Permanent Visual Loss as a Complication of Decompressive Surgery for the Treatment of Posterior Fossa Tumours: A Report of Two Cases.

Posterior fossa tumours are one of the most common types of solid neoplasia in paediatric patients. Although impaired vision can occur at presentation, it usually stabilises or improves after decompressive surgery. However, cases of permanent and profound visual loss have been reported following successful tumour resection, despite receiving little attention from the medical community. In this paper, we present two cases of young patients who experienced severe and permanent visual loss following uncomplicated surgery for posterior fossa tumour removal. We discuss the possible mechanism involved in the visual loss and measures to prevent such a dreadful complication.

Site matters: Central neuropathic pain characteristics and somatosensory findings after brain and spinal cord lesions.

BACKGROUND: It is unknown if different etiologies or lesion topographies influence central neuropathic pain (CNP) clinical manifestation. METHODS: We explored the symptom-somatosensory profile relationships in CNP patients with different types of lesions to the central nervous system to gain insight into CNP mechanisms. We compared the CNP profile through pain descriptors, standardized bedside examination, and quantitative sensory test in two different etiologies with segregated lesion locations: the brain, central poststroke pain (CPSP, n = 39), and the spinal cord central pain due to spinal cord injury (CPSCI, n = 40) in neuromyelitis optica. RESULTS: Results are expressed as median (25th to 75th percentiles). CPSP presented higher evoked and paroxysmal pain scores compared to CPSCI (p < 0.001), and lower cold thermal limen (5.6°C [0.0-12.9]) compared to CPSCI (20.0°C [4.2-22.9]; p = 0.004). CPSCI also had higher mechanical pain thresholds (784.5 mN [255.0-1078.0]) compared to CPSP (235.2 mN [81.4-1078.0], p = 0.006) and higher mechanical detection threshold compared to control areas (2.7 [1.5-6.2] vs. 1.0 [1.0-3.3], p = 0.007). Evoked pain scores negatively correlated with mechanical pain thresholds (r = -0.38, p < 0.001) and wind-up ratio (r = -0.57, p < 0.001). CONCLUSIONS: CNP of different etiologies may present different pain descriptors and somatosensory profiles, which is likely due to injury site differences within the neuroaxis. This information may help better design phenotype mechanism correlations and impact trial designs for the main etiologies of CNP, namely stroke and spinal cord lesions. This study provides evidence that topography may influence pain symptoms and sensory profile. The findings suggest that CNP mechanisms might vary according to pain etiology or lesion topography, impacting future mechanism-based treatment choices.

Paracentral Acute Middle Maculopathy Associated with Severe Anti-Mog (Myelin Oligodendrocyte Glycoprotein)-Positive Optic Neuritis.

Retinal complications in patients with inflammatory optic neuritis (ON) are generally related to post-infectious neuroretinitis and are considered uncommon in autoimmune/demyelinating ON, whether isolated or caused by multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). More recently, however, cases with retinal complications have been reported in subjects positive for myelin oligodendrocyte glycoprotein (MOG) antibodies. We report a 53-year-old woman presenting with severe bilateral ON associated with a focal area of paracentral acute middle maculopathy (PAMM) in one eye. Visual loss recovered remarkably after high-dose intravenous corticosteroid treatment and plasmapheresis, but the PAMM lesion remained visible on both optical coherence tomography and angiography as an ischaemic lesion affecting the middle layers of the retina. The report emphasises the possible occurrence of retinal vascular complications in MOG-related optic neuritis, an important addition to the diagnosis of, and possible differentiation from, MS-related or NMOSD-related ON.

Dural-based lesions: is it a meningioma?

