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Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex, and dysfunctional activity of Purkinje cells has been associated with ataxic movements. However, the synaptic characteristics of Purkinje cells in cases of ataxia are not yet well understood. The nicotinamide antagonist 3-acethylpyridine (3-AP) selectively destroys inferior olivary nucleus neurons so it is widely used to induce cerebellar ataxia. Five days after 3-AP treatment (65mg/kg) in adult male Sprague-Dawley rats, motor incoordination was revealed through BBB and Rotarod testing. In addition, in Purkinje cells from lobules V-VII of the cerebellar vermis studied by the Golgi method, the density of dendritic spines decreased, especially the thin and mushroom types. Western blot analysis showed a decrease in AMPA and PSD-95 content with an increase of the α-catenin protein, while GAD-67 and synaptophysin were unchanged. Findings suggest a limited capacity of Purkinje cells to acquire and consolidate afferent excitatory inputs and an aberrant, rigid profile in the movement-related output patterns of Purkinje neurons that likely contributes to the motor-related impairments characteristic of cerebellar ataxias., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: The use of immune checkpoint inhibitors, which have an important role in the treatment of malignant tumors, is increasing. Although rarely observed, neurological immune-related adverse events associated with immune checkpoint inhibitors result in high morbidity and mortality. Small cell lung cancer is a common cause of neurological paraneoplastic syndromes. The differentiation between paraneoplastic syndromes and neurological immune-related adverse events is important in patients using immune checkpoint inhibitors. Cerebellar ataxia caused by atezolizumab is a rare immune-related adverse event., Case Report: In this context, we present a 66-year-old man with small cell lung cancer who developed immune-mediated cerebellar ataxia after three cycles of atezolizumab, a programmed cell death ligand-1 inhibitor. The admission of brain and spinal gadolinium-based contrast-enhanced magnetic resonance imaging supported the preliminary diagnosis and indicated leptomeningeal involvement. However, the blood tests and a lumbar puncture did not reveal any structural, biochemical, paraneoplastic, or infectious cause., Management and Outcome: High-dose steroid treatment resulted in an improvement in the radiological involvement, as evidenced both clinically and on follow-up whole spine magnetic resonance imaging. Therefore, the immunotherapy was discontinued. The patient was discharged on day 20 without neurological sequelae., Discussion: In light of this, we present this case to emphasize the differential diagnosis of neurological immune-related adverse events originating from immune checkpoint inhibitors, which require rapid diagnosis and treatment, and clinically similar paraneoplastic syndromes and radiologically similar leptomeningeal involvement, in a case of small cell lung cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Acute cerebellar ataxia (ACA) and acute cerebellitis represent disorders characterized by a para-infectious, post-infectious, or post-vaccination cerebellar inflammation. They are relatively common neurologic disorders among children, and may follow infections, or, more rarely, vaccinations. Few cases are instead described among infants. Although the immunization with meningococcal group B (MenB) vaccine has been associated with some neurological side effects, suspected ACA has been reported only once in the literature., Case Presentation: we describe a 7-month-old female that presented ACA within 24 h from the MenB second dose vaccination. Extensive laboratory studies and magnetic resonance imaging excluded other causes. We then conducted an extended review of other vaccine related cases reported in the literature, focusing on the clinical characteristics of ACA and finding that ataxia and cerebellitis of para- or post-infectious cause are very rarely described in the first year of life. We collected 20 articles published in the last 30 years, including an amount of 1663 patients (1-24 years) with ACA., Conclusions: a very small number of suspected post-vaccinal ataxias has been described in recent years, compared to other causes, and vaccination remains an unquestionable medical need. Further research is needed to clarify the complex pathogenesis of this disorder and its eventual link with vaccinations., (© 2023. The Author(s).)

