Outcomes in Elderly Japanese Patients Treated for Aneurysmal Subarachnoid Hemorrhage: A Retrospective Nationwide Study.

OBJECTIVE: Japan has the largest elderly population in the world. As data on the clinical outcomes in elderly patients with aneurysmal subarachnoid hemorrhage (aSAH), including those older than 80 years, are lacking, we analyzed the characteristics of 54,805 aSAH patients and recorded their treatments and clinical outcomes using a Japanese nationwide inpatient database. METHODS: Using the Japanese Diagnostic Procedure Combination database, we identified aSAH patients aged 18 years or older who were hospitalized between July 1, 2010 and March 31, 2016. They were categorized as less than or equal to 60-, 61-70-, 71-80-, 81-90-, and greater than or equal to 91 years of age. The primary outcome was the modified Rankin Scale (mRS) score at discharge. Multivariable logistic regression analysis was performed to examine factors affecting the mRS score at discharge. RESULTS: Of 54,805 patients, 37.5% were aged less than or equal to 60 years; 24.8% were 61-70-, 21.8% were 71-80-, 13.9% were 81-90-, and 2.0% were greater than or equal to 91 years old at the time of the insult. Among 46,107 patients younger than 81 years, 58.9% underwent surgical clipping (SC), 22.9% endovascular coiling (EC), and 18.2% were treated conservatively. There were 8,698 patients aged 81 years or older, 32.4% underwent SC, 23.2% EC, and 44.4% were treated conservatively. A poor mRS score (3-6) at discharge was recorded in 87.2% of patients older than 80 years. Multivariable logistic regression was used to compare their estimated odds ratio (OR) for a poor mRS score at discharge with that of patients aged less than or equal to 60 years. The OR increased by 87% in patients between 61 and 70 years of age (P < .001; OR, 1.87; 95% confidence interval (CI), 1.77-1.98), by 358% in patients aged from 71 to 80 years (P < .001; OR, 4.58; 95%CI, 4.29-4.89), by 1,035% in patients between 81 and 90 years (P < .001; OR, 11.35; 95%CI, 10.32-12.49), and by 1,710% in patients aged more than or equal to 91 years (P < .001; OR, 18.10; 95%CI, 13.96-23.46). CONCLUSIONS: As the treatment outcomes in elderly aSAH patients, especially those 80 years old or older, were poor, the appropriate therapy decisions must be made on a case-by-case basis.

Fluorescence investigation of the retinal delivery of hydrophilic compounds via liposomal eyedrops.

We examined the feasibility of using submicron-sized liposomes (ssLips) for retinal delivery of hydrophilic compounds, which would also have a wide range of applications. To evaluate the uptake into conjunctival cell line and the intraocular behavior of hydrophilic compound-containing ssLips after eyedrop application, fluorometric investigation was carried out by using a hydrophilic fluorescence probe, 5(6)-carboxyfluorescein (CF). A relatively high amount of CF (>50%) could be incorporated into an internal phase of ssLips by a calcium acetate gradient method. CF being entrapped within the liposomes markedly enhanced both the uptake of CF into conjunctival cells and CF-oriented emission in the retina in mice after eyedrop application, while the free CF did not clear delivery efficiency in both in vitro and in vivo study. In addition, the cellular uptake and luminescence intensity in the retina were higher when a ssLip formulation composed of L-α-distearoyl phosphatidylcholine was applied than when a ssLip formulation composed of egg phosphatidylcholine was applied. Consequently, ssLips of appropriate composition were considered to have good potential to carry hydrophilic compounds into the retina.

Severe Aneurysmal Subarachnoid Hemorrhage after Warning Headache during Pregnancy: A Case Report.

BACKGROUND: Aneurysmal subarachnoid hemorrhage is a rare but important cause of maternal death during pregnancy. CASE DESCRIPTION: A 34-year-old primigravida (31 weeks of pregnancy) with acute headache but no neurological deficits or neck stiffness was prescribed medication and returned home. Four weeks later she presented with severe headache and consciousness disturbance. She was admitted to our hospital, where she fell into a deep coma. Brain CT and three-dimensional CT angiography showed subarachnoid hemorrhage and a 5-mm right internal carotid-posterior communicating artery aneurysm. Fetal heart rate was 60 beats per minute. Emergent cesarean section and surgical clipping were performed. Intraoperative examination revealed that the aneurysm originated at the right posterior communicating artery. There were no postoperative neurological focal deficits. On postoperative day 13 she developed delayed cerebral ischemia of the right temporo-parieto-occipital lobe. She was discharged home 36 days after surgery with left hemianopsia. The infant was free of complications and was discharged at age 17 days. CONCLUSIONS: A pregnant woman with severe headache should undergo brain CT or magnetic resonance imaging to rule out subarachnoid hemorrhage.

