A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity.

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Using a mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of pro-inflammatory IL-1ß, we sought to uncover causes of cerebellar damage. In this model, IL-1ß is administered between postnatal day (P) 1 to day 5, a timing equivalent to the last trimester for brain development in humans. Structural MRI analysis revealed that systemic IL-1ß treatment induced specific reductions in gray and white matter volumes of the mouse cerebellar lobules I and II (5% false discovery rate [FDR]) from P15 onwards. Preceding these MRI-detectable cerebellar volume changes, we observed damage to oligodendroglia, with reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) at P10 and P15. Increased density of IBA1+ cerebellar microglia were observed both at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebellums and cerebrums revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but cerebellar microglia displayed a unique type I interferon signaling dysregulation. Collectively, these data suggest that perinatal inflammation driven by systemic IL-1ß leads to specific cerebellar volume deficits, which likely reflect oligodendrocyte pathology downstream of microglial activation. Further studies are now required to confirm the potential of protective strategies aimed at preventing sustained type I interferon signaling driven by cerebellar microglia as an important therapeutic target.

Phenytoin and damage to the cerebellum - a systematic review of published cases.

INTRODUCTION: The antiseizure medication phenytoin has been associated with changes in the cerebellum, cerebellar signs, and permanent cerebellar damage. We have systematically reviewed the clinical and radiological features, and their correlation. AREAS COVERED: We identified sixty case reports and case series of the effects of phenytoin on the cerebellum by searching Medline and Embase and relevant reference lists. The reports described 92 [median 1, range 1-5] cases, documented median age 28 [2.7-78] years. Eighty-one cases described one or more clinical sign of ataxia (present in 96%), dysarthria (63%), and nystagmus (70%). The neurological outcome (in 76 cases): 10 (13%) recovered by 12 months; 55 (72%) suffered residual disability; and 11 (14%) died. Median serum phenytoin concentration (48 cases) was 50 (interquartile range 31-66) mg/L; only three values were below 20 mg/L. The radiological findings included cerebellar atrophy in 41 of 61 patients (67%) with at least one scan. EXPERT OPINION: Evidence mainly comes from case reports, and is inevitably biased. Most patients with cerebellar dysfunction have phenytoin concentrations above the reference range. Clinical signs of ataxia can persist without radiological evidence of cerebellar atrophy, and cerebellar atrophy is seen without any clinical evidence of cerebellar dysfunction.

The protective effect of nnano-selenium against cadmium-induced cerebellar injury via the heat shock protein pathway in chicken.

Cadmium (Cd) is one of the toxic environmental heavy metals that poses health hazard to animals due to its toxicity. Nano-Selenium (Nano-Se) is a Nano-composite form of Se, which has emerged as a promising therapeutic agent for its protective roles against heavy metals-induced toxicity. Heat shock proteins (HSPs) play a critical role in cellular homeostasis. However, the potential protective effects of Nano-Se against Cd-induced cerebellar toxicity remain to be illustrated. To investigate the toxic effects of Cd on chicken's cerebellum, and the protective effects of Nano-Se against Cd-induced cerebellar toxicity, a total of 80 male chicks were divided into four groups and treated as follows: (A) 0 mg/kg Cd, (B) 1 mg/kg Nano-Se (C) 140 mg/kg Cd + 1 mg/kg Nano-Se (D) 140 mg/kg Cd for 90 days. We tested heat shock protein pathway-related factors including heat shock factors (HSFs) HSF1, HSF2, HSF3 and heat shock proteins (HSPs) HSP10, HSP25, HSP27, HSP40, HSP60, HSP70 and HSP90 expressions. Histopathological results showed that Cd treatment caused degradation of Purkinje cells. In addition, HSFs and HSPs expression decreased significantly in the Cd group. Nano-Se co-treatment with Cd enhanced the expression of HSFs and HSPs. In summary, our findings explicated a potential protective effect of Nano-Se against Cd-induced cerebellar injury in chicken, suggesting that Nano-Se is a promising therapeutic agent for the treatment of Cd toxicity.

Modulation of vigabatrin induced cerebellar injury: the role of caspase-3 and RIPK1/RIPK3-regulated cell death pathways.

