topiramate and Brain-Edema

Brain edema is a common complication of brain metastases (BM) and associated treatment. The extent to which cytotoxic edema, the first step in the sequence that leads to ionic edema, vasogenic edema, and brain swelling, contributes to radiation-induced brain edema during BM remains unknown. This study aimed to determine whether radiation-associated treatment of BM induces cytotoxic edema and the consequences of blocking the edema in preclinical models of breast-cancer brain metastases (BCBM).. Using in vitro and in vivo models, we measured astrocytic swelling, trans-electric resistance (TEER), and aquaporin 4 (AQP4) expression following radiation. Genetic and pharmacological inhibition of AQP4 in astrocytes and cancer cells was used to assess the role of AQP4 in astrocytic swelling and brain water intake. An anti-epileptic drug that blocks AQP4 function (topiramate) was used to prevent cytotoxic edema in models of BM.. Radiation-induced astrocytic swelling and transient upregulation of AQP4 occurred within the first 24 hours following radiation. Topiramate decreased radiation-induced astrocytic swelling and loss of TEER in astrocytes in vitro, and acute short-term treatment (but not continuous administration), prevented radiation-induced increase in brain water content without pro-tumorigenic effects in multiple preclinical models of BCBM. AQP4 was expressed in clinical BM and breast-cancer cell lines, but AQP4 targeting had limited direct pro-tumorigenic or radioprotective effects in cancer cells that could impact its clinical translation.. Patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using anti-epileptic drugs able to block AQP4 function.

Topics: Aquaporin 4; Astrocytes; Brain; Brain Edema; Brain Neoplasms; Breast Neoplasms; Edema; Female; Humans; Topiramate

Introduction Variants in the CACNA1A gene on chromosome 19p13 result in a spectrum of neurological phenotypes ranging from familial or sporadic hemiplegic migraine to congenital or progressive encephalopathies. Patients with CACNA1A variants often show acute attacks with ataxia or hemiplegia till coma, sometimes related to unilateral brain oedema. No guidelines for the medical management of these attacks are available since treatment is empiric, and many cases do not respond to common antimigraine drugs. Case description We report on the emergency personalized treatment protocol used in an 11 year-old girl with CACNA1A-related encephalopathy for the management of acute attacks of headache, hemiconvulsions and hemiplegia with coma. Discussion Combined corticosteroid pulses and hypertonic solution led to a reduction in severity and duration of acute attacks when administered in the early stages, characterized by migraine, seizure, fever, vomiting and impairment of consciousness associated to hemispheric slowing on the EEG.

Topics: Anticonvulsants; Brain Edema; Calcium Channels; Child; Dexamethasone; Drug Eruptions; Female; Fructose; Glucocorticoids; Humans; Lamotrigine; Migraine with Aura; Mutation, Missense; Topiramate; Triazines

Early brain injury (EBI) following aneurysmal subarachnoid haemorrhage (SAH) insults contributes to the poor prognosis and high mortality observed in SAH patients. Topiramate (TPM) is a novel, broad-spectrum, antiepileptic drug with a reported protective effect against several brain injuries. The current study aimed to investigate the potential of TPM for neuroprotection against EBI after SAH and the possible dose-dependency of this effect. An endovascular perforation SAH model was established in rats, and TPM was administered by intraperitoneal injection after surgery at three different doses (20mg/kg, 40mg/kg, and 80mg/kg). The animals' neurological scores and brain water content were evaluated, and ELISA, Western blotting and immunostaining assays were conducted to assess the effect of TPM. The results revealed that TPM lowers the elevated levels of myeloperoxidase and proinflammatory mediators observed after SAH in a dose-related fashion, and the nuclear factor-kappa B (NF-κB) signalling pathway is the target of neuroinflammation regulation. In addition, TPM ameliorated SAH-induced cortical neuronal apoptosis by influencing Bax, Bcl-2 and cleaved caspase-3 protein expression, and the effect of TPM was enhanced in a dose-dependent manner. Various dosages of TPM also upregulated the protein expression of the γ-aminobutyric acid (GABA)-ergic signalling molecules, GABAA receptor (GABAAR) α1, GABAAR γ2, and K(+)-Cl(-) co-transporter 2 (KCC2) together and downregulated Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1) expression. Thus, TPM may be an effective neuroprotectant in EBI after SAH by regulating neuroinflammation and neuronal cell death.