Development and in vitro characterization of liposomes coated with thiolated poly(acrylic acid) for oral drug delivery.

Mucoadhesive drug delivery systems offer promising opportunities for oral drug delivery. The aim of this study was to investigate the feasibility of preparing liposomes that are coated with the multifunctional polymer poly(acrylic acid)-cysteine (PAA-Cys). Cationic multilamellar vesicles (MLV) as well as cationic submicron-sized liposomes (ssLip) were prepared and coated with PAA-Cys. Size, zeta potential, amount of free thiol groups, aggregation behavior, drug-loading, and drug release of these novel carriers were evaluated. A switch of the initial positive zeta potential to a negative value after coating indicated the successful coating procedure. In both size ranges, MLV and ssLip, the amount of free thiol groups was comparable to that in a PAA-Cys solution of the same concentration. Drug loading of the hydrophilic marker fluorescence-isothiocyanate 4 kDa (FD4) was higher in PAA-Cys liposomes in comparison to noncoated liposomes, but lower in comparison to liposomes coated with unmodified poly(acrylic acid) (PAA). Only a minor ssLip or no increase MLV of the drug-loading was observed when using carboxyfluorescein (CF). These effects were attributed to interactions between the markers and the poly(acrylates). Coating of liposomes with PAA-Cys and PAA did not influence the release profile of FD4 and CF, whereas the release profile was affected by the molecular mass of the marker and the liposome size. In conclusion, the feasibility of coating liposomes with PAA-Cys was demonstrated, and it could be shown that this novel carrier system fulfills the basic requirements for an intended use in oral drug delivery.

Hydrocephalus Secondary to Intradural Extramedullary Malignant Melanoma of Spinal Cord.

BACKGROUND: Hydrocephalus secondary to spinal cord tumors is rare. CASE DESCRIPTION: We present a 39-year-old male with gradual-onset headache whose initial diagnosis was cerebral aneurysm and communicating hydrocephalus. The correct diagnosis was primary intradural extramedullary malignant melanoma of the spinal cord. Initial brain magnetic resonance imaging demonstrated slight dilation of cerebral ventricles and a 3-mm unruptured anterior communicating artery aneurysm. He was placed under observation therapy. Two months later he was seen again due to severe headache. There was no intracranial hemorrhage on brain computed tomography scans. As we suspected rupture of the aneurysm, we operated on him for surgical clipping; however, there was no aneurysmal rupture. We found no lesions responsible for hydrocephalus, so we placed a ventriculoperitoneal shunt. His headache subsequently resolved. Nine months later he developed gait disturbance; a large volume of ascites was observed. Gadolinium-enhanced lumbar magnetic resonance imaging revealed an intradural extramedullary mass at the L-1 to S-5 level. Cytology and immunohistochemistry of the cerebrospinal fluid and ascites identified a few atypical cells positive for HMB-45, S-100 protein, and Melan-A. Whole-body examinations detected no primary lesions outside the central nervous system. Our final diagnosis was primary intradural extramedullary malignant melanoma of the spinal cord with cerebrospinal fluid dissemination. CONCLUSIONS: Our findings indicate that communicating hydrocephalus may be due to primary malignant melanoma of the spinal cord.

Cerebral Aneurysm Associated with an Arachnoid Cyst: 3 Case Reports and a Systematic Review of the Literature.

BACKGROUND: Arachnoid cysts and intracranial aneurysms are not rare, but it is unusual for an aneurysm to be associated with an arachnoid cyst. The objective of this study was to reveal the association between arachnoid cysts and intracranial aneurysms. METHODS: Methods included to report 3 cases with these 2 pathologies and to perform a systematic review of the English and Japanese literature using PubMed, Scopus, and Ichushi Web. RESULTS: The first case was of a 46-year-old man with a subarachnoid hemorrhage on the basal cistern and bilateral arachnoid cysts in the middle fossa, the second was that of a 29-year-old woman with a subarachnoid hemorrhage at the basal cistern and an arachnoid cyst in the left middle fossa, and the third was that of a 60-year-old man with a right putaminal hemorrhage and contralateral unruptured aneurysm and arachnoid cyst. A literature search for similar cases found 27 patients. CONCLUSIONS: It was difficult to diagnose a ruptured aneurysm in some cases with an arachnoid cyst because computed tomography scan showed atypical findings, such as no hemorrhage, intracystic localized hemorrhage, or subdural hematoma. This review revealed that aneurysms and arachnoid cysts were significantly located ipsilaterally and that they occurred together in relatively young patients.