PURPOSE: Meningiomas are the most common extra-axial intracranial neoplasms with typical radiological findings. In approximately 2% of cases, histopathological reports reveal different neoplasms or non-neoplastic lesions that can closely mimic meningiomas. We describe radiological features of meningioma mimics highlighting imaging red flags to consider a differential diagnosis. METHODS: A total of 348 lesions with radiological diagnosis of meningiomas which underwent to surgical treatment or biopsy between December of 2000 and September of 2014 were analyzed. We determined imaging features that are not a typical finding of meningiomas, suggesting other lesions. The following imaging characteristics were evaluated on CT and MRI: (a) bone erosion; (b) hyperintensity on T2WI; (c) hypointensity on T2WI; (d) bone destruction; (e) dural tail; (f) leptomeningeal involvement; (g) pattern of contrast enhancement; (h) dural displacement sign. RESULTS: We have a relatively high prevalence of meningioma mimics (7.2%). Dural-based lesions with homogeneous contrast enhancement (52%) are easily misdiagnosed as meningiomas. Most lesions mimic convexity (37.5%) or parafalcine (21.9%) meningiomas. We have determined five imaging red flags that can alert radiologists to consider meningioma mimics: (1) bone erosion (22.2%); (2) dural displacement sign (36%); (3) marked T2 hypointensity (32%); (4) marked T2 hyperintensity (12%); (5) absence of dural tail (48%). The most common mimic lesion in our series was hemangiopericytomas, followed by lymphomas and schwannomas. CONCLUSION: The prevalence of meningioma mimics is not negligible. It is important to have awareness on main radiological findings suggestive of differential diagnosis due to a wide range of differentials which lead to different prognosis and treatment strategies.

Clinical, cerebrospinal fluid, and neuroimaging findings in COVID-19 encephalopathy: a case series.

OBJECTIVE: To describe the clinical, neurological, neuroimaging, and cerebrospinal fluid (CSF) findings associated with encephalopathy in patients admitted to a COVID-19 tertiary reference center. METHODS: We retrospectively reviewed records of consecutive patients with COVID-19 evaluated by a consulting neurology team from March 30, 2020 through May 15, 2020. RESULTS: Fifty-five patients with confirmed SARS-CoV-2 were included, 43 of whom showed encephalopathy, and were further divided into mild, moderate, and severe encephalopathy groups. Nineteen patients (44%) had undergone mechanical ventilation and received intravenous sedatives. Eleven (26%) patients were on dialysis. Laboratory markers of COVID-19 severity were very common in encephalopathy patients, but did not correlate with the severity of encephalopathy. Thirty-nine patients underwent neuroimaging studies, which showed mostly non-specific changes. One patient showed lesions possibly related to CNS demyelination. Four had suffered an acute stroke. SARS-CoV-2 was detected by RT-PCR in only one of 21 CSF samples. Two CSF samples showed elevated white blood cell count and all were negative for oligoclonal bands. In our case series, the severity of encephalopathy correlated with higher probability of death during hospitalization (OR = 5.5 for each increment in the degree of encephalopathy, from absent (0) to mild (1), moderate (2), or severe (3), p < 0.001). CONCLUSION: In our consecutive series with 43 encephalopathy cases, neuroimaging and CSF analysis did not support the role of direct viral CNS invasion or CNS inflammation as the cause of encephalopathy.

Adult Leukodystrophies: A Step-by-Step Diagnostic Approach.

Leukodystrophies usually affect children, but in the last several decades, many instances of adult leukodystrophies have been reported in the medical literature. Because the clinical manifestation of these diseases can be nonspecific, MRI can help with establishing a diagnosis. A step-by-step approach to assist in the diagnosis of adult leukodystrophies is proposed in this article. The first step is to identify symmetric white matter involvement, which is more commonly observed in these patients. The next step is to fit the symmetric white matter involvement into one of the proposed patterns. However, a patient may present with more than one pattern of white matter involvement. Thus, the third step is to evaluate for five distinct characteristics-including enhancement, lesions with signal intensity similar to that of cerebrospinal fluid, susceptibility-weighted MRI signal intensity abnormalities, abnormal peaks at MR spectroscopy, and spinal cord involvement-to further narrow the differential diagnosis. ©RSNA, 2019.

Imaging Patterns of Toxic and Metabolic Brain Disorders.

Toxic and metabolic brain disorders are relatively uncommon diseases that affect the central nervous system, but they are important to recognize as they can lead to catastrophic outcomes if not rapidly and properly managed. Imaging plays a key role in determining the most probable diagnosis, pointing to the next steps of investigation, and providing prognostic information. The majority of cases demonstrate bilateral and symmetric involvement of structures at imaging, affecting the deep gray nuclei, cortical gray matter, and/or periventricular white matter, and some cases show specific imaging manifestations. When an appropriate clinical situation suggests exogenous or endogenous toxic effects, the associated imaging pattern usually indicates a restricted group of diagnostic possibilities. Nonetheless, toxic and metabolic brain disorders in the literature are usually approached in the literature by starting with common causal agents and then reaching imaging abnormalities, frequently mixing many different possible manifestations. Conversely, this article proposes a systematic approach to address this group of diseases based on the most important imaging patterns encountered in clinical practice. Each pattern is suggestive of a most likely differential diagnosis, which more closely resembles real-world scenarios faced by radiologists. Basic pathophysiologic concepts regarding cerebral edemas and their relation to imaging are introduced-an important topic for overall understanding. The most important imaging patterns are presented, and the main differential diagnosis for each pattern is discussed. Online supplemental material is available for this article. ©RSNA, 2019.

