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Brain Edema Formation and Functional Outcome After Surgical Decompression in Murine Closed Head Injury Are Modulated by Acetazolamide Administration.

ABSTRACT: Acetazolamide (ACZ), carbonic anhydrase inhibitor, has been successfully applied in several neurosurgical conditions for diagnostic or therapeutic purposes. Furthermore, neuroprotective and anti-edematous properties of ACZ have been postulated. However, its use in traumatic brain injury (TBI) is limited, since ACZ-caused vasodilatation according to the Monro-Kellie doctrine may lead to increased intracranial blood volume / raise of intracranial pressure. We hypothesized that these negative effects of ACZ will be reduced or prevented, if the drug is administered after already performed decompression. To test this hypothesis, we used a mouse model of closed head injury (CHI) and decompressive craniectomy (DC). Mice were assigned into following experimental groups: sham, DC, CHI, CHI+ACZ, CHI+DC, and CHI+DC+ACZ (n = 8 each group). 1d and 3d post injury, the neurological function was assessed according to Neurological Severity Score (NSS) and Beam Balance Score (BBS). At the same time points, brain edema was quantified by MRI investigations. Functional impairment and edema volume were compared between groups and over time. Among the animals without skull decompression, the group additionally treated with acetazolamide demonstrated the most severe functional impairment. This pattern was reversed among the mice with decompressive craniectomy: CHI+DC treated but not CHI+DC+ACZ treated animals showed a significant neurological deficit. Accordingly, radiological assessment revealed most severe edema formation in the CHI+DC group while in CHI+DC+ACZ animals, volume of brain edema did not differ from DC-only animals. In our CHI model, the response to acetazolamide treatment varies between animals with decompressive craniectomy and those without surgical treatment. Opening the cranial vault potentially creates an opportunity for acetazolamide to exert its beneficial effects while vasodilatation-related risks are attenuated. Therefore, we recommend further exploration of this potentially beneficial drug in translational research projects.

SUBMITTER: Szczygielski J

PROVIDER: S-EPMC6443632 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Brain Edema Formation and Functional Outcome After Surgical Decompression in Murine Closed Head Injury Are Modulated by Acetazolamide Administration.

Szczygielski Jacek J Hubertus Vanessa V Kruchten Eduard E Müller Andreas A Albrecht Lisa Franziska LF Mautes Angelika E AE Schwerdtfeger Karsten K Oertel Joachim J

Frontiers in neurology 20190326

Acetazolamide (ACZ), carbonic anhydrase inhibitor, has been successfully applied in several neurosurgical conditions for diagnostic or therapeutic purposes. Furthermore, neuroprotective and anti-edematous properties of ACZ have been postulated. However, its use in traumatic brain injury (TBI) is limited, since ACZ-caused vasodilatation according to the Monro-Kellie doctrine may lead to increased intracranial blood volume / raise of intracranial pressure. We hypothesized that these negative effec ...[more]

PMID: 30972006

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Project description:BackgroundJuvenile X-linked retinoschisis (RS1, OMIM: 312700) is a hereditary vitreoretinal dystrophy characterized by bilateral foveal schisis and, in half of the patients, splitting through the nerve fiber layer in the peripheral retina. In the first decade of life, patients usually develop a decrease in visual acuity. Long-term visual outcomes can be poor due to the limited number of known successful treatments.PurposeThe purposes of this study were to present, for the first time, a p.Arg197Cys missense mutation in the RS1 gene (OMIM: 300839) in a four-generation Italian family with RS1 and to examine the clinical response to the treatment with acetazolamide tablets alone or in combination with dorzolamide eye drops as assessed by spectral-domain optical coherence tomography (SD-OCT).MethodsEleven individuals, including two brothers with RS1 (patients 1 and 2), underwent a full medical history examination and a comprehensive ocular assessment that involved SD-OCT, fluorescein angiography, electroretinography and DNA analysis. Each RS1 patient received oral acetazolamide (375 mg daily) during the first three months. Thereafter, patient 1 continued only with dorzolamide eyedrops three times a day for a period of three months, while patient 2 spontaneously stopped both medications.ResultsSequence analysis of the RS1 gene identified a hemizygous c.589C>T (p.Arg197Cys) missense mutation in exon 6, which has not been previously reported in an Italian family. A different response to the medical therapy was observed in the four eyes of the two affected brothers hemizygous for this abnormality. Of note, after acetazolamide interruption, a rebound effect on cystoid macular edema reduced the beneficial effects of the initial therapy for RS1 from p.Arg197Cys mutation. Indeed, a minimal rebound effect on cystoid macular edema, and an improvement in visual acuity, was observed in patient 1 during the six months of treatment. Conversely, in patient 2, an initial improvement in cystoid macular edema was not associated with visual acuity changes, followed by a marked rebound effect.ConclusionThis study showed that the sequential use of acetazolamide tablets and dorzolamide eye drops should be considered and studied further as a possible treatment for macular edema and visual impairment in patients with RS1 from a hemizygous p.Arg197Cys mutation.