Outcome and Refractory Factor of Intensive Treatment for Geriatric Traumatic Brain Injury: Analysis of 1165 Cases Registered in the Japan Neurotrauma Data Bank.

OBJECTIVE: With the increase in the aged population, geriatric traumatic brain injury (gTBI) is also rapidly increasing in Japan. There is thus a need to review the effect of intensive treatments for gTBIs. The aim of this study was 1) to assess how intensive treatments influenced patient outcome and 2) to identify the refractory factor against these intensive treatments in gTBI, from the Japan Neurotrauma Data Bank (JNTDB). METHODS: Of all 3194 patients in the JNTDB, 1165 (≥ 65 years old) with severe gTBIs were enrolled in this study. The clinical features and their outcomes based on the Glasgow Outcome Scale on discharge and 6 months after injury were compared. RESULTS: Intensive treatments were administered to 71.4% of all patients with severe gTBI showing a significant increase over 15 years. Accordingly, mortality decreased significantly (from 62.7% to 51.1%, P = 0.001). On the other hand, severely disabled dependent survivors, who need daily help from others for living, increased accordingly (from 63.2% to 68.4%). The existence of intraventricular hemorrhage (IVH) rather than the patient's age was identified as the strongest refractory factor (odds ratio, 5.762; 95% confidence interval, 1.317-25.216) against intensive treatment. CONCLUSIONS: This study clarified that 1) intensive treatments are associated with higher survival rates (however, they also increase the incidence of severely disabled survivors) and 2) the strongest refractory factor for intensive treatment in cases of severe gTBI was not age but the existence of IVH. These results warrant further establishment of a seamless strategy for both the acute and the chronic phase of gTBI.

Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency in human arylsulfatase A (hASA). We recently reported that ependymal cells and the choroid plexus are selectively transduced by intracerebroventricular (ICV) injection of adeno-associated virus serotype 1 (AAV1) vector and serve as a biological reservoir for the secretion of lysosomal enzymes into the cerebrospinal fluid (CSF). In the present study, we examined the feasibility of this AAV-mediated gene therapy to treat MLD model mice. Preliminary experiments showed that the hASA level in the CSF after ICV injection of self-complementary (sc) AAV1 was much higher than in mice injected with single-stranded AAV1 or scAAV9. However, when 18-week-old MLD mice were treated with ICV injection of scAAV1, the concentration of hASA in the CSF gradually decreased and was not detectable at 12 weeks after injection, probably due to the development of anti-hASA antibodies. As a result, the sulfatide levels in brain tissues of treated MLD mice were only slightly reduced compared with those of untreated MLD mice. These results suggest that this approach is potentially promising for treating MLD, but that controlling the immune response appears to be crucial for long-term expression of therapeutic proteins in the CSF.

Retinal drug delivery using eyedrop preparations of poly-L-lysine-modified liposomes.

The purpose of this study was to develop surface-modified liposomes that enhance the efficiency of eye drop drug delivery to the retina. Various molecular weights and concentrations of the water-soluble cationic polymer poly-L-lysine (PLL) were used to modify the surface of submicronized (100 nm) liposomes. Physicochemical properties of surface-modified liposomes were determined in vitro, and the efficiency of drug delivery to the retina was investigated in vivo. Using coumarin-6 as a model drug and fluorescent marker, we show that liposome surface modification by PLL dramatically increased delivery to mouse retina segments after eye drop administration. However, when PLL of high molecular weight (>30,000) was used at higher concentrations (>0.05%), aggregation of surface-modified liposomes increased particle size and hampered distribution to inner ocular tissues. As a result, the efficiency of drug delivery of these aggregated surface-modified liposomes was the same as unmodified liposomes. The optimal molecular weight and concentration of PLL in drug-delivering liposomes were 15,000-30,000 and 0.005%, respectively. Under these conditions, PLL-modified liposomes were not cytotoxic in corneal or conjunctival cells. In conclusion, surface-modified liposomes have great potential as effective retinal drug delivery carriers in eye drop formulations.

