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Ibuprofen is the most widely used non-steroidal anti-inflammatory drug (NSAID) for the treatment of inflammation, mild-to-moderate pain and fever in children, and is the only NSAID approved for use in children aged ≥3 months. Its efficacy and safety profile have led to its increasing use in paediatric care, even without medical prescription. However, an increase of suspected adverse reactions to ibuprofen has been noted in concomitance with the raised, often medically unsupervised, consumption of the drug. The purpose of this work was a critical review of the paediatric literature over the last 15 years on side effects and adverse events associated with ibuprofen, in order to highlight circumstances associated with higher risks and to promote safe and appropriate use of this drug. The literature from 2000 to date demonstrates that gastrointestinal events are rare, but (when they occur) include both upper and lower digestive tract lesions. Dehydration plays an important role in triggering renal damage, so ibuprofen should not be given to patients with diarrhoea and vomiting, with or without fever. Likewise, ibuprofen should never be administered to patients who are sensitive to it or to other NSAIDs. It is contraindicated in neonates and in children with wheezing and persistent asthma and/or during varicella. Most of the analysed studies reported adverse events when ibuprofen was being used for fever symptoms or flu-like syndrome. Ibuprofen should not be used as an antipyretic, except in rare cases. Ibuprofen remains the drug of first choice in the treatment of inflammatory pain in children.

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4 + T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24–71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, neurological immune-related adverse events (n-irAEs) associated with these agents are increasingly recognized. However, kelch-like protein-11(KLHL11)-IgG cerebellitis has not been reported as an n-irAE. We report a case of a 53-year-old man with lung adenocarcinoma treated with tislelizumab who developed KLHL11-IgG cerebellitis. First-line immunotherapy, comprising intravenous methylprednisolone and immunoglobulin, failed to improved his symptoms. Subsequent administration of efgartigimod (10 mg/kg weekly for 4 doses) led to seroconversion of KLHL11-IgG and marked clinical recovery. This is the first report of efgartigimod as a successful rescue therapy for isolated ICI-related KLHL11-IgG cerebellitis. These findings support efgartigimod as a promising treatment option for this condition.

Cerebellar Motor Disorders (CMDs) are characterized by unsteady gait and uncoordinated movements. Reports indicate that CMDs are caused by congenital malformations, hereditary ataxia, and heavy metal exposure, such as Lead. The antioxidant-rich nature of plants, such as Cucumis sativus (Cucumber), has been well-documented. Accordingly, this study investigated the protective activity of aqueous Cucumis sativus fruit extract (CS) in a lead acetate (Pb) rat model of CMD. Forty Wistar rats (n = 8) were randomly assigned into five groups and treated for twenty-eight days as follows: Group A served as control; Group B received 100 mg/kg body weight (bw) of Pb; Group C received 500 mg/kg bw of CS and Pb; Group D received 1000 mg/kg bw of CS and Pb; Group E received 200 mg/kg bw of Vitamin-E and Pb. Thereafter, neurobehavioral activities, antioxidant enzymes, lipid peroxidation, nitric oxide, Pb concentration, Caspase-3, TNF-α, and cerebella histology were evaluated. Findings revealed that Pb-exposed rats demonstrated significant ( p  < 0.05) weight loss, impaired motor functions, dysregulated antioxidant enzymes activity, increased lipid peroxidation, elevated cerebellar nitric oxide and Pb concentration, as well as degenerating Purkinje cells and vacuolations in the cerebellum. Also, a significant upregulation ( p  < 0.05) of Caspase-3 and TNF-α was observed in the cerebella of Pb-exposed rats. However, pretreatment with CS mitigated ( p  < 0.05) these adverse effects induced by Pb. Taken together, this study offers novel insights into the role of CS as a promising neuroprotective agent and provides translational research evidence demonstrating that CS can be further developed into drugs useful against CMDs.

Oleoylethanolamide (OEA) is an endocannabinoid that has been proposed to prevent neuronal damage and neuroinflammation. In this study, we evaluated the effects of OEA on the disruption of both cerebellar structure and physiology and on the behavior of Purkinje cell degeneration (PCD) mutant mice. These mice exhibit cerebellar degeneration, displaying microtubule alterations that trigger the selective loss of Purkinje cells and consequent behavioral impairments. The effects of different doses (1, 5, and 10 mg/kg, i.p.) and administration schedules (chronic and acute) of OEA were assessed at the behavioral, histological, cellular, and molecular levels to determine the most effective OEA treatment regimen. Our in vivo results demonstrated that OEA treatment prior to the onset of the preneurodegenerative phase prevented morphological alterations in Purkinje neurons (the somata and dendritic arbors) and decreased Purkinje cell death. This effect followed an inverted U-shaped time-response curve, with acute administration on postnatal day 12 (10 mg/kg, i.p.) being the most effective treatment regimen tested. Indeed, PCD mice that received this specific OEA treatment regimen showed improvements in motor, cognitive and social functions, which were impaired in these mice. Moreover, these in vivo neuroprotective effects of OEA were mediated by the PPARα receptor, as pretreatment with the PPARα antagonist GW6471 (2.5 mg/kg, i.p.) abolished them. Finally, our in vitro results suggested that the molecular effect of OEA was related to microtubule stability and structure since OEA administration normalized some alterations in microtubule features in PCD-like cells. These findings provide strong evidence supporting the use of OEA as a pharmacological agent to limit severe cerebellar neurodegenerative processes.