Project description:For primary open angle glaucoma (POAG), laser treatment or surgery is used when the target intraocular pressure (IOP) cannot be achieved by pharmacological agents, such as prostaglandin (PG) analogs; these drugs also have varied effects. We retrospectively reviewed the medical records of 74 POAG patients (74 eyes) whose IOP was inadequately controlled by PG analogs (bimatoprost [13 eyes], latanoprost [34 eyes], tafluprost [11 eyes], and travoprost [16 eyes]) and underwent primary trabeculectomy. The proportion of patients with no recurrent IOP elevation within 24 months post-trabeculectomy was significantly (P < 0.001) lower in the bimatoprost group (31.3%) than in the latanoprost (83.2%), tafluprost (45.5%), or travoprost groups (65.6%). Deepening of the upper eyelid sulcus (DUES) was observed before trabeculectomy in 18 of 74 eyes (24.3%) treated with bimatoprost (9 eyes; 50.0%), latanoprost (3 eyes; 16.7%), tafluprost (1 eye; 5.5%) and travoprost (5 eyes; 27.8%). The proportion of patients with no recurrent IOP elevation up to 24 months post-trabeculectomy was significantly (P < 0.0001) lower in the DUES(+) group (34.7%) than in the DUES(-) group (74.3%). Multivariate stepwise logistic regression analysis, with no recurrent IOP elevation used as dependent variable, and bimatoprost, latanoprost, travoprost, tafluprost, β-blocker, carbonic anhydrase inhibitor, brimonidine, gender, age, preoperative IOP, mean deviation, duration of PG analog use before surgery, and the number of ophthalmic solutions used as independent variables, identified only bimatoprost as a significant independent factor (P = 0.0368). Thus, the outcome of trabeculectomy varied depending on the PG analog used preoperatively, and bimatoprost use was associated with a high risk of recurrent IOP elevation up to 2 years post-trabeculectomy. This may indicate that the incidence of DUES differed with the PG analog used. Patients with glaucoma who are treated with bimatoprost should be monitored for DUES, and when these patients undergo trabeculectomy, the postoperative course of IOP should be followed carefully.

Project description:ImportanceThe optimal clinical management of central cord syndrome (CCS) remains unclear; yet this is becoming an increasingly relevant public health problem in the face of an aging population.ObjectiveTo provide a head-to-head comparison of the neurologic and functional outcomes of early (<24 hours) vs late (≥24 hours) surgical decompression for CCS.Design, setting, and participantsPatients who underwent surgery for CCS (lower extremity motor score [LEMS] - upper extremity motor score [UEMS] ≥ 5) were included in this propensity score-matched cohort study. Data were collected from December 1991 to March 2017, and the analysis was performed from March 2020 to January 2021. This study identified patients with CCS from 3 international multicenter studies with data on the timing of surgical decompression in spinal cord injury. Participants were included if they had a documented baseline neurologic examination performed within 14 days of injury. Participants were eligible if they underwent surgical decompression for CCS.ExposuresEarly surgery was compared with late surgery.Main outcomes and measuresPropensity scores were calculated as the probability of undergoing early compared with late surgery using the logit method and adjusting for relevant confounders. Propensity score matching was performed in a 1:1 ratio by an optimal-matching technique. The primary end point was motor recovery (UEMS, LEMS, American Spinal Injury Association [ASIA] motor score [AMS]) at 1 year. Secondary end points were Functional Independence Measure (FIM) motor score and complete independence in each FIM motor domain at 1 year.ResultsThe final study cohort consisted of 186 patients with CCS. The early-surgery group included 93 patients (mean [SD] age, 47.8 [16.8] years; 66 male [71.0%]), and the late-surgery group included 93 patients (mean [SD] age, 48.0 [15.5] years; 75 male [80.6%]). Early surgical decompression resulted in significantly improved recovery in upper limb (mean difference [MD], 2.3; 95% CI, 0-4.5; P = .047), but not lower limb (MD, 1.1; 95% CI, -0.8 to 3.0; P = .30), motor function. In an a priori-planned subgroup analysis, outcomes were comparable with early or late decompressive surgery in patients with ASIA Impairment Scale (AIS) grade D injury. However, in patients with AIS grade C injury, early surgery resulted in significantly greater recovery in overall motor score (MD, 9.5; 95% CI, 0.5-18.4; P = .04), owing to gains in both upper and lower limb motor function.Conclusions and relevanceThis cohort study found early surgical decompression to be associated with improved recovery in upper limb motor function at 1 year in patients with CCS. Treatment paradigms for CCS should be redefined to encompass early surgical decompression as a neuroprotective therapy.

Dataset Information

Brain Edema Formation and Functional Outcome After Surgical Decompression in Murine Closed Head Injury Are Modulated by Acetazolamide Administration.

Publications

Brain Edema Formation and Functional Outcome After Surgical Decompression in Murine Closed Head Injury Are Modulated by Acetazolamide Administration.

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