Simple solution for preventing cerebrospinal fluid loss and brain shift during multitrack deep brain stimulation surgery in the semisupine position: polyethylene glycol hydrogel dural sealant capping: rapid communication.

This study evaluated preliminary findings on the efficacy of polyethylene glycol (PEG) hydrogel dural sealant capping for the prevention of cerebrospinal fluid (CSF) leakage and pneumocephalus during deep brain stimulation (DBS) surgery in the semisupine position. Group A consisted of 5 patients who underwent bilateral subthalamic nucleus (STN)-DBS surgery without PEG hydrogel dural sealant capping. Group B consisted of 5 patients who underwent bilateral STN-DBS surgery with PEG hydrogel dural sealant capping. The immediate postoperative intracranial air volume was measured in all patients and compared between the 2 groups using the Welch test. Adverse effects were also examined in both groups. The intracranial air volume in Group A was 32.3 ± 12.3 ml (range 19.1-42.5 ml), whereas that in Group B was 1.3 ± 1.5 ml (range 0.0-3.5 ml), showing a significant difference (p < 0.005). No hemorrhage or venous air embolisms were observed in either group. The effect of brain shift was discriminated by STN recordings in Group B. These preliminary findings indicate that PEG hydrogel dural sealant capping may reduce adverse effects related to CSF leakage and brain shift during DBS surgery.

Liposomal diclofenac eye drop formulations targeting the retina: formulation stability improvement using surface modification of liposomes.

An efficient liposomal formulation for targeting the retina was produced as an optimal means of distributing therapeutic agents to the retina. Diclofenac was used as a model compound for liposome encapsulation, and the release rate and distribution to the retina were investigated. The calcium acetate gradient method was found to be the optimal method for encapsulating diclofenac into liposomes. Entrapment efficiency using this method was greater than 97%, whereas conventional hydration method achieved 51.3%. The resultant formulation obtained with the gradient method caused aggregation and/or fusion of liposomes. To avoid inhibition of retinal delivery due to the aggregation of the carrier, surface modification was performed simultaneously with the gradient method. The increase in particle size of the liposomal formulation clearly was inhibited for a long time in the presence of polyvinyl alcohol or its derivative. This observation may be explained by surface modification of the liposomes by physisorption or anchoring effect of polymers on the surface of the lipid bilayer. Furthermore, the sustained release profile of the diclofenac formulation was retained after modification. An in vivo animal study revealed that concentration of the accumulated diclofenac in the retina-choroid was enhanced 1.8-fold by surface-modified liposome entrapment compared to that of the unaltered diclofenac solution.

Edaravone-loaded liposomes for retinal protection against oxidative stress-induced retinal damage.

To optimize the retinal protective effects of submicron-sized liposomes (ssLips) containing edaravone for intravitreal administration, we investigated the effects of liposomal formulation on the pharmacological effects. Loading of edaravone into ssLips of around 50% entrapment efficiency was achieved by a calcium acetate gradient method. The in vitro radical-scavenging capacity of edaravone-loaded ssLip based on egg phosphatidylcholine (EPC-ssLip) and L-α-distearoyl phosphatidylcholine (DSPC-ssLip) was determined in RGC-5, a neuronal precursor cell line that can be differentiated to resemble retinal ganglion cells. Edaravone-loaded EPC-ssLip scavenged intracellular H(2)O(2) radical more strongly than DSPC-ssLip, although there was only a small difference in cellular uptake of edaravone into RGC-5. An in vivo N-methyl-D-aspartate (NMDA)-induced disease model was used to investigate the retinal protective effects in mice. The edaravone-loaded EPC-ssLip significantly reduced NMDA-induced ganglion cell layer (GCL) cell death compared with free edaravone. Such protective effect was small in the case of DSPC-ssLip. These results may be related to the release profile of the edaravone from ssLips across the inner layers of the retina including GCL, indicating effective retinal protection of EPC-ssLip compared to that of DSPC-ssLip. EPC-ssLip is a promising carrier for edaravone in treating oxidative stress-induced retinal diseases.

Edaravone-loaded liposome eyedrops protect against light-induced retinal damage in mice.