A novel complex neurological phenotype due to a homozygous mutation in FDX2.

Defects in iron-sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.

Clinical and genetic characterization of leukoencephalopathies in adults.

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.

Intracranial germinoma causing cerebral haemiatrophy and hypopituitarism.

A young woman presented with primary amenorrhoea, progressive haemiparesis, visual disturbance, dementia and focal motor seizures. Investigations showed hypopituitarism, unilateral cerebral atrophy and inflamed cerebrospinal fluid. A trans-sphenoidal biopsy gave a unifying diagnosis of a pituitary germinoma.

Substantia nigra fractional anisotropy is not a diagnostic biomarker of Parkinson's disease: A diagnostic performance study and meta-analysis.

OBJECTIVES: Our goal was to estimate the diagnostic accuracy of substantia nigra fractional anisotropy (SN-FA) for Parkinson's disease (PD) diagnosis in a sample similar to the clinical setting, including patients with essential tremor (ET) and healthy controls (HC). We also performed a systematic review and meta-analysis to estimate mean change in SN-FA induced by PD and its diagnostic accuracy. METHODS: Our sample consisted of 135 subjects: 72 PD, 21 ET and 42 HC. To address inter-scanner variability, two 3.0-T MRI scans were performed. MRI results of this sample were pooled into a meta-analysis that included 1,432 subjects (806 PD and 626 HC). A bivariate model was used to evaluate diagnostic accuracy measures. RESULTS: In our sample, we did not observe a significant effect of disease on SN-FA and it was uninformative for diagnosis. The results of the meta-analysis estimated a 0.03 decrease in mean SN-FA in PD relative to HC (CI: 0.01-0.05). However, the discriminatory capability of SN-FA to diagnose PD was low: pooled sensitivity and specificity were 72 % (CI: 68-75) and 63 % (CI: 58-70), respectively. There was high heterogeneity between studies (I2 = 91.9 %). CONCLUSIONS: SN-FA cannot be used as an isolated measure to diagnose PD. KEY POINTS: • SN-FA appears insufficiently sensitive and specific to diagnose PD. • Radiologists must be careful when translating mean group results to clinical practice. • Imaging protocol and analysis standardization is necessary for developing reproducible quantitative biomarkers.

Leukoencephalopathy resolution after atypical mycobacterial treatment: a case report.

BACKGROUND: Association of leukoencephalopathy and atypical mycobacteriosis has been rarely reported. We present a case that is relevant for its unusual presentation and because it may shed further light on the pathogenic mechanisms underlying reversible encephalopathies. CASE REPORT: We report the case of a Hispanic 64-year-old woman with cognitive decline and extensive leukoencephalopathy. Magnetic resonance imaging revealed white-matter lesions with increased water diffusivity, without blood-brain-barrier disruption. Brain biopsy showed tissue rarefaction with vacuolation, mild inflammation, few reactive astrocytes and decreased aquaporin water-channel expression in the lesions. Six months later, she was diagnosed with atypical mycobacterial pulmonary infection. Brain lesions resolved after antimycobacterial treatment. CONCLUSION: We hypothesize leukoencephalopathic changes and vasogenic edema were associated with decreased aquaporin expression. Further studies should clarify if reversible leukoencephalopathy has a causal relationship with decreased aquaporin expression and atypical mycobacterial infection, and mechanisms underlying leukoencephalopathy resolution after antimycobacterial treatment. This article may contribute to the understanding of pathogenic mechanisms underlying magnetic resonance imaging subcortical lesions and edema, which remain incompletely understood.

Mevalonic Aciduria in a Pediatric Patient: A Case Report and Literature Review of Neuroimaging Findings.

Mevalonic aciduria is a rare autosomal recessive disorder resulting from mevalonate kinase deficiency. Neuroimaging findings associated with the disease have been documented in only a few case reports. We present a case of mevalonic aciduria with both already reported and novel neuroimaging findings and conduct a literature review regarding the role of neuroimaging in the understanding and diagnosis of mevalonate kinase deficiency disorders. The brain magnetic resonance imaging of the reported case revealed several notable findings, including polymicrogyric cortical thickening, an interhypothalamic adhesion or small hypothalamic hamartoma (findings not classically associated with mevalonic aciduria), and mild cerebellar atrophy. This case underscores the significance of recognizing the diverse spectrum of neuroimaging findings associated with the disease, encompassing both well-documented features and those that have not been traditionally reported.