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have led to a revolution in cancer management, mainly due to lasting long-term durable responses in a subset of patients with metastatic solid tumours (Gettinger et al. in JCO 36(17):1675-1684, 2018). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological immune-related adverse events (irAEs) has increased (2). Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs (Johnson et al. in J Immuno Cancer 7(1):134, 2019; Wang et al. in JAMA Oncol 4(12):1721, 2018). Small-cell lung cancer (SCLC) is common cause of neurologic paraneoplastic syndrome (Sebastian et al. in J Thorac Oncol 14(11):1878-1880, 2019). Nevertheless, the distinction between neurologic iRAEs and paraneoplastic neurological syndromes (PNSs) in patients with SCLC treated by ICIs remains challenging (Williams et al. JAMA Neurol 73(8):928, 2016). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological autoimmune adverse events has increased. Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs and have yet to be fully understood. We report a case of an immune induced cerebellar ataxia in a 47 year-old small-cell neuroendocrine carcinoma patient undergoing checkpoint blockade by atezolizumab, a programmed cell death-1 ligand (PDL-1) inhibitor. After 4 cycles of immunotherapy, the patient presented with kinetic and static cerebellar syndrome leading to the diagnosis of TRIM9-Abs ICI-related cerebellar irAE. Therapeutic management was discussed in multidisciplinary meetings in the lack of therapeutic guidelines. There was no clinical improvement. Because of high morbidity and no treatment evidence, neurologic symptoms developing under ICI require early diagnosis and may indicate the need for definitive treatment discontinuation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. This study aims to investigate the therapeutic effects of melittin (MEL) on a 3-acetylpyridine-induced (3-AP) cerebellar ataxia (CA) rat model., Methods: Initially, CA rat models were generated by 3-AP administration followed by the subcutaneous injection of MEL. The open-field test was used for the evaluation of locomotion and anxiety. Immunohistochemistry was also conducted for the autophagy markers of LC3 and Beclin1. In the next step, the morphology of the astrocyte, the cell responsible for maintaining homeostasis in the CNS, was evaluated by the Sholl analysis., Results: The findings suggested that the administration of MEL in a 3-AP model of ataxia improved locomotion and anxiety (P < 0.001), decreased the expression of LC3 (P < 0.01) and Beclin1 (P < 0.05), increased astrocyte complexity (P < 0.05) and reduced astrocyte cell soma size (P < 0.001)., Conclusions: Overall, the findings imply that the MEL attenuates the 3-AP-induced autophagy, causes cell death and improves motor function. As such, it could be used as a therapeutic procedure for CA due to its neuroprotective effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

Cerebellar ataxia (CA) is a condition in which cerebellar dysfunction leads to movement disorders such as dysmetria, asynergy and dysdiadochokinesia. This study investigates the therapeutic effects of Melittin (MEL) on 3-acetylpyridine-induced (3-AP) cerebellar ataxia (CA) rat model. Initially, CA rat models were generated by 3-AP administration followed by the intraperitoneal injection of MEL. Then, motor performance and electromyography (EMG) activity were assessed. Afterwards, the pro-inflammatory cytokines were analyzed in the cerebellar tissue. Moreover, the anti-apoptotic role of MEL in CA and its relationship with the protection of Purkinje cells were explored. The findings showed that the administration of MEL in a 3-AP model of ataxia improved motor coordination (P < 0.001) and neuro-muscular activity (p < 0.05), prevented the cerebellar volume loss (P < 0.01), reduced the level of inflammatory cytokines (p < 0.05) and thwarted the degeneration of Purkinje cells against 3-AP toxicity (P < 0.001). Overall, the findings imply that the MEL attenuates the 3-AP-induced inflammatory response. As such, it could be used as a treatment option for CA due to its anti-inflammatory effects., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Alcohol intoxication produces ataxia by affecting the cerebellum, which coordinates movements. Fragile X mental retardation (FMR) protein is a complex regulator of RNA and synaptic plasticity implicated in fragile X-associated tremor/ataxia syndrome, which features ataxia and increased Fmr1 mRNA expression resulting from epigenetic dysregulation of FMRP. We recently demonstrated that acute ethanol-induced ataxia is associated with increased cerebellar Fmr1 gene expression via histone modifications in rats, but it is unknown whether similar behavioral and molecular changes occur following chronic ethanol exposure. Here, we investigated the effects of chronic ethanol exposure on ataxia and epigenetically regulated changes in Fmr1 expression in the cerebellum., Methods: Male adult Sprague-Dawley rats were trained on the accelerating rotarod and then fed with chronic ethanol or a control Lieber-DeCarli diet while undergoing periodic behavioral testing for ataxia during ethanol exposure and withdrawal. Cerebellar tissues were analyzed for expression of the Fmr1 gene and its targets using a real-time quantitative polymerase chain reaction assay. The epigenetic regulation of Fmr1 was also investigated using a chromatin immunoprecipitation assay., Results: Ataxic behavior measured by the accelerating rotarod behavioral test developed during chronic ethanol treatment and persisted at both the 8-h and 24-h withdrawal time points compared to control diet-fed rats. In addition, chronic ethanol treatment resulted in up-regulated expression of Fmr1 mRNA and increased activating epigenetic marks H3K27 acetylation and H3K4 trimethylation at 2 sites within the Fmr1 promoter. Finally, measurement of the expression of relevant FMRP mRNA targets in the cerebellum showed that chronic ethanol up-regulated cAMP response element binding (CREB) Creb1, Psd95, Grm5, and Grin2b mRNA expression without altering Grin2a, Eaa1, or histone acetyltransferases CREB binding protein (Cbp) or p300 mRNA transcripts., Conclusions: These results suggest that epigenetic regulation of Fmr1 and subsequent FMRP regulation of target mRNA transcripts constitute neuroadaptations in the cerebellum that may underlie the persistence of ataxic behavior during chronic ethanol exposure and withdrawal., (© 2021 Research Society on Alcoholism. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background and Aim: Neurodegeneration has been associated with the use of combination antiretroviral therapy (cART). This study is aimed at determining if any constituent of cART can induce cerebellar limb dysmetria and spatial memory impairments., Materials and Methods: Forty adult male Wistar rats were randomly grouped into four (n = 10): control (distilled water 0.5 mL); Tenofovir (6 mg/kg); Lamivudine (6 mg/kg) and Efavirenz (12 mg/kg). The following neurobehavioral studies were conducted: open field, beam walk, and Morris water maze. Immunohistochemistry of CD 68 and GFAP were used to test for neuroinflammation and neurodegeneration., Results: There was marked increase in pyknotic pyramidal cells of the hippocampus and ghost Purkinje cells in the cerebellum of treatment groups. There was also a significant increase in oxidative stress in lamivudine and efavirenz groups. In addition, Lamivudine caused a significant increase of microglial and astrocytic activity (p < 0.001, 0.05 respectively) compared to control. The open field test showed a significant decrease (p < 0.0001) of the line crossing performance in the efavirenz, lamivudine and tenofovir (with means: 26.4, 4.6, 17.4 respectively) compared to control (50.6). There was also a significant decrease in the grooming (p < 0.05) and rearing (p < 0.01) in lamivudine group. Whereas, walk latency increased in efavirenz (p < 0.01), and lamivudine (p < 0.0001) compared to control. While hind limb slips significantly increased in efavirenz (p < 0.05) and lamivudine (p < 0.0001) compared with control group. Likewise, Lamivudine and Tenofovir exposed groups experienced a significant delay in the time to identify the hidden platform in compared to control (p < 0.05)., Conclusion: Lamivudine altered efferent stimuli along the cerebellospinal tracts thereby causing motor impairments. The degenerating Purkinje fibers may have induced marked neurodegeneration in the hippocampus resulting in impaired spatial memory., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although several studies have demonstrated the neuroprotective effects of Hericium erinaceus (H.E.), its mechanisms in cerebellar ataxia remain largely unknown. Here, we investigated the neuroprotective effects of H.E. treatment in an animal model of 3-acetylpyridine (3-AP)-induced cerebellar ataxia. Animals administered 3-AP injection exhibited remarkable impairments in motor coordination and balance. There were no significant effects of 25 mg/kg H.E. on the 3-AP treatment group compared to the 3-AP saline group. Interestingly, there was also no significant difference in the 3-AP treatment group compared to the non-3-AP control, indicating a potential rescue of motor deficits. Our results revealed that 25 mg/kg H.E. normalised the neuroplasticity-related gene expression to the level of non-3-AP control. These findings were further supported by increased protein expressions of pERK1/2-pCREB-PSD95 as well as neuroprotective effects on cerebellar Purkinje cells in the 3-AP treatment group compared to the 3-AP saline group. In conclusion, our findings suggest that H.E. potentially rescued behavioural motor deficits through the neuroprotective mechanisms of ERK-CREB-PSD95 in an animal model of 3-AP-induced cerebellar ataxia.

