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Medical Science Monitor : International... Mar 2022Adie's pupil, also called tonic pupil, is mainly seen in young women. Most patients have unilateral eye involvement. The pupil of the affected side is significantly... (Review)
Review
Adie's pupil, also called tonic pupil, is mainly seen in young women. Most patients have unilateral eye involvement. The pupil of the affected side is significantly larger than that on the healthy side. The direct and indirect light reflection from the pupil on the affected side disappears. The pupil on the affected side is sensitive to low concentrations of pilocarpine. The pathogeneses of Adie's pupil are complex, some of which are insidious and lack corresponding specific diseases. Through a literature review, we found that Adie's pupil is mainly associated with infectious diseases, most commonly syphilis, followed by immune diseases and paraneoplastic syndromes. The ophthalmological symptoms and pupil abnormalities can disappear after active treatment of the primary disease. Pilocarpine can be used to treat ophthalmologic symptoms, such as blurred vision, for which patients might visit an ophthalmologist or neurologist. It is essential for clinicians to improve their understanding of the disease to avoid misdiagnosis. Differential diagnosis between Adie's pupil, oculomotor nerve palsy, anticholinergic drug overdose, Argyll-Robertson pupil, and congenital mydriasis need to be identified by the physician. Here, the clinical manifestations, pathogenesis, relationship between Adie's pupil and diseases, and differential diagnosis of Adie's pupil are reviewed.
Topics: Adie Syndrome; Diagnosis, Differential; Humans; Physicians; Pupil; Tonic Pupil
PubMed: 35304432
DOI: 10.12659/MSM.934657 -
Neurobiology of Disease May 2023Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models.... (Review)
Review
Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models. Interictal activity, which is recorded with cortical and intracerebral EEG recordings, comprises spikes, sharp waves and high-frequency oscillations, and has been used in clinical practice to identify the epileptic zone. However, its relation with seizures remains debated. Moreover, it is unclear whether specific EEG changes in interictal activity occur during the time preceding the appearance of spontaneous seizures. This period, which is termed "latent", has been studied in rodent models of MTLE in which spontaneous seizures start to occur following an initial insult (most often a status epilepticus induced by convulsive drugs such as kainic acid or pilocarpine) and may mirror epileptogenesis, i.e., the process leading the brain to develop an enduring predisposition to seizure generation. Here, we will address this topic by reviewing experimental studies performed in MTLE models. Specifically, we will review data highlighting the dynamic changes in interictal spiking activity and high-frequency oscillations occurring during the latent period, and how optogenetic stimulation of specific cell populations can modulate them in the pilocarpine model. These findings indicate that interictal activity: (i) is heterogeneous in its EEG patterns and thus, presumably, in its underlying neuronal mechanisms; and (ii) can pinpoint to the epileptogenic processes occurring in focal epileptic disorders in animal models and, perhaps, in epileptic patients.
Topics: Animals; Humans; Epilepsy, Temporal Lobe; Pilocarpine; Seizures; Epilepsies, Partial; Epilepsy; Electroencephalography
PubMed: 36907521
DOI: 10.1016/j.nbd.2023.106065 -
JFMS Open Reports 2023Two 6-month-old littermate Russian Blue cross kittens presented for megaesophagus, intermittent vomiting and regurgitation. The male kitten was diagnosed with aspiration...
CASE SUMMARY
Two 6-month-old littermate Russian Blue cross kittens presented for megaesophagus, intermittent vomiting and regurgitation. The male kitten was diagnosed with aspiration pneumonia and was suspected to have a hiatal hernia on thoracic radiographs. It presented 1 month later in acute respiratory distress and was euthanized. Post-mortem examination revealed a severe gastroesophageal intussusception with approximately 90% of the stomach inverted into the distal esophagus. Histologic examination confirmed dysautonomia with marked neuronal dropout and degeneration with necrosis, satellitosis of the celiac ganglion and the myenteric and submucosal plexuses throughout the gastrointestinal tract. The less-affected littermate showed improvement on cisapride and was doing well at home at the time of writing.