PURPOSE: To investigate the pharmacologic effects of eyedrops containing liposomes loaded with edaravone (3-methyl-1-phenyl-2-pyrazolin-5-1) against light-induced retinal damage in mice. METHODS: Edaravone was incorporated into submicron-sized liposomes (ssLips) by the calcium acetate gradient method. Retinal damage in mice was induced in dark-adapted mice by exposure to white light at 8000 lux for 3 hours. Edaravone-loaded ssLips were dropped into the left eye just before and after light exposure and then three times daily for 5 days after light exposure. Retinal damage was evaluated by recording the scotopic electroretinogram (ERG) and measuring the thickness of the outer nuclear layer (ONL) and by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. The scavenging capacity of reactive oxygen species (ROS) of edaravone-loaded ssLips was determined using a murine cone photoreceptor cell line (661W). The human corneal and conjunctival cell lines were exposed to edaravone-loaded ssLips to determine cytotoxicity. RESULTS: Eyedrop administration of edaravone-loaded ssLips significantly prevented both the decrease in a- and b-wave amplitudes of flash ERG and the shrinkage of the ONL compared with the control group (treated with empty ssLips) after 5 days of light exposure. The edaravone-loaded ssLips prevented the increase in the numbers of TUNEL-positive cells after 48 hours of light exposure. This marked protection was not found in the group treated with free edaravone. Edaravone-loaded ssLips showed a stronger inhibition of in vitro light-induced ROS production and cell death than did free edaravone. The ssLips showed little cytotoxicity toward ocular cell lines. CONCLUSIONS: Edaravone-loaded ssLips protected against light-induced retinal dysfunction by eyedrop administration. Liposomal eyedrops may become one of the therapeutic candidates for drug delivery to posterior eye segments.

Physicochemical properties affecting retinal drug/coumarin-6 delivery from nanocarrier systems via eyedrop administration.

PURPOSE: To elucidate the effect of physicochemical properties of nanocarrier systems on drug delivery efficiency to the retina by eyedrop administration in mice, rabbits, and monkeys. METHODS: Submicron-sized liposomes (ssLips) of different particle size, cholesterol content, surface charge, and multilamellar vesicles (MLV) were prepared by the hydration METHOD: Fluorescence probe (coumarin-6)-incorporated liposomes, lipid emulsions, and FITC-labeled polystyrene particles were used to investigate their intraocular behavior after eyedrop administration, using epifluorescence microscopy in mice, rabbits, and monkeys. RESULTS: Delivery efficiency of fluorescent probes to the mouse retina from dropped liposomes was extensively improved by reducing their particle size (<600 nm) and cholesterol content, whereas negligible improvement was observed in the case of MLV. Furthermore, FITC-labeled polystyrene particles and coumarin-6-incorporated lipid emulsions showed an insufficient effect on retinal delivery in mice even if their size was controlled at 110 nm. The highest accumulation of the fluorescent probe in the retina was observed around 30 minutes with any type of ssLip used, followed by the prompt disappearance of their fluorescence within 120 minutes in mice. Changes in the fluorescence intensity of coumarin-6 in rabbits and monkeys were observed in a manner similar to that described in mice. Retinal flat-mount images suggest that coumarin-6 incorporated in ssLip diffused from the iris and ciliary body side to the optic disc side in the retina after eyedrop administration. CONCLUSIONS: The delivery efficiency of coumarin-6 to the retina was altered depending on particle size, constituents, and rigidity. ssLips with appropriate features would be promising drug carriers for retinal delivery through eyedrops.

Design and evaluation of a liposomal delivery system targeting the posterior segment of the eye.

The purpose of this study was to evaluate the potential of submicron-sized liposomes (ssLips) as a novel system for delivering ocular drugs to the eye's posterior segment. Fluorescence emission of coumarin-6 formulated into ssLip was obvious in that segment in mice after eyedrop administration of the liposomal suspension. Such fluorescence was not observed after administration of either multilamellar vesicles or dimethyl sulfoxide (DMSO) solution containing the same amount of coumarin-6. The highest fluorescence of ssLip occurred 30 min after eyedrop administration, and all fluorescence disappeared after 180 min. The ssLip based on l-alpha-distearoyl phosphatidylcholine (DSPC ssLip) showed higher fluorescence emission in the retina than that based on egg phosphatidylcholine (EPC ssLip). These results confirmed that the magnitude of fluorescence in the retina was closely related to both liposome rigidity and particle size. Images of the entire eye showed that ssLip was delivered via the non-corneal pathway after administration. The liposomes tested in ocular cells showed little cytotoxicity. These results suggest that ssLip can be used to deliver drugs to the posterior segment of the eye.