Contributions of neuroimaging in central poststroke pain: a review.

BACKGROUND: Central neuropathic poststroke pain (CNPSP) affects up to 12% of patients with stroke in general and up to 18% of patients with sensory deficits. This pain syndrome is often incapacitating and refractory to treatment. Brain computed tomography and magnetic resonance imaging (MRI) are widely used methods in the evaluation of CNPSP. OBJECTIVE: The present study aims to review the role of neuroimaging methods in CNPSP. METHODS: We performed a literature review of the main clinical aspects of CNPSP and the contribution of neuroimaging methods to study its pathophysiology, commonly damaged brain sites, and possible differential diagnoses. Lastly, we briefly mention how neuroimaging can contribute to the non-pharmacological CNPSP treatment. Additionally, we used a series of MRI from our institution to illustrate this review. RESULTS: Imaging has been used to explain CNPSP pathogenesis based on spinothalamic pathway damage and connectome dysfunction. Imaging locations associated with CNPSP include the brainstem (mainly the dorsolateral medulla), thalamus (especially the ventral posterolateral/ventral posteromedial nuclei), cortical areas such as the posterior insula and the parietal operculum, and, more recently, the thalamocortical white matter in the posterior limb of the internal capsule. Imaging also brings the prospect of helping search for new targets for non-pharmacological treatments for CNPSP. Other neuropathic pain causes identified by imaging include syringomyelia, multiple sclerosis, and herniated intervertebral disc. CONCLUSION: Imaging is a valuable tool in the complimentary evaluation of CNPSP patients in clinical and research scenarios.

ANTECEDENTES: A dor neuropática central pós-acidente vascular cerebral (DNPAVC) afeta até 12% dos pacientes com AVC em geral e até 18% dos pacientes com déficits sensoriais. Essa síndrome dolorosa costuma ser incapacitante e refratária ao tratamento. A tomografia computadorizada e a ressonância magnética do cérebro são métodos amplamente utilizados na avaliação da DNPAVC. OBJETIVO: Este estudo tem como objetivo revisar o papel dos métodos de neuroimagem na DNPAVC. MéTODOS: Realizamos uma revisão da literatura sobre os principais aspectos clínicos da DNPAVC e a contribuição dos métodos de neuroimagem para estudar a fisiopatologia da DNPAVC, locais cerebrais comumente lesados na DNPAVC e possíveis diagnósticos diferenciais. Por fim, mencionamos brevemente como a neuroimagem pode contribuir no tratamento não farmacológico da DNPAVC. Além disso, utilizamos uma série de imagens de ressonância magnética da nossa instituição para ilustrar esta revisão. RESULTADOS: Os exames de imagem têm sido usados para explicar a patogênese da DNPAVC com base no dano da via espinotalâmica e na disfunção do conectoma. Os locais de imagem associados à DNPAVC incluem o tronco cerebral (principalmente o bulbo dorsolateral), o tálamo (especialmente os núcleos ventral posterolateral/ventral posteromedial), áreas corticais como a ínsula posterior e o opérculo parietal e, mais recentemente, a substância branca tálamo-cortical no membro posterior da cápsula interna. Os exames de imagem também trazem a perspectiva de auxiliar na busca de novos alvos para tratamentos não farmacológicos para DNPAVC. Outras causas de dor neuropática identificadas por exames de imagem incluem siringomielia, esclerose múltipla e hérnia de disco intervertebral. CONCLUSãO: Os exames de imagem são uma ferramenta valiosa na avaliação complementar de pacientes com DNPAVC em cenários clínicos e de pesquisa.

Resolution of Wing-Beating Tremor and Magnetic Resonance Imaging Lesions in Wilson's Disease Following Penicillamine.

Background: The wing-beating tremor, characteristic of Wilson's disease (WD), is a disabling symptom that can be resistant to anti-copper and anti-tremor medications. Phenomenology Shown: This video illustrates severe bilateral wing-beating tremor, moderate head and lower limb tremors, mild cervical dystonia, and subtle cerebellar ataxia, with nearly resolution after penicillamine treatment. Educational Value: This case highlights a typical aspect of WD, emphasizing the importance of early detection and treatment, and its correlation with MRI findings. Highlights: This case highlights the typical wing-beating tremor in Wilson's disease and its correlation with the involvement of the dentato-rubro-thalamic pathway. The early diagnosis and initiation of treatment with penicillamine resulted in an excellent clinical and radiological response.