Most cerebellar ataxias (CAs) are incurable neurological disorders, resulting in a lack of voluntary control by inflamed or damaged cerebellum. Although CA can be either directly or indirectly related to cerebellar inflammation, there is no suitable animal model of CA with neuroinflammation. In this study, we evaluated the utility of an intracerebellar injection of lipopolysaccharide (LPS) to generate an animal model of inflammatory CA. We observed that LPS administration induced the expression of pro-inflammatory molecules following activation of glial cells. In addition, the administration of LPS resulted in apoptotic Purkinje cell death and induced abnormal locomotor activities, such as impaired motor coordination and abnormal hindlimb clasping posture. Our results suggest that intracerebellar LPS administration in experimental animals may be useful for studying the inflammatory component of CA.

The cerebellum is widely known as a motor structure because it regulates and controls motor learning, coordination, and balance. However, it is also critical for non-motor functions such as cognitive processing, sensory discrimination, addictive behaviors and mental disorders. The cerebellum has the highest relative abundance of neuronal nitric oxide synthase (nNos) and is sensitive to ethanol. Although it has been demonstrated that the interaction of γ-aminobutyric acid (GABA) and nitric oxide (NO) might play an important role in the regulation of ethanol-induced cerebellar ataxia, the molecular mechanisms through which ethanol regulates nNos function to elicit this behavioral effect have not been studied extensively. Here, we investigated the dose-dependent effects of acute ethanol treatment on motor impairment using the rotarod behavioral paradigm and the alterations of nNos mRNA expression in cerebellum, frontal cortex (FC), hippocampus and striatum. We also examined the link between acute ethanol-induced motor impairment and nNos by pharmacological manipulation of nNos function. We found that acute ethanol induced a dose-dependent elevation of ethanol blood levels which was associated with the impairment of motor coordination performance and decreased expression of cerebellar nNos. In contrast, acute ethanol increased nNos expression in FC but did not to change the expression for this enzyme in striatum and hippocampus. The effects of acute ethanol were attenuated by l-arginine, a precursor for NO and potentiated by 7-nitroindazole (7-NI), a selective inhibitor of nNos. Our data suggests that differential regulation of nNos mRNA expression in cerebellum and frontal cortex might be involved in acute ethanol-induced motor impairment., (Published by Elsevier Inc.)

Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. Cell replacement therapy (CRT) has been considered as a potential treatment for neurological disorders. In this report, we investigated the neuro-restorative effects of human chorionic stem cells (HCSCs) transplantation on rat model of CA induced by 3-acetylpyridine (3-AP). In this regard, HCSCs were isolated and phenotypically determined. Next, a single injection of 3-AP was administered for ataxia induction, and bilateral HCSCs implantation was conducted 3 days after 3-AP injection, followed by expression analysis of a number of apoptotic, autophagic and inflammatory genes as well as vascular endothelial growth factor (VEGF) level, along with assessment of cerebellar neurodegeneration, motor coordination and muscle activity. The findings revealed that grafting of HCSCs in 3-AP model of ataxia decreased the expression levels of several inflammatory, autophagic and apoptotic genes and provoked the up-regulation of VEGF in the cerebellar region, prevented the degeneration of Purkinje cells caused by 3-AP toxicity and ameliorated motor coordination and muscle function. In conclusion, these data indicate in vivo efficacy of HCSCs in the reestablishment of motor skills and reversal of CA.

We herein report a 68-year-old man with neurologic immune-related adverse events (irAEs) who exhibited nivolumab-induced steroid-responsive progressive ataxia, tremor, and anti-thyroid antibodies. His symptoms matched abnormalities on N-isopropyl-p-(123I)-iodoamphetamine single-photon emission computed tomography (SPECT) and dopamine transporter SPECT. Based on these clinical findings, we diagnosed the patient with a condition similar to the cerebellar type of Hashimoto's encephalopathy with nivolumab-induced anti-thyroid antibodies. Neurologic irAEs can be difficult to diagnose due to their varied clinical courses and lack of specific examinations. Therefore, a comprehensive approach, including assessments of autoantibodies and functional imaging, might be important for the diagnosis of neurologic irAEs.

Background: Cerebellar ataxias comprise a group of terminal illnesses with ataxia as the main symptom. Curcumin as a yellow polyphenol was extracted from the rhizome ofCurcuma longa. Owing to its antioxidant, anti-inflammatory, anti-fibrotic and anti-tumor features, curcumin is considered as a potential therapeutic agent., Aim: In this study, we aim to investigate the neuroprotective effects of oral administration of curcumin on a rat model of cerebellar ataxia induced by neurotoxin 3-acetylpyridine., Methods: The animals were randomly separated into three groups (control, 3-acetylpyridine, and curcumin + 3-acetylpyridine). Next, motor performance and muscle electromyography activity were assessed. Then, in the molecular part of the study, the anti-apoptotic role of curcumin in cerebellar ataxia and its relationship to protection of Purkinje cells were investigated., Results: Curcumin treatment improved motor coordination and muscular activity, reduced cleaved caspase-3, and increased glutathione level in 3-AP-lesioned rats as well as total volumes of cerebellar granular and molecular layers., Conclusion: the present study implies that curcumin might have neuroprotective effects to counteract neurotoxicity of 3-AP-induced ataxia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Case presentation: A 66-year-old gentleman with metastatic non-small-cell lung cancer developed a wide-based gait following treatment on a clinical trial with cytotoxic chemotherapy and an anti-PD-L1 drug. He had no other significant past medical history of note. Brain imaging, blood tests and lumbar puncture did not reveal a structural, biochemical, paraneoplastic or infective cause. The main differential diagnoses were immune-mediated toxicity or a paraneoplastic syndrome. He was started on prednisolone on the suspicion that his symptoms represented an immune-mediated toxicity. His condition improved following this and his immunotherapy treatment was discontinued. Upon steroid withdrawal, his symptoms recurred and responded to further prednisolone. Conclusions: Immune-mediated toxicities can affect any part of the nervous system and should form part of the differential diagnosis for new neurological symptoms in a patient receiving immunotherapy. Corticosteroids should be the first-line treatment of immune-mediated toxicities. Immunotherapy should be permanently discontinued following severe toxicities.

