Effect of an interdisciplinary inpatient program for patients with CRPS in reducing disease activity -a single center prospective cohort study.

OBJECTIVE: The aim of this study was to evaluate the benefit of inpatient treatment in reducing disease activity in patients with CRPS who have exhausted outpatient options. Furthermore, the study sought to identify patient-related outcome variables that predict a reduction in disease activity. METHODS: The primary outcome was disease severity (CRPS Severity Score, range 0-16 points)). Secondary outcomes included depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities, all of which were assessed using the Promis-29. Furthermore, pain catastrophizing, neuropathic pain, quality of life, pain self-efficacy, medication intake, and the patient's global impression of change were examined in accordance with current international agreed recommendations, assessed at discharge, three-month and six-month post-discharge. Mixed-effects models were conducted to identify baseline variables associated with CRPS severity. RESULTS: Twenty-five patients completed the program (mean age 49.28 (SD 11.23) years, 92% females, mean symptom duration 8.5 (SD 6.5) months). Results showed a significant reduction between baseline and discharge of disease activity (CSS -2.36, p < 0.0001), pain (PROMIS-29 pain -0.88, p = 0.005) and emotional function (PROMIS-29 depression -5.05, p < 0.001; fatigue -4.63, p = 0.002). Moderate evidence for a reduction between baseline and discharge could be observed for pain interference (+2.27, p = 0.05), social participation (PROMIS-29 +1.93, p = 0.05), anxiety (PROMIS-29 -3.32, p = 0.02) and physical function (PROMIS-29 +1.3, p = 0.03). On discharge, 92% of patients (23 of 25) reported improvement in their overall condition. In the follow-up period, medication intake could be reduced after 3 (MQS -8.22, p = 0.002) and 6 months (MQS -8.69, p = 0.001), and there was further improvement in social participation after 3 months (PROMIS-29 +1.72, 0.03) and sleep after 6 months (PROMIS-29 +2.38, 0.008). In the mixed models, it was demonstrated that patients experiencing less pain at baseline also exhibited lower disease activity. CONCLUSION: The results of this study confirm that inpatient interdisciplinary treatment of CRPS patients improves disease activity, pain, physical function, emotional function, and social participation. Most improvements were maintained for up six months after discharge. The majority of patients reported that their overall condition had improved during the study period.

A conformational switch controlling the toxicity of the prion protein.

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond ('H-latch'), altering the flexibility of the α2-α3 and ß2-α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.

Spinal arachnoid web-a distinct entity of focal arachnopathy with favorable long-term outcome after surgical resection: analysis of a multicenter patient population.

BACKGROUND CONTEXT: Spinal arachnoid web (SAW) is a rare condition characterized by focal thickening of the arachnoid membrane causing displacement and compression of the spinal cord with progressive symptoms and neurological deficits. Recent reports and clinical experience suggest that SAW is a distinct entity with specific radiological findings and treatment strategies distinguishable from other arachnopathies and potential differential diagnoses. PURPOSE: To better define the diagnostic and clinical features, treatment options and outcomes of surgically treated SAW. STUDY DESIGN: Multicentric retrospective cohort study. PATIENT SAMPLE: Twelve cases of SAW surgically treated at three different centers. OUTCOME MEASURES: Self-reported and neurological outcome measurements (pain, sensory-motor deficits, vegetative dysfunctions) were assessed at follow-up timepoints. METHODS: Retrospective review of prospectively collected data on all patients surgically treated for SAW from three participating neurosurgical centers between 2014 and 2020. Clinicopathological data, including neurological presentation, radiological and histological findings and outcome data were analyzed. RESULTS: Twelve radiologically and surgically confirmed cases of SAW were analyzed. Mean patient age was 54.7 [±12.7], 67% were male. All SAWs were located in the posterior thoracic dural sac. On magnetic resonance imaging (MRI), the "scalpel sign" - a characteristic focal dorsal indentation of the spinal cord resembling a scalpel blade - was identified in all patients. A focal intramedullary syrinx was present in 83%. Preoperative clinical symptoms included signs of myelopathy, pain, weakness and sensory loss, most commonly affecting the trunk/upper back or lower extremities. Laminectomy or laminoplasty with intradural excision of the SAW was the surgical treatment of choice in all cases. Intraoperative ultrasound was valuable to visualize the cerebrospinal fluid (CSF) flow obstruction, confirm the SAW location before dura incision and to control adequacy of resection. After surgery, sensory loss and weakness in particular showed significant improvement. CONCLUSIONS: The present study comprises the largest series of surgically treated SAW, underscoring the unique clinical, radiographic, histopathological, and surgical findings. We want to emphasize SAW being a distinct entity of spinal arachnopathy with a favorable long-term outcome if diagnosed correctly and treated surgically. Intraoperative ultrasound aids visualizing the SAW before dural incision, as well as verifying restored CSF flow after resection.

The prion protein is not required for peripheral nerve de- and remyelination after crush injury.

The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.

An immunocompetent farmer with isolated cerebral alveolar echinococcosis: illustrative case.