Topics: Animals; Brain; Brain Edema; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Fructose; Ion Channels; Male; Neuroimmunomodulation; Neurons; Neuroprotective Agents; NF-kappa B; Random Allocation; Rats, Sprague-Dawley; Severity of Illness Index; Subarachnoid Hemorrhage; Topiramate

We report about a patient (66 years) who was referred to our psychiatric hospital because of a progressive confusional state with acute onset. The colleagues of the referring psychiatric hospital considered a first manic episode as the cause of the symptoms and under therapy with haloperidol the confusional state had shown a progression.The clinical examination's findings were a mild central facial paresis on the right side and a mild hemiparesis on the right side with elevated reflex levels.The patient was disoriented, he had cognitive and mnestic deficits. His reasoning was slowed, incoherent and perseverating. The patient had a slight euphoria.An EEG recording showed a continuous regional EEG-seizure pattern. In combination with the clinical symptoms we diagnosed a nonconvulsive status epilepticus. Under anticonvulsive treatment with Lorazepam and Valproic acid the status epilepticus sustended but a control EEG recording showed signs of a Valproate-encephalopathy. Under treatment with Topiramate symptoms ameliorated but due to a vascular dementia the patient still showed fluctuating symptoms of cognitive and mnestic disturbances.

Topics: Affect; Aged; Anticonvulsants; Antipsychotic Agents; Brain Edema; Confusion; Delirium; Dibenzothiazepines; Drug Substitution; Drug Therapy, Combination; Electroencephalography; Frontal Lobe; Fructose; Humans; Lorazepam; Magnetic Resonance Imaging; Male; Mental Status Schedule; Neurologic Examination; Quetiapine Fumarate; Referral and Consultation; Signal Processing, Computer-Assisted; Status Epilepticus; Topiramate; Valproic Acid

The aim of this study is to investigate the neuroprotective effects of the anticonvulsant topiramate in a new model of traumatic brain injury in rats. A new model of traumatic brain injury, based on the weight-drop technique, was developed for the purpose of this study. Seventy-five male Wistar rats weighing 320-470 g were studied. All rats were anesthetized, subsequently submitted to a round craniectomy in the left parietal region and a weight of 50 g was used for the production of a cortical contusion. In study I, 44 rats were randomized in three groups to receive either topiramate 40 mg/kg (n=13), topiramate 60 mg/kg (n=14), or water for injection (n=17) i.p. 30 min after the injury and every 12 h thereafter for 3 days. The rats were tested clinically 24 h, 72 h, 10 days and 20 days after the injury. On day 21 the animals were sacrificed and the brains were removed and prepared for histopathological analysis. In study II, 19 rats were randomized to receive either topiramate 60 mg/kg (n=10) or water for injection (n=9) i.p. 30 min after the injury and every 12 h (four doses in total). 48 h after the injury the animals were sacrificed and the brains were rapidly removed and analyzed for water content with the dry-wet weight technique. The animals that received topiramate performed significantly better in neurological tests compared to the animals that received vehicle ten (P<0.05) and 20 (P<0.001) days after the injury. There was no difference between the high and the low dose of the drug. Topiramate had no effect on the anatomic volume of the lesion. The animals that received topiramate had a tendency to present with less cerebral edema formation, but the difference was not statistically significant (P>0.05). These findings suggest that topiramate promotes neurological recovery in rats after traumatic brain injury without affecting the final size of the traumatic lesion and that it might play a role in the reduction of post-traumatic cerebral edema.

Topics: Animals; Brain Edema; Brain Injuries; Disease Models, Animal; Fructose; Functional Laterality; Male; Multivariate Analysis; Nervous System Diseases; Neurologic Examination; Neuroprotective Agents; Rats; Rats, Wistar; Recovery of Function; Time Factors; Topiramate

The efficacy of topiramate, a novel therapeutic agent approved for the treatment of seizure disorders, was evaluated in a model of traumatic brain injury (TBI). Adult male rats were anesthetized (sodium pentobarbital, 60 mg/kg, i.p.), subjected to lateral fluid percussion brain injury (n = 60) or sham injury (n = 47) and randomized to receive either topiramate or vehicle at 30 min (30 mg/kg, i.p.), and 8, 20 and 32 h postinjury (30 mg/kg, p.o.). In Study A, memory was evaluated using a Morris water maze at 48 h postinjury, after which brain tissue was evaluated for regional cerebral edema. In Study B, animals were evaluated for motor function at 48 h and 1, 2, 3, and 4 weeks postinjury using a composite neuroscore and the rotating pole test and for learning ability at 4 weeks. Brains were analyzed for hemispheric tissue loss and hippocampal CA3 cell loss. Topiramate had no effect on posttraumatic cerebral edema or histologic damage when compared to vehicle. At 48 h, topiramate treatment improved memory function in sham but not brain-injured animals, while at one month postinjury it impaired learning performance in brain-injured but not sham animals. Topiramate significantly improved composite neuroscores at 4 weeks postinjury and rotating pole performance at 1 and 4 weeks postinjury, suggesting a potentially beneficial effect on motor function following TBI.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain Edema; Brain Injuries; Fructose; Male; Maze Learning; Memory; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Topiramate; Treatment Outcome