To report an increasingly prevalent fundoscopic manifestation of syphilitic uveitis. METHODS: Case report of a patient with acute retinal necrosis secondary to syphilis. RESULTS: A 48-year-old man presented with decreased vision, anterior segment inflammation, and a wedge-shaped retinal lesion in the superior periphery, with a diaphanous leading edge extending down toward the superior arcade. The patient was HIV+ and poorly compliant with therapy. The top three differential diagnoses were herpetic necrotizing retinitis, syphilis, and lymphoma. An extensive lab workup was positive for syphilis. The patient was treated with IV penicillin G and demonstrated improvement in visual acuity and examination. CONCLUSION: There have been an increasing number of reports of syphilis patients, especially in the population of men who have sex with men, who present with fundus findings similar to acute retinal necrosis. These findings include a characteristic ground glass, translucent appearance of unifocal or multifocal lesions, primarily affecting the inner retina and sometimes associated with co-localizing occlusive vasculitis. Treatment with IV penicillin G is warranted and has demonstrated good visual recovery.

Pentosan Polysulfate Sodium Exposure and Drug-Induced Maculopathy in Commercially Insured Patients in the United States.

PURPOSE: To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy. DESIGN: Large, multicenter, retrospective cohort study of commercially insured patients in the MarketScan database (Truven Health Analytics, San Jose, CA). PARTICIPANTS: Two hundred twenty-seven thousand three hundred twenty-five patients with IC who were enrolled continuously in the MarketScan database. METHODS: Cox proportional hazards models (controlling for patient gender, age at index diagnosis of IC, and diagnosis with diabetes mellitus) followed up patients from index diagnosis of IC for 5 years, or until patients discontinued insurance coverage, or until patients' first diagnosis with a maculopathy. As a sensitivity analysis, we re-estimate all models after excluding all patients with diabetes. To assess for dose response, we calculated the total days of PPS prescriptions filled and created a categorical variable indicating total exposure. MAIN OUTCOME MEASURES: The primary outcome measure was association between binary PPS exposure and any maculopathy. Secondary outcome measures included exposure between binary and categorical, time-dependent, exposure to PPS and to drusen, nonexudative age-related macular degeneration (AMD), exudative AMD, hereditary maculopathy, and toxic maculopathy. RESULTS: The most common diagnoses of maculopathy in patients with IC were exudative AMD (1.5%), drusen (0.8%), nonexudative AMD (0.3%), toxic maculopathy (0.1%), and hereditary dystrophy (0.04%). In unadjusted analyses, the percentage of patients who filled a PPS prescription and were diagnosed later with a maculopathy (2.37%) was very similar to the percentage of patients who did not fill a prescription (2.77%). Survival models using a binary variable indicating PPS exposure showed no significant associations between PPS exposure and diagnosis of drusen, nonexudative AMD, exudative AMD, toxic maculopathy, hereditary dystrophy, or an aggregate variable of any maculopathy. Similarly, there was no dose-dependent relationship between PPS exposure and diagnosis of any maculopathy. These findings remained stable in sensitivity analysis models that excluded patients with diabetes mellitus. CONCLUSIONS: In this large, commercial claims database analysis, no association was found between PPS exposure and subsequent diagnosis of maculopathy.

Serum-free light-chain assay: clinical utility and limitations.

In the last decade, the introduction of the serum-free light-chain (sFLC) assay has been an important advance in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The immunoassay was developed to detect free light chains in serum by using anti-FLC antibodies which specifically recognised epitopes on light chains that were 'hidden' in intact immunoglobulins. Since its introduction in 2001, there have been several publications in the English language literature discussing the clinical utility as well as analytical limitations of the sFLC assay. These studies have highlighted both positive and negative aspects of the assay particularly with regard to its sensitivity and specificity and the technical challenges that can affect its performance. The contribution and significance of the sFLC assay in the management of light-chain myeloma, primary amyloid light-chain (AL) amyloidosis and non-secretory myeloma are well recognised and will be addressed in this review. The aim of this article is to also review the published literature with a view to providing a clear understanding of its utility and limitations in the diagnosis, prognosis and monitoring of plasma dyscrasias including intact immunoglobulin multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS). The increasing interest in using this assay in other haematological conditions will also be briefly discussed.

Striking intrafamilial phenotypic variability in Aicardi-Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C.