The new era of artificial intelligence in neuroradiology: current research and promising tools.

Radiology has a number of characteristics that make it an especially suitable medical discipline for early artificial intelligence (AI) adoption. These include having a well-established digital workflow, standardized protocols for image storage, and numerous well-defined interpretive activities. The more than 200 commercial radiologic AI-based products recently approved by the Food and Drug Administration (FDA) to assist radiologists in a number of narrow image-analysis tasks such as image enhancement, workflow triage, and quantification, corroborate this observation. However, in order to leverage AI to boost efficacy and efficiency, and to overcome substantial obstacles to widespread successful clinical use of these products, radiologists should become familiarized with the emerging applications in their particular areas of expertise. In light of this, in this article we survey the existing literature on the application of AI-based techniques in neuroradiology, focusing on conditions such as vascular diseases, epilepsy, and demyelinating and neurodegenerative conditions. We also introduce some of the algorithms behind the applications, briefly discuss a few of the challenges of generalization in the use of AI models in neuroradiology, and skate over the most relevant commercially available solutions adopted in clinical practice. If well designed, AI algorithms have the potential to radically improve radiology, strengthening image analysis, enhancing the value of quantitative imaging techniques, and mitigating diagnostic errors.

A radiologia tem uma série de características que a torna uma disciplina médica especialmente adequada à adoção precoce da inteligência artificial (IA), incluindo um fluxo de trabalho digital bem estabelecido, protocolos padronizados para armazenamento de imagens e inúmeras atividades interpretativas bem definidas. Tal adequação é corroborada pelos mais de 200 produtos radiológicos comerciais baseados em IA recentemente aprovados pelo Food and Drug Administration (FDA) para auxiliar os radiologistas em uma série de tarefas restritas de análise de imagens, como quantificação, triagem de fluxo de trabalho e aprimoramento da qualidade das imagens. Entretanto, para o aumento da eficácia e eficiência da IA, além de uma utilização clínica bem-sucedida dos produtos que utilizam essa tecnologia, os radiologistas devem estar atualizados com as aplicações em suas áreas específicas de atuação. Assim, neste artigo, pesquisamos na literatura existente aplicações baseadas em IA em neurorradiologia, mais especificamente em condições como doenças vasculares, epilepsia, condições desmielinizantes e neurodegenerativas. Também abordamos os principais algoritmos por trás de tais aplicações, discutimos alguns dos desafios na generalização no uso desses modelos e introduzimos as soluções comercialmente disponíveis mais relevantes adotadas na prática clínica. Se cautelosamente desenvolvidos, os algoritmos de IA têm o potencial de melhorar radicalmente a radiologia, aperfeiçoando a análise de imagens, aumentando o valor das técnicas de imagem quantitativas e mitigando erros de diagnóstico.

Young-Onset Alzheimer Dementia Due to a Novel Pathogenic Presenilin 1 Variant Initially Misdiagnosed as Autoimmune Encephalitis.

OBJECTIVES: Pathogenic variants in presenilin 1 (PSEN1) are related to early-onset Alzheimer disease (AD) and may occur as de novo variants. In comparison with sporadic forms, it can present with psychiatric manifestations, seizures, myoclonus, and focal presentation. Because PSEN1 can occur in young patients who lack a family history of neurologic disorders and because these symptoms are also frequent in autoimmune encephalitis (AE), diagnosis may be overlooked. Our aim was to demonstrate the challenge in diagnosing young patients with neurodegenerative diseases that simulate AE. METHODS: We describe a case of a young patient with insidious progressive dementia, myoclonus, seizures, and aphasia, with no family history of dementia, along with signs suggestive of neuroinflammation on brain MRI and CSF examination. RESULTS: She was initially misdiagnosed as having AE. Further investigation was performed, leading to the discovery of a novel and de novo pathogenic variant in PSEN1. DISCUSSION: This case demonstrates the importance of considering PSEN1 in young patients with insidious progressive dementia with atypical clinical and neuroimaging features, even in patients without a family history of neurologic disorders. Not adhering to published criteria of possible and probable AE and overinterpretation of subtle inflammatory findings in CSF and MRI contribute to misdiagnosis.

Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.