Introduction: Capecitabine is a fluoropyrimidine commonly used in the treatment of colorectal cancer which may cause central nervous system toxicity, namely cerebellar dysfunction., Case Report: We describe a 77-year-old man undergoing adjuvant treatment of colon cancer with capecitabine and oxaliplatin who presented with acute cerebellar ataxia and encephalopathy that progressed to coma. Diagnosis of toxic encephalopathy was made after the exclusion of alternative causes of neurological dysfunction and complete resolution of clinical findings with permanent discontinuation of chemotherapy., Discussion: When patients with cancer develop symptoms and signs of central nervous dysfunction, metabolic and infectious causes plus tumor involvement of central nervous system must be sought. However, chemotherapy may also cause toxicity to the central nervous system. Capecitabine is no exception, although cerebellar dysfunction is rarely reported., Conclusion: Although rare, capecitabine-induced encephalopathy may be severe and physicians should be aware of this possible side effect.

A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases.

Background: Purkinje cells (PCs) pathology is important in cerebellar disorders like ataxia. The spatial arrangement of PCs after different treatments has not been studied extensively. Immunohistochemistry (IHC) analysis of cerebellum can give a proper tool for explaining the pathophysiology of PCs in ataxia. Here we stereologically analysed the 3-dimensional spatial arrangement of PCs in the cerebellum of rats after ataxia induction with 3-acetylpyridine (3-AP)., Materials and Methods: Ataxia was induced in rats by intraperitoneal injection of 3-AP (65 mg/kg). Spatial arrangement of PCs for differences in ataxic rats with (3-AP-SC) or without (3-AP) Sertoli cells (SCs) transplantation was evaluated using second-order stereology. The IHC method by using antibodies to anti-calbindin in the cerebellum was applied., Results: Our results showed that a random arrangement is at larger distances between PCs in 3-AP and 3-Ap-SC groups. Therefore the PCs are not normally arranged after 3-AP and SCs transplantation stored the spatial arrangements of the cells after ataxia induction in rats. IHC analyse shows that number of PCs was significantly improved after the SC transplantation., Conclusions: Segregation of PCs can be observed at some areas in the ataxic rats' cerebellum. However, the spatial arrangement of PCs was unchanged in SCs transplanted rats. (Folia Morphol 2018; 77, 2: 194-200).

We present a case of cerebellar dysfunction due to severe hypothyroidism induced by pembrolizumab, a member of the 'immune checkpoint inhibitor' class of cancer immunotherapies. Thyroxine replacement completely resolved his symptoms and signs. We also discuss the neurological immune-related complications of checkpoint inhibitors., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Transgenic knock-in (KI) mice that express Ca V 2.1 channels containing an R192Q gain-of-function mutation in the α 1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold. This implies that intrinsic neuronal conductances may shape action potential generation in response to ATP, which could act as a mediator of migraine headache. Here we investigated whether the hyperpolarization-activated conductance I h , mediated by hyperpolarization activated cyclic nucleotide-gated channels (HCN), contributes to sub-threshold behavior and firing in wild-type (WT) and KI trigeminal ganglia (TG) neurons. Whereas most WT and KI trigeminal neurons expressed I h current, blocked by the specific inhibitor ZD7288, it was smaller in KI neurons despite similar activation and deactivation kinetics. HCN1 and HCN2 were the most abundantly expressed subunits in TG, both in situ and in culture. In KI TG neurons, HCN2 subunits were predominantly present in the cytoplasm, not at the plasma membrane, likely accounting for the smaller I h of such cells. ZD7288 hyperpolarized the membrane potential, thereby raising the firing threshold, and prolonging the spike trajectory to generate fewer spikes due to P2X3 receptor activation. The low amplitude of I h in KI TG neurons suggests that down-regulation of I h current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyperexcitability, manifested under certain stressful stimuli., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity., Competing Interests: I have read the journal's policy and have the following conflicts: Takayoshi Shimohata is an academic advisor for ShimoJani LLC, entrepreneurial venture, San Francisco,CA, USA. Other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment.

The neurological toxicity of many antibiotics has been reported in a number of articles and clinical notes. In this review antibiotics are classified according to the physiopathogenic mechanism that can give rise to a gait disorder, taking both clinical and experimental data into account. An exhaustive search was conducted in Google Scholar and PubMed with the aim of finding reviews, articles and clinical cases dealing with gait disorders secondary to different antibiotics. The different antibiotics were separated according to the physiopathogenic mechanism that could cause them to trigger a gait disorder. They were classified into antibiotics capable of producing cerebellar ataxia, vestibular ataxia, sensitive ataxia or an extrapyramidal gait disorder. The main aim was to group all the drugs that can give rise to a gait disorder, in order to facilitate the clinical suspicion and, consequently, the management of patients.