BACKGROUND: Alveolar echinococcosis is a rare condition, but living or working in a rural environment is a substantial risk factor. The liver is the organ primarily affected, with additional extrahepatic manifestations in approximately 25% of cases. Primary extrahepatic disease is rare, and isolated cerebral involvement is extremely unusual. OBSERVATIONS: The authors described an illustrative case of isolated cerebral alveolar echinococcosis in an immunocompetent farmer. Magnetic resonance imaging of the brain showed a predominantly cystic lesion with perifocal edema and a "bunch of grapes" appearance in the left frontal lobe. Histology revealed sharply demarcated fragments of a fibrous cyst wall accompanied by marked inflammation and necrosis. Higher magnification showed remnants of protoscolices with hooklets and calcified corpuscles. Immunohistochemistry and polymerase chain reaction (PCR) analysis confirmed the diagnosis of cerebral alveolar echinococcosis. Interestingly, serology and thoracic and abdominal computed tomography results were negative, indicative of an isolated primary extrahepatic manifestation. LESSONS: Isolated, primary central nervous system echinococcosis is extremely rare, with only isolated case reports. As in the authors' case, it can occur in immunocompetent patients, especially persons with a rural vocational history. Negative serology results do not exclude cerebral echinococcosis, which requires histological confirmation. Immunohistochemical staining and PCR analysis are especially useful in cases without classic morphological findings.

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice.

The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.

[Mononeuritis Multiplex: A Diagnostic Challenge]. / Mononeuritis multiplex als diagnostische Herausforderung.

Mononeuritis Multiplex: A Diagnostic Challenge Abstract. Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is a multifaceted disease. Due to the variability in vascular and organ involvement, EPGA can manifest itself very differently. We report a case of a 60-year-old patient with a known bronchial asthma, pansinusitis and newly blood eosinophilia with a rapid-onset mononeuritis multiplex. The diagnosis was confirmed based on a histological examination. After initiation of therapy the patient can walk independently with a mobility aid.

Determination of the formation rate of phosphatidylethanol by phospholipase D (PLD) in blood and test of two selective PLD inhibitors.

Phosphatidylethanol (PEth) is an alcohol biomarker formed from phosphatidylcholine (PC) by the enzyme phospholipase D (PLD) in the presence of ethanol. A drinking study revealed individual differences in maximum PEth levels after drinking to a targeted blood alcohol concentration (BAC) of 0.1%. This seemed to be due to different PLD activities in the tested persons. Furthermore, post-sampling formation of PEth occurred in blood samples, still containing alcohol. Therefore, a standardized in vitro test for measuring individual PEth formation rates was developed. Two PLD inhibitors were tested for their potency to inhibit post-sampling PEth formation. PEth-negative blood samples were collected from a volunteer. Ethanol was added in different concentrations (0.01-0.3% BAC) directly after blood sampling. The specimens were incubated at 37 °C. Aliquots were taken at the start of the incubation, and every hour until 8 h after start of incubation, and one sample was taken on subsequent days over 1 week. PEth 16:0/18:1 and PEth 16:0/18:2 were determined by online SPE-LC-MS/MS. Furthermore, this test system was applied to blood samples of 12 volunteers. For the inhibition tests, fresh blood (spiked with 0.1% ethanol) was spiked with 30, 300, 3000, or 30,000 nM of either halopemide or 5-fluoro-2-indolyl-deschlorohalopemide (FIPI), and incubated at 37 °C. PEth concentrations were determined hourly over 5 h on the first day and once on day 2 and day 3. PEth formation was linear in the first 7 h of incubation and dependent on the alcohol concentration. The formation rates of PEth 16:0/18:1 were 0.002 µmol L-1 h-1 (0.01% BAC), 0.016 µmol L-1 h-1 (0.1% BAC), 0.025 µmol L-1 h-1 (0.2% BAC), and 0.029 µmol L-1 h-1 (0.3% BAC). For PEth 16:0/18:2, the formation rates were 0.002 µmol L-1 h-1 (0.01% BAC), 0.019 µmol L-1 h-1 (0.1% BAC), 0.025 µmol L-1 h-1 (0.2% BAC), and 0.030 µmol L-1 h-1 (0.3% BAC). Maximum concentrations reached 431 ng/mL (PEth 16:0/18:1) and 496 ng/mL (PEth 16:0/18:2) at 0.3% BAC after 3 days. Maximum velocity (vmax) was not reached under these conditions. PEth formation in blood of the 12 volunteers ranged between 0.011 and 0.025 µmol L-1 h-1 for PEth 16:0/18:1 and between 0.014 and 0.021 µmol L-1 h-1 for PEth 16:0/18:2. PEth formation in human blood was inhibited by halopemide in a concentration-dependent manner. However, a complete inhibition was not achieved by the applied maximum concentration of 30,000 nM. FIPI showed a better inhibition of PEth formation. A complete inhibition could be achieved by a concentration of 30,000 nM for the first 24 h (for PEth 16:0/18:1) and for 48 h (for PEth 16:0/18:2). Formation of PEth was found to be dependent on the BAC. As a consequence, it is essential to inhibit PLD activity after blood collection to avoid post-sampling formation of PEth in blood samples with a positive BAC. Inhibition of PEth formation was more effective using FIPI, compared to halopemide.