Vigabatrin is the drug of choice in resistant epilepsy and infantile spasms. Ataxia, tremors, and abnormal gait have been frequently reported following its use indicating cerebellar involvement. This study aimed, for the first time, to investigate the involvement of necroptosis and apoptosis in the VG-induced cerebellar cell loss and the possible protective role of combined omega-3 and vitamin B12 supplementation. Fifty Sprague-Dawley adult male rats (160-200 g) were divided into equal five groups: the control group received normal saline, VG200 and VG400 groups received VG (200 mg or 400 mg/kg, respectively), VG200 + OB and VG400 + OB groups received combined VG (200 mg or 400 mg/kg, respectively), vitamin B12 (1 mg/kg), and omega-3 (1 g/kg). All medications were given daily by gavage for four weeks. Histopathological changes were examined in H&E and luxol fast blue (LFB) stained sections. Immunohistochemical staining for caspase-3 and receptor-interacting serine/threonine-protein kinase-1 (RIPK1) as well as quantitative real-time polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP), caspase-3, and receptor-interacting serine/threonine-protein kinase-3 (RIPK3) genes were performed. VG caused a decrease in the granular layer thickness and Purkinje cell number, vacuolations, demyelination, suppression of MBP gene expression, and induction of caspases-3, RIPK1, and RIPK3 in a dose-related manner. Combined supplementation with B12 and omega-3 improved the cerebellar histology, increased MBP, and decreased apoptotic and necroptotic markers. In conclusion, VG-induced neuronal cell loss is dose-dependent and related to both apoptosis and necroptosis. This could either be ameliorated (in low-dose VG) or reduced (in high-dose VG) by combined supplementation with B12 and omega-3.

Amiodarone-induced Ataxia: A Case Report of Severe Cerebellar Dysfunction and Review of Literature.

Amiodarone therapy is widely prescribed in patients with atrial fibrillation. The higher prevalence of this arrhythmic heart disease, and the specific age-related issues of homeostasis in the elderly population, makes this group particularly exposed to its adverse effects. Among the many described side-effects, neurological impairments are the less documented and studied. Because amiodarone can be responsible for severe complications, as described in the case below, a close monitoring is necessary throughout its prescription. Awareness should be brought on the amiodarone-induced neurological side-effects as they could be overlooked.

Metronidazole-induced reversible cerebellar dysfunction.

A 73-year-old man who presented with fever and abdominal discomfort was diagnosed to have a liver abscess. He was treated with antimicrobials which included metronidazole. One month into treatment, he developed neurological symptoms and signs that were suggestive of cerebellar pathology. MRI of the brain showed T2/fluid attenuated inversion recovery hyperintensities involving bilateral dentate, fastigial and interpositus nuclei. After excluding common aetiologies, the possibility of metronidazole-induced neurotoxicity was considered. After stopping metronidazole, his symptoms and signs resolved. A subsequent MRI scan of the brain showed reversal of changes. Neurotoxicity caused by metronidazole is an uncommon adverse effect of a commonly used antimicrobial drug and should be considered in the appropriate clinical scenario.

Toxin-Induced Cerebellar Disorders.

The cerebellum plays an important role in motor and nonmotor systems, with damage resulting in clinical manifestations presenting as weakness, ataxia, dysarthria, and nystagmus. There are numerous environmental and industrial agents as well as medications that, through either accidental or intentional use, can result in a range of neurologic presentations. The variability in the presentation is important to recognize promptly so that early cessation in exposure, use, or abuse can be initiated to reduce the severity of symptoms. Recognition of an agent causing the particular pathology is important so that the route of exposure, and subsequent treatment options can be identified.

Síndrome cerebeloso secundario a metronidazol / Cerebellar syndrome caused by metronidazole

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Ethanol exposure induces cerebellar neuronal loss in rats

Ethanol exposure causes cerebellar dysfunction and cerebellar ataxia. Cerebellar Purkinje cells damage has not been explained as a constant finding in studies addressing the alcoholic brain or in experimental studies. The present study aimed to find out the changes of cerebellar Purkinje cells in adult rats. Adult rats were divided into control (C) and ethanol treated (E) groups eight animal each. The rats in group E were exposed to ethanol 1g/kg bodyweight for three months. Moderate ethanol intake produces significant reduction in the count of Purkinje cells in the anterior lobe of cerebellum with irregular shrunken outline losing their characteristic pyriform shape. Eosinophilic swelling seen adjacent to Purkinje cell bodies. Purkinje cells were observed without a prominent nucleolus or well defined nuclear membrane. Pyknosis of Purkinje cells was also observed

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Curcumin Attenuates Lead-Induced Cerebellar Toxicity in Rats via Chelating Activity and Inhibition of Oxidative Stress.