Acute ataxia in a pediatric patient poses a diagnostic dilemma for any physician. While the most common etiologies are benign, occasional individuals require urgent intervention. Children with stroke, toxic ingestion, infection, and neuro-inflammatory disorders frequently exhibit ataxia as an essential-if not the only-presenting feature. The available retrospective research utilize inconsistent definitions of acute ataxia, precluding the ability to pool data from these studies. No prospective data exist that report on patients presenting to the emergency department with ataxia. This review examines the reported causes of ataxia and attempts to group them into distinct categories: post-infectious and inflammatory central and peripheral phenomena, toxic ingestion, neurovascular, infectious and miscellaneous. From there, we synthesize the existing literature to understand which aspects of the history, physical exam, and ancillary testing might aid in narrowing the differential diagnosis. MRI is superior to CT in detecting inflammatory or vascular insults in the posterior fossa, though CT may be necessary in emergent situations. Lumbar puncture may be deferred until after admission in most instances, with suspicion for meningitis being the major exception. There is insufficient evidence to guide laboratory evaluation of serum, testing should be ordered based on clinical judgement-recommended studies include metabolic profiles and screening labs for metabolic disorders (lactate and ammonia). All patients should be reflexively screened for toxic ingestions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Acute encephalopathy in a patient with alcoholic liver disease (ALD) is a commonly encountered emergency situation occurring most frequently due to liver failure precipitated by varying etiologies. Acute reversible cerebellar ataxia with confusion secondary to prolonged metronidazole use has been reported rarely as a cause of encephalopathy in patients with ALD., Case Report: We describe a decompensated ALD patient with recurrent pyogenic cholangitis associated with hepatolithiasis who presented to the emergency department with sudden-onset cerebellar ataxia with dysarthria and mental confusion after prolonged use of metronidazole. Magnetic resonance imaging (MRI) of the brain was suggestive of bilateral dentate nuclei hyper intensities on T2 and fluid-attenuated inversion recovery sections seen classically in metronidazole-induced encephalopathy (MIE). Decompensated liver cirrhosis resulted in decreased hepatic clearance and increased cerebrospinal fluid concentration of metronidazole leading to toxicity at a relatively low total cumulative dose of 22 g. Both the clinical symptoms and MRI brain changes were reversed at 7 days and 6 weeks, respectively, after discontinuation of metronidazole. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A patient with ALD presenting with encephalopathy creates a diagnostic dilemma for the emergency physician regarding whether to continue metronidazole and treat for hepatic encephalopathy or to suspect for MIE and withhold the drug. Failure to timely discontinue metronidazole may worsen the associated hepatic encephalopathy in these patients. Liver cirrhosis patients have higher mean concentration of metronidazole and its metabolite in the blood, making it necessary to keep the cumulative dose of metronidazole to < 20 g in them., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Drug-induced cerebellar ataxias (DICA) represent an important group of secondary cerebellar ataxias. Herein, we reported a case series of progressive cerebellar ataxia induced by HMG-CoA reductase inhibitors (statins)., Methods: Observational study with a Brazilian case series of patients with cerebellar ataxia due to statins use., Results: We described four patients with cerebellar ataxia, predominantly gait ataxia, due to statins use. Mean age was 67.5 years old, predominantly male, with several comorbidities, such as dyslipidemia, diabetes mellitus, hypertension, and myocardial revascularization. After statin withdrawal, and treatment with coenzyme Q10 in some patients, progressive improvement of gait ataxia was observed., Discussion: We presented a case series of four patients with cerebellar ataxia due to statins use, which represents a new rare side-effect of statins, probably related to coenzyme Q10 deficiency., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The oral iron chelator deferiprone is associated with various side effects including agranulocytosis, arthropathy, and deranged liver function tests. Rarely, neurological and visual side effects have been reported with high doses. The authors describe rare neurological manifestations of cerebellar ataxia, hypertonia, and bilateral cataract in an 11-year-old boy with thalassemia major on recommended therapeutic doses of deferiprone. The neurological abnormalities resolved with stoppage of deferiprone. Central nervous system toxicity and lenticular opacities may be attributed to the low molecular weight of deferiprone and its ability to cross the blood-brain and blood-ocular barrier, respectively. Clinicians should be alert to the possibility of neurological abnormalities that may occur during deferiprone therapy.

The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.