Silica nanoparticles (SiNPs) have been touted for their role in the management of non-communicable diseases. Their neuroprotective benefits against heavy metal-induced neurotoxicity remain largely unexplored. This is a comparative evaluation of the oxido-inflammatory and neurotrophic effects of Ni, Al, and Ni/Al mixture on the cerebellum of male albino rats with or without treatment with SiNPs generated from melon seed husk. The study complied with the ARRIVE guidelines for reporting in vivo experiments. A total of 91, 7–9 week-old weight-matched male Sprague rats (to avoid sex bias) were randomly divided into 13 different dosing groups where Group 1 served as the control. Other groups received 0.2 mg/kg Ni, 1 mg/kg Al, and 0.2 mg/kg Ni + 1 mg/kg Al mixture with or without different doses of SiNP for 90 days. Rotarod performance was carried out. Oxidative stress markers, Ni, Al, Ca, Fe, Mg, neurotrophic factors, amyloid beta (Aβ-42), cyclooxygenase-2 (COX-2), and acetylcholinesterase (AChE) were determined in the cerebellum. SiNPs from melon seed husk caused a significant decrease in Aβ-42 level and activities of AChE and COX-2 and a significant increase in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mediated by Ni, Al, and Ni/Al mixture exposure in rats. Neurotoxicity of the Ni/Al mixture is via heightened neuronal lipoperoxidative damage, decreased Mg, and increased Fe, and co-administration of SiNPs from melon seed husk with the Ni/Al mixture attenuated some of these biochemical changes in the cerebellum.

Purpose We aimed to evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating cerebellar mutism syndrome (CMS). Methods We retrospectively reviewed all pediatric patients who underwent a posterior fossa tumor resection between May 2007 to September 2022 at a single quaternary pediatric hospital. We evaluated clinical presentation and hospital course, including imaging findings, pathology, and surgical approaches. Propensity score matching was used to compare the symptom duration of patients who received SSRIs versus those who did not. Results A total of 292 patients met the criteria with 25% ( n  = 73) being diagnosed with CMS. Several factors were significantly associated with a CMS diagnosis, such as pre-operative hydrocephalus ( p  = 0.002), a vermis-splitting approach ( p  = 0.007), tumor in the fourth ventricle ( p  = 0.010), medulloblastoma diagnosis ( p  = 0.009), and postoperative complication ( p  < 0.001). Of the patients diagnosed with CMS, 32.9% ( n  = 24) received SSRI treatment, specifically fluoxetine ( n  = 18) and sertraline ( n  = 6). Overall, treatment did not decrease the duration of CMS symptoms or shorten the inpatient rehab course compared to matched controls. However, within the cohort of fluoxetine-treated patients, earlier initiation of medication was significantly correlated with a shorter duration of mutism ( p  = 0.007). Conclusions We report the largest cohort of CMS patients treated with SSRIs. The lack of overall clinical benefit when compared to untreated patients in our study may be due to the length of delay in starting an SSRI, since early initiation of fluoxetine correlated with shorter CMS symptoms. These results support the importance of early clinical detection of CMS and potentially treating CMS early in the patient’s postoperative course.

Abstract Objectives In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brain stem or spinal cord. The advent of disease-modifying treatments for MS has increased attention on early stages of the disease. Therefore, the aim of this study was to evaluate the effect of interferon on relapses and progression of disability in patients with a CIS. Patients and methods This randomized, clinical trial was conducted in 25 patients who presented with a CIS indicative of MS. They were evaluated in two groups: 11 patients who were receiving interferon-beta1a (Rebif, Serono) subcutaneous injections three times a week (group A), and 14 patients who were not receiving disease-modifying treatment (group B). The progression of disability was determined using the Kurtzke Expanded Disability Status Scale (EDSS) and the numbers of new relapses were recorded during 21 months of follow-up. Results The mean numbers of new relapses and changes in EDSS at the end of study period were 0.68 (standard deviation [S.D.] = 0.80) and −1.09 (S.D. = 0.49), and 1.79 (S.D. = 1.05) and −0.64 (S.D. = 0.49) in groups A and B, respectively. Statistical analysis showed that disease-modifying treatment with interferon-beta1a may reduce relapses ( P = 0.007) and prevent progressive disability ( P = 0.034). Conclusion Interferon-beta1a significantly delayed progression to disability and incidence of new relapses.