Lead (Pb) is a toxic, environmental heavy metal that induces serious clinical defects in all organs, with the nervous system being its primary target. Curcumin is the main active constituent of turmeric rhizome (Curcuma longa) with strong antioxidant and anti-inflammatory properties. This study is aimed at evaluating the therapeutic potentials of curcumin on Pb-induced neurotoxicity. Thirty-six male Sprague Dawley rats were randomly assigned into five groups with 12 rats in the control (normal saline) and 6 rats in each of groups, i.e., the lead-treated group (LTG) (50 mg/kg lead acetate for four weeks), recovery group (RC) (50 mg/kg lead acetate for four weeks), treatment group 1 (Cur100) (50 mg/kg lead acetate for four weeks, followed by 100 mg/kg curcumin for four weeks) and treatment group 2 (Cur200) (50 mg/kg lead acetate for four weeks, followed by 200 mg/kg curcumin for four weeks). All experimental groups received oral treatment via orogastric tube on alternate days. Motor function was assessed using a horizontal bar method. The cerebellar concentration of Pb was evaluated using ICP-MS technique. Pb-administered rats showed a significant decrease in motor scores and Superoxide Dismutase (SOD) activity with increased Malondialdehyde (MDA) levels. In addition, a marked increase in cerebellar Pb concentration and alterations in the histological architecture of the cerebellar cortex layers were recorded. However, treatment with curcumin improved the motor score, reduced Pb concentration in the cerebellum, and ameliorated the markers of oxidative stress, as well as restored the histological architecture of the cerebellum. The results of this study suggest that curcumin attenuates Pb-induced neurotoxicity via inhibition of oxidative stress and chelating activity.

Methadone-induced Toxic Encephalopathy In Pediatric Patients: Two Case Reports.

Toxic encephalopathy is a wide spectrum of encephalopathy secondary to insult from toxic substances, with variable clinical presentations from minor cognitive impairment to severe neurological dysfunction and death. Methadone-induced toxic encephalopathy is an extremely rare form of toxic encephalopathy which typically demonstrates abnormal imaging findings in the dentate nuclei or cerebellum. This is a report of methadone-induced toxic encephalopathy in two toddlers secondary to accidental ingestion. They were brought in unconscious to the emergency department of a tertiary hospital and were found to be cyanotic and pulseless, requiring cardiopulmonary resuscitation and mechanical ventilation. Magnetic resonance imaging (MRI) of the brain of both patients showed similar findings of symmetrical hyperintense foci in bilateral cerebellar hemispheres on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. These areas also demonstrated diffusion restriction on diffusion weighted imaging (DWI). Blood and urine toxicology results confirmed the presence of methadone in both patients. As the exact substance of accidental ingestion may not be known at the time of presentation, early radiological diagnosis of methadone-induced encephalopathy may prompt early initiation of treatment to prevent further life-threatening complications, particularly in vulnerable pediatric population.

Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics.

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU) is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been rarely reported as peripheral neuropathy, cerebellar syndrome, and multifocal leukoencephalopathy. Although very little is known about the pathogenetic mechanisms responsible for this toxicity, dihydropyrimidine dehydrogenase (DPD) deficiency has been found in few of these patients. TYMS gene encodes for the human thymidylate synthase, and is considered a candid factor for toxicity and efficacy of 5-FU and capecitabine. However, TYMS polymorphism has been associated previously with capecitabine-induced neurotoxicity. We report here a 31-year-old patient with metastatic colorectal cancer undergoing chemotherapy consisting of oxaliplatin and capecitabine who developed acute cerebellar syndrome during cycle 5. MRI did not show any abnormalities. We performed pharmacogenetic studies related to capecitabine including DPD deficiency and TYMS polymorphism. DPD gene mutation analysis was negative for the IVS14+1G>A mutation in the DPD gene, which accounts for 50% of the DPD deficiency alleles. However, the patient was found to have 3RG/3RC genotype and Del/Del genotype of TYMS 3'-untranslated region. Withdrawal of capecitabine improved his neurotoxicity in 9 days. No re-challenge was given to this patient but he was able to tolerate irinotecan, oxaliplatin, and bevacizumab without any toxicities. To the best of our knowledge, this is the first patient in the literature who developed acute cerebellar syndrome following capecitabine and was found to have mutations of TYMS. Patients on fluoropyrimidines, including capecitabine with new neurological symptoms must be investigated for a rare but real central neurotoxicity. Though the treatment of 5-FU neurotoxicity is supportive care but use of uridine triacetate may be indicated in few patients, especially with overdose.

Cerebellar Dysfunction in an Elderly Male After a Brief Course of Metronidazole.

BACKGROUND: Metronidazole, a widely used antibacterial and antiprotozoal drug, is often the drug of choice in amoebic liver abscess. The drug, otherwise safe, can cause serious central nervous disturbances in rare circumstances. CASE REPORT: Here, we report a case of cerebellar dysfunction in the form of slurring of speech and episodes of falls, in an elderly male following a three-week course of metronidazole therapy. RESULTS AND CONCLUSION: The patient manifested classic radiologic features of metronidazole neurotoxicity. Marked improvement in clinical symptoms was seen following drug discontinuation.