Objective: We previously showed that the cerebellum modulates the immune system. Here we determined whether cerebellar ataxia alters immunological function to further demonstrate an involvement of the cerebellum in immune modulation., Methods: Neurotoxin 3-acetylpyridine (3-AP) was intraperitoneally injected in rats to induce cerebellar ataxia. Behavior and motor coordination were tested on day 7 following 3-AP injection. Nissl staining and high-performance liquid chromatography (HPLC) were used to determine neuronal loss and neurotransmitter contents, respectively, in all the three cerebellar nuclei, fastigial nucleus (FN), interposed nucleus (IN) and dentate nucleus (DN). T and B lymphocyte differentiation and function were measured by flow cytometry, Western blot and ELISA., Results: 3-AP induced motor discoordination and locomotor reduction. In all the three cerebellar nuclei, FN, IN and DN, there was a neuronal loss and a decrease in contents of glutamate and GABA (but not glycine) after 3-AP injection. Importantly, CD4+ T cells, but not CD8+ T cells, were increased by the 3-AP treatment. Moreover, interferon (IFN)-γ-producing cells and interleukin (IL)-17-producing cells were decreased in cerebellar ataxia rats, but IL-4-producing cells and CD25-expressing cells were increased. Expression of the T helper (Th)1- and Th17-related cytokines, IFN-γ, IL-2, IL-17 and IL-22, was downregulated in CD4+ cells in cerebellar ataxia rats, while expression of the Th2 and regulatory T (Treg)-related cytokines, IL-4, IL-5, IL-10 and transforming growth factor (TGF)-β, was upregulated. Furthermore, B lymphocyte number and anti-bovine serum albumin (BSA) IgM and IgG antibody levels were elevated in cerebellar ataxia., Conclusion: Cerebellar ataxia alters cellular and humoral immunity.

Background and Objectives: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR)., Methods: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMBASE (1988 to January 2014) to identify all of the drugs that can have ataxia as an ADR and to assess the frequency of drug-induced ataxia for individual drugs. Furthermore, we collected reports of drug-induced ataxia over the past 20 years in the Netherlands by querying a national register of ADRs., Results: Drug-induced ataxia was reported in association with 93 individual drugs (57 from the literature, 36 from the Dutch registry). The most common groups were antiepileptic drugs, benzodiazepines, and antineoplastics. For some, the number needed to harm was below 10. Ataxia was commonly reversible, but persistent symptoms were described with lithium and certain antineoplastics., Conclusions: It is important to be aware of the possibility that ataxia might be drug-induced, and for some drugs the relative frequency of this particular ADR is high. In most patients, symptoms occur within days or weeks after the introduction of a new drug or an increase in dose. In general, ataxia tends to disappear after discontinuation of the drug, but chronic ataxia has been described for some drugs.

We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In the last five years in western Mongolia, a neurological disorder and resultant economic loss have developed in goats, sheep, cattle and horses: association of the disease with ingestion of Oxytropis glabra, a toxic plant, was suggested. Affected goats showed neurological signs, including ataxia, incoordination, hind limb paresis, fine head tremor and nystagmus. Three goats, one with moderate clinical signs and the other two with severe clinical signs, were necropsied and examined to describe and characterize the histologic, immunohistochemical and ultrastructural lesions. Although no gross pathological changes were observed in a variety of organs including the central nervous system of these goats, microscopic examination of the cerebellum demonstrated degenerative changes in all these goats, such as vacuolar changes and loss of Purkinje cells, torpedo formation in the granular layer, increased number of spheroids in the cerebellar medulla, and loss of axons and myelin sheaths of Purkinje cells. The chemical analysis of the dried plant detected 0.02-0.05% (dry weight basis) of swainsonine. This is the first report describing the clinical and pathological findings in Mongolian goats suspected to be affected by O. glabra poisoning.

A 30-year-old woman with chronic foot pain after an orthopaedic surgery and chronic neck pain presented to the emergency department (ED) with a history of self-rotatory vertigo with unsteadiness. She had started low-dose pregabalin, 25 mg two times a day 9 months before experiencing symptoms with the dose gradually increased to 150 mg two times a day over this period. Clinical examination revealed difficulty performing eye pursuit with left eye and dysdiadochokinesia of the left arm. Owing to a suspicion of multiple sclerosis she underwent cerebral MRI, which was normal. Pregabalin was tapered over 2 months with a complete disappearance of the symptoms. We concluded that symptoms were due to pregabalin treatment.

Pethidine is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, pethidine may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, pethidine potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity.

Background: We have previously shown that brain adenosine A1 receptors and nitric oxide (NO) play an important role in ethanol (EtOH)-induced cerebellar ataxia (EICA) through glutamate/NO/cGMP pathway. I now report possible modulation of EICA by the cerebellar NO/cGMP/K(ATP) pathway., Methods: EICA was evaluated by Rotorod in CD-1 male mice. All drugs (K(ATP) activators pinacidil, 0.05, 0.1, 0.5 nmol; minoxidil, 0.01, 0.1, 1.0 pmol; antagonists glipizide/glibenclamide, 0.01, 0.05, 0.1 nmol; NO donor l-arginine, 20 nmol; NOS inhibitors [iNOS] inhibitor L-NAME, 50 nmol; glutamate, 1.5 nmol; adenosine A1 receptor agonist N(6) -cyclohexyladenosine [CHA], 6, 12 pmol; antagonist DPCPX, 0.1 or 0.4 nmol) were given by direct intracerebellar microinfusion via stereotaxically implanted guide cannulas, except EtOH (2 g/kg, i.p.)., Results: Pinacidil and minoxidil dose-dependently accentuated, whereas glipizide and glibenclamide markedly attenuated EICA, indicating tonic participation of K(ATP) channels. Glipizide abolished the pinacidil potentiation of EICA, which confirmed both drugs acted via K(ATP) channels. A possible link between K(ATP) channels and glutamate/NO pathway was suggested when (i) CHA (12 pmol) totally abolished l-arginine-induced attenuation of EICA; (ii) L-NAME abolished l-arginine-induced attenuation of EICA associated with further increase in EICA; and (iii) the combined l-arginine and glutamate infusion virtually abolished EICA. Also, whereas CHA abolished glibenclamide-induced attenuation and potentiated pinacidil/minoxidil-induced accentuation of EICA, the effects of DPCPX were just the opposite to those of CHA., Conclusions: The results with CHA therefore suggest a functional link between K(ATP) and A1 receptors and between K(ATP) and glutamate/NO and as an extension may involve participation of NO/cGMP/K(ATP) pathway in EICA., (Copyright © 2013 by the Research Society on Alcoholism.)