Aicardi-Goutières syndrome (AGS) is an encephalopathy of early childhood which is most commonly inherited as an autosomal recessive trait. The disorder demonstrates significant genetic heterogeneity with causative mutations in five genes identified to date. Although most patients with AGS experience a severe neonatal or infantile presentation, poor neurodevelopmental outcome and reduced survival, clinical variability in the onset and severity of the condition is being increasingly recognized. A later presentation with a more variable effect on development, morbidity and mortality has been particularly observed in association with mutations in SAMHD1 and RNASEH2B. In contrast, the recurrent c.205C > T (p.R69W) RNASEH2C Asian founder mutation has previously only been identified in children with a severe AGS phenotype. Here, to our knowledge, we present the first report of marked phenotypic variability in siblings both harboring this founder mutation in the homozygous state. In this family, one female child had a severe AGS phenotype with an onset in infancy and profound developmental delay, whilst an older sister was of completely normal intellect with a normal head circumference and was only diagnosed because of the presence of chilblains and a mild hemiplegia. An appreciation of intrafamilial phenotypic expression is important in the counseling of families considering prenatal diagnosis, and may also be relevant to the assessment of efficacy in future clinical trials. In addition, marked phenotypic variation raises the possibility that more mildly affected patients are not currently identified.

WITHDRAWN: Humanised substitutes for animal sera in human mesenchymal stem cell culture and differentiation.

This epub Ahead of Print has been withdrawn by the Publisher.

Self-infusion programmes for immunoglobulin replacement at home: feasibility, safety and efficacy.

This review of the currently available literature from more than two decades of clinical experience with self-infusions of immunoglobulin at home provides evidence to support the feasibility, safety, and efficacy in all age groups. Self-infusions at home not only increase patient confidence and their understanding of the immune deficiency but also contribute to the improvement of health-related quality of life. Such home therapy programs should be encouraged, and wherever possible, experienced centers should extend their services to include patients who require immunoglobulin therapy for immunomodulation. Home therapy programs play an important role in long-term health outcome.

Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury.

BACKGROUND AND PURPOSE: Nortriptyline, an antidepressant, was identified as a strong inhibitor of mitochondrial permeability transition by our screening of a library of 1040 drugs. Because mitochondrial permeability transition and consequent mitochondrial dysfunction have been implicated in acute neuronal death, we proposed to investigate the possible neuroprotective effects of nortriptyline in cerebral ischemia. METHODS: The effects of nortriptyline were first studied in oxygen/glucose deprivation-induced death of primary cerebrocortical neurons, a cellular model of cerebral ischemia. Mitochondrial membrane potential, mitochondrial factor release, and caspase 3 activation were evaluated after its treatment. Nortriptyline was also studied in a mouse model, which was established by occlusion of the middle cerebral artery. The infarct volume, neurological function, and biochemical events were examined in the absence or the presence of nortriptyline. RESULTS: Nortriptyline inhibits oxygen/glucose deprivation-induced cell death, loss of mitochondrial membrane potential, downstream release of mitochondrial factors, and activation of caspase 3 in primary cerebrocortical neurons. Furthermore, it decreases infarct size and improves neurological scores after middle cerebral artery occlusion in mice. CONCLUSIONS: The ability of nortriptyline to inhibit mitochondrial factor release and caspase activation and further protect the animals correlates to its inhibitory effect on mitochondrial permeability transition in isolated mitochondria. This study indicated that nortriptyline is neuroprotective against cerebral ischemia. It also suggested mitochondrial permeability transition might be a valuable therapeutic target for acute neurodegeneration.

The mitochondrial permeability transition as a target for neuroprotection.

Mitochondria serve as checkpoints and amplifiers on cell death pathways. In the central nervous system, mitochondrial involvement seems essential for normal expression of cell death phenotypes, and interference with these pathways thus seems a reasonable approach to neuroprotection. We have been involved in examining the potential involvement of the mitochondrial permeability transition (mPT) as one of several possible mechanisms by which mitochondria may be drawn into these death cascades. This possibility, though still controversial, is supported by evidence that factors that may stimulate mPT induction are associated with some forms of cell death (e.g., in stroke) and are modulated by diseases of the central nervous system (e.g., Huntington's). Evidence of neuroprotection seen with compounds such as N -Met-Val cyclosporine also support this possibility.

Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.