RELEVANCE AND NOVEL INFORMATION
Dysautonomia is rare in cats, with only a few reports of affected littermates. Both kittens are significantly younger than the median age previously reported. Detailed descriptions of diagnostic and histopathology findings are included. Gastroesophageal intussusception is a novel complication to consider when managing feline dysautonomia.
PubMed: 37151741
DOI: 10.1177/20551169231164579 -
Frontiers in Pharmacology 2023Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, but still one-third of patients cannot be properly treated by current medication. Thus, we...
Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, but still one-third of patients cannot be properly treated by current medication. Thus, we investigated the therapeutic effects of a novel small molecule, NecroX-7, in TLE using both a low [Mg]-induced epileptiform activity model and a mouse model of pilocarpine-induced status epilepticus (SE). NecroX-7 post-treatment enhanced the viability of primary hippocampal neurons exposed to low [Mg] compared to controls in an MTT assay. Application of NecroX-7 after pilocarpine-induced SE also reduced the number of degenerating neurons labelled with Fluoro-Jade B. Immunocytochemistry and immunohistochemistry showed that NecroX-7 post-treatment significantly alleviated ionized calcium-binding adaptor molecule 1 (Iba1) intensity and immunoreactive area, while the attenuation of reactive astrocytosis by glial fibrillary acidic protein (GFAP) staining was observed in cultured hippocampal neurons. However, NecroX-7-mediated morphologic changes of astrocytes were seen in both and models of TLE. Finally, western blot analysis demonstrated that NecroX-7 post-treatment after acute seizures could decrease the expression of mixed lineage kinase domain-like pseudokinase (MLKL) and phosphorylated MLKL (p-MLKL), markers for necroptosis. Taken all together, NecroX-7 has potential as a novel medication for TLE with its neuroprotective, anti-inflammatory, and anti-necroptotic effects.
PubMed: 37601059
DOI: 10.3389/fphar.2023.1187819 -
IScience May 2023Salivary gland cells, which secrete water in response to neuronal stimulation, are closely connected to other neurons. Transcriptomic studies show that salivary glands...
Salivary gland cells, which secrete water in response to neuronal stimulation, are closely connected to other neurons. Transcriptomic studies show that salivary glands also express some proteins responsible for neuronal function. However, the physiological functions of these common neuro-exocrine factors in salivary glands are largely unknown. Here, we studied the function of Neuronal growth regulator 1 (NEGR1) in the salivary gland cells. NEGR1 was also expressed in mouse and human salivary glands. The structure of salivary glands of knockout (KO) mice was normal. KO mice showed tempered carbachol- or thapsigargin-induced intracellular Ca increases and store-operated Ca entry. Of interest, the activity of the large-conductance Ca-activated K channel (BK channel) was increased, whereas Ca-activated Cl channel ANO1 channel activity was not altered in KO mice. Pilocarpine- and carbachol-induced salivation was decreased in KO mice. These results suggest that NEGR1 influence salivary secretion though the muscarinic Ca signaling.
PubMed: 37216094
DOI: 10.1016/j.isci.2023.106773 -
American Journal of Ophthalmology Sep 2023To evaluate the safety, efficacy, and pharmacokinetics of pilocarpine hydrochloride 1.25% (Pilo hereafter) compared with vehicle when administered bilaterally, twice... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the safety, efficacy, and pharmacokinetics of pilocarpine hydrochloride 1.25% (Pilo hereafter) compared with vehicle when administered bilaterally, twice daily (6 hours apart) for 14 days in participants with presbyopia.
DESIGN
Phase 3, randomized (1:1), controlled, double-masked, multicenter study.
METHODS
Participants (40-55 years of age) had objective and subjective evidence of presbyopia affecting daily activities with mesopic, high-contrast, binocular distance-corrected near visual acuity (DCNVA) of 20/40 to 20/100. The primary/key secondary endpoint was the proportion of participants gaining ≥3 lines in mesopic/photopic, high-contrast, binocular DCNVA on day 14 (last study visit), hour 9 (3 hours after the second dose), with no more than a 5-letter loss in mesopic/photopic corrected distance visual acuity with the same refractive correction. Key safety measures included treatment-emergent adverse events (TEAEs) and some ocular measurements. Pilocarpine plasma levels were assessed in approximately 10% of enrolled participants.