Background Acute cerebellitis (AC) and acute cerebellar ataxia (ACA) are the principal causes of acute cerebellar dysfunction in childhood. Nevertheless. there is no accepted consensus regarding the best management of children with AC/ACA: the aim of the study is both to assess clinical, neuroimaging and electrophysiologic features of children with AC/ACA and to evaluate the correlation between clinical parameters, therapy and outcome. Methods A multicentric retrospective study was conducted on children ≤ 18 years old admitted to 12 Italian paediatric hospitals for AC/ACA from 01/01/2003 to 31/12/2013. A score based on both cerebellar and extracerebellar signs/symptoms was computed for each patient. One point was given for each sign/symptom reported. Severity was divided in three classes: low, moderate, severe. Results A total of 124 children were included in the study. Of these, 118 children received a final diagnosis of ACA and 6 of AC. The most characteristic finding of AC/ACA was a broad-based gait disturbance. Other common symptoms included balance disturbances, slurred speech, vomiting, headache and fever. Neurological sequelae were reported in 6 cases (5%) There was no correlation among symptoms, cerebrospinal fluid findings, clinical outcome. There was no correlation between clinical manifestations and clinical score on admission and length of hospital stay, sex, age and EEG findings with sequelae ( P > 0.05). Children with pathological magnetic resonance imaging (MRI) or computed tomography (CT) had a higher probability of having clinical sequelae. Treatment was decided independently case by case. Patients with a higher clinical score on admission had a higher probability of receiving intravenous steroids. Conclusions We confirmed the literature data about the benign course of AC/ACA in most cases but we also highlighted a considerable rate of patients with neurological sequelae (5%). Pathological MRI or CT findings at admission correlate to neurological sequelae. These findings suggest the indication to perform an instrumental evaluation in all patients with AC/ACA at admission to identify those at higher risk of neurological outcome. These patients may benefit from a more aggressive therapeutic strategy and should have a closer follow-up. Randomized controlled trials are needed to confirm these observations. The ultimate goal of these studies could be to develop a standardized protocol on AC/ACA. The MRI/CT data, associated with the clinical manifestations, may allow us to define the class risk of patients for a neurological outcome.

The aim of this study was to assess the efficacy and the safety of ondansetron administered orally in patients with a cerebellar disorder. The study was a randomised, multi-center, double-blind trial. The patients were randomised either to oral ondansetron 8 mg or to placebo twice daily for seven days. Cerebellar dysfunction was quantified before and after treatment using the International Cooperative Ataxia Rating Scale (ICARS). We performed a global analysis (total scores), we analysed by subscores (4 subscores: oculomotor, speech, kinetic, postural) and subgroups (4 subgroups: Cerebellar Cortical Atrophy (CCA), Multiple Systemic Atrophy (MSA), Familial Cerebellar Degeneration (FCD) and miscellaneous cerebellar disorders), and we also performed an analysis by individual test items. We investigated whether ondansetron and placebo had different effects upon ICARS total scores and subscores in the 4 subgroups considered together or separately. For p values < 0.05, we subsequently applied the Mann-Whitney test to compare ondansetron and placebo effect for each individual item. We evaluated 45 of the 46 patients included. No effect was found in global analysis. We found no difference in the analysis of the ICARS subscores. Concerning the individual test items, there was a significant difference between the placebo and ondansetron for the finger-to-nose test (p = 0.049), the Heel-to-Knee test (HK); (p = 0.03), the Body Sway Eyes Closed (p = 0.017) and the Body Sway Eyes Open (BSEO); (p = 0.014). There was no significant difference for tremor in upper limbs (p = 0.32) or for gait (p = 0.49). The Mann-Whitney test showed a greater effect of ondansetron than placebo for BSEO in miscellaneous disorders (p = 0.013) and for HK in FCD (p = 0.036), but ondansetron was deleterious for HK in CCA (p = 0.019). Our study showed no effect of oral ondansetron on global cerebellar dysfunction. The analysis by subgroups showed that the oral form of ondansetron (a) is deleterious for coordination in patients with CCA, (b) has no effect upon tremor in upper limbs, and (c) has a mild effect upon posture and coordination in lower limbs in some subgroups of ataxic diseases.