Introduction: We report the case of a patient who developed symptoms of acute cerebellar ataxia (ACA) after administration of the human papilloma virus (HPV)-16/18 vaccine., Patient and Method: This patient developed symptoms of ACA, including nausea, vertigo, severe limb and truncal ataxia, and bilateral spontaneous continuous horizontal nystagmus with irregular rhythm, 12 days after administration of the HPV-16/18 AS04-adjuvanted cervical cancer vaccine. After this, the patient received methylprednisolone pulse and intravenous immunoglobulin (IVIG) therapies as well as immunoadsorption plasmapheresis., Results: Severe ACA symptoms did not improve after methylprednisolone pulse and IVIG therapies, but the patient recovered completely after immunoadsorption plasmapheresis., Conclusion: This temporal association strongly suggests that ACA was induced by the vaccination., (Georg Thieme Verlag KG Stuttgart · New York.)

The role of antibodies against the P/Q type voltage-gated calcium channels (VGCC-ab) in the pathogenesis of paraneoplastic cerebellar degeneration (PCD) and lung cancer is unclear. We evaluated in mice the effect of intrathecal injection of IgG purified from serum of a patient with both PCD and Lambert-Eaton myasthenic syndrome (LEMS), and from another patient with isolated LEMS. Mice injected with PCD/LEMS IgG developed marked, reversible ataxia compared with those injected with LEMS or control IgG. These findings suggest that P/Q-type VGCC-ab may play a role in the pathogenesis of ataxia in patients with PCD and SCLC., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Metronidazole is a widely used antimicrobial usually prescribed by many specialist doctors for a short duration of 10-15 days. Prolonged use of metronidazole is rare. The present case is of a patient who used the drug for 4 months and developed peripheral neuropathy, convulsions, and cerebellar ataxia. He was treated with diazepam and levetiracetam. The patient recovered completely following discontinuation of metronidazole.

Autoantibodies to the gamma-aminobutyric acid-B (GABAB) receptor were recently described in patients with limbic encephalitis presenting with early or prominent seizures. We report on a 64-year-old man with malignant melanoma who during adjuvant therapy with interferon (IFN)-alpha developed cerebellar ataxia. Indirect immunofluorescence on brain tissue sections revealed high-titer (1:20,000) IgG1 serum autoantibodies to the cerebellar molecular and granular layer, which were confirmed to be directed against GABAB receptor in a cell-based assay. This case highlights cerebellar ataxia in the absence of seizures as a clinical manifestation of GABAB receptor autoimmunity and extends the spectrum of tumors underlying this condition to malignant melanoma. IFN-alpha therapy may have contributed to the development of autoimmunity in this patient., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Context: There have been recent concerns about increasing use and accessibility of methoxetamine, a ketamine derivative. Few data are available to describe the clinical features associated with methoxetamine exposure. We report three cases that presented to hospital with acute neurological toxicity associated with analytically confirmed methoxetamine exposure., Case Details: A 19-year-old male presented with severe truncal ataxia, nystagmus, incoordination and reduced conscious level several hours after nasal insufflation of what was initially thought to be ketamine. Features of cerebellar toxicity persisted for 3-4 days before gradual recovery. Two more patients aged 17 and 18 years presented with severe cerebellar ataxia, imbalance and reduced conscious level 40 minutes after nasal insufflation of methoxetamine (MXE). Both had slurred speech, incoordination and cerebellar ataxia that resolved within 24 hours. Serum methoxetamine concentrations were 0.24 mg/L, 0.45 mg/L and 0.16 mg/L, respectively, and no other drugs were identified on an extended toxicological screen., Discussion: Methoxetamine may cause rapid onset of neurological impairment, characterised by acute cerebellar toxicity. Spontaneous recovery was observed, but the duration of recovery may extend to several days. Presentation with an acute cerebellar toxidrome should alert clinicians to the possibility of methoxetamine exposure.