RESULTS
Overall, 230 participants were randomized to Pilo twice daily (N = 114) and vehicle (N = 116). The proportion of participants achieving the primary and key secondary efficacy endpoints was statistically significantly greater with Pilo twice daily than vehicle, with between-treatment differences of 27.3% (95% CI = 17.3, 37.4) and 26.4% (95% CI = 16.8, 36.0), respectively. The most common TEAE was headache, reported in 10 participants (8.8%, Pilo group) and 4 participants (3.4%, vehicle group). Pilocarpine's accumulation index on day 14 was ≤1.11 after the second dose.
CONCLUSIONS
Near-vision improvements were statistically greater with Pilo twice daily than with vehicle, without compromising distance acuity. The safety profile of Pilo twice daily was consistent with that of Pilo once daily, and systemic accumulation was minimal, supporting twice daily administration.
Topics: Humans; Pilocarpine; Presbyopia; Visual Acuity; Refraction, Ocular; Double-Blind Method
PubMed: 37149245
DOI: 10.1016/j.ajo.2023.05.008 -
Journal of Cancer Research and... 2023Patients with head-and-neck cancers can develop salivary gland hypofunction after radiotherapy. Oral pilocarpine has been shown to be effective treatment for... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Patients with head-and-neck cancers can develop salivary gland hypofunction after radiotherapy. Oral pilocarpine has been shown to be effective treatment for radiation-induced xerostomia, although its usefulness is being discussed.
AIMS
We aimed to evaluate the efficacy and safety profile of oral pilocarpine in radiation-induced xerostomia.
MATERIALS AND METHODS
Sixty patients with oropharyngeal carcinoma were planned for radiotherapy and divided into two arms randomly: Arm A (30 patients) received oral pilocarpine and Arm B (30 patients) received placebo tablets for 12 weeks after 3 months of completion of radiotherapy. Salivary gland scintigraphy and xerostomia questionnaire (XQ) were obtained from each patient at baseline and at 3 and 6 months of completion of radiotherapy.
RESULTS
There was a marked decrease in uptake ratio (UR) and excretion fraction (EF) after 3 months of completion of radiotherapy. There was a statistically significant difference between both the arms in relation to UR, but no significant difference was observed between the two arms in relation to EF after 6 months of completion of radiotherapy. A statistically significant difference was found comparing the XQ results in both the arms. The XQ results did not correlate with salivary gland dysfunction observed by means of salivary scintigraphy. Adverse effects due to xerostomia were generally mild and occasionally of moderate severity.
CONCLUSION
The use of oral pilocarpine did not significantly improve salivary gland excretory function, despite better results on salivary uptake at 6 months. However, oral pilocarpine significantly improved symptoms of xerostomia with minor side effects that were predominantly limited to sweating.
Topics: Humans; Head and Neck Neoplasms; Pilocarpine; Radiation Injuries; Salivary Glands; Xerostomia
PubMed: 37470612
DOI: 10.4103/jcrt.jcrt_2346_21 -
Frontiers in Endocrinology 2020Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been...
Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline- pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3beta-methylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebo-controlled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.
Topics: Allosteric Regulation; Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Agonists; Humans; Neurosteroids; Seizures; Treatment Outcome
PubMed: 33117274
DOI: 10.3389/fendo.2020.541802 -
Neurobiology of Disease Jan 2020The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABA and glutamate receptors. The... (Review)
Review
The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAR left to be able to restore inhibition with maximal GABAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.
Topics: Animals; Anticonvulsants; Cholinesterase Inhibitors; Drug Therapy, Combination; Ketamine; Male; Midazolam; Muscarinic Agonists; Nerve Agents; Pilocarpine; Rats; Rats, Sprague-Dawley; Soman; Status Epilepticus; Valproic Acid
PubMed: 31454548
DOI: 10.1016/j.nbd.2019.104537