doi:10.1093/braincomms/fcaa178 BRAIN COMMUNICATIONS 2020: Page 1 of 23 | 1 BRAIN AIN COMMUNICATIONS Magnetic resonance imaging pattern recognition in childhood bilateral basal ganglia disorders Shekeeb S. Mohammad,1,2,3 Rajeshwar Reddy Angiti,4,5 Andrew Biggin,3 Hugo Morales-Brice~ no,6 Robert Goetti,7 Belen Perez-Due~nas,8 Allison Gregory,9 Penelope Hogarth, Joanne Ng, Apostolos Papandreou, Kaustuv Bhattacharya,11 9 10 10 Shamima Rahman,12 Kristina Prelog,7 Richard I. Webster,2 Evangeline Wassmer,13 Susan Hayflick,9 John Livingston,14 Manju Kurian,10 W. Kling Chong15 and Russell C. Dale1,2,3; Basal Ganglia MRI Study Group* * A complete list of Basal ganglia MRI study group members can be found in the Appendix, with further details in the Supplementary material. Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic find- ings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnor- malities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1—T2-weighted hyperintensities in the putamen; Cluster 2—T2-weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3—T2-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4—T1- weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic dis- orders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric acidu- ria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syn- drome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern was exemplified by distinct T1-weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10. Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice. Received June 5, 2020. Revised August 24, 2020. Accepted September 18, 2020. Advance Access publication October 26, 2020 C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2 | BRAIN COMMUNICATIONS 2020: Page 2 of 23 S. S. Mohammad et al. 1 Kids Neuroscience Centre, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia 2 TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia 3 The Children’s hospital at Westmead Clinical School, Faculty of Medicine, University of Sydney, Sydney, NSW 2145, Australia 4 Newborn and Peadiatric Emergency Transport Service (NETS), Bankstown, NSW, Australia 5 Department of Neonatology, Liverpool Hospital, Liverpool, NSW, Australia 6 Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW 2145, Australia 7 Medical Imaging, The Children’s Hospital at Westmead and Sydney Medical School, University of Sydney, Sydney, Australia 8 Paediatric Neurology Department, Hospital Vall d’Hebrón Universitat Autónoma de Barcelona, Vall d’Hebron Research Institute Barcelona, Barcelona, Spain 9 Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA 10 Molecular Neurosciences, Developmental Neurosciences, UCL-Institute of Child Health, London, UK 11 Western Sydney Genomics Program, The Children’s Hospital at Westmead and Sydney Medical School, University of Sydney, Sydney, Australia 12 Mitochondrial Research Group, Genetics and Genomic Medicine, Institute of Child Health, University College London and Metabolic Unit, Great Ormond Street Hospital, London, UK 13 Department of Paediatric Neurology, Birmingham Children’s Hospital, Birmingham, UK 14 Department of Paediatric Neurology, Leeds Teaching Hospitals Trust, University of Leeds, UK 15 Department of Radiology, Great Ormond Street Hospital, London, UK Correspondence to: Dr Shekeeb S. Mohammad, FRACP, PhD, Clinical School, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: shekeeb.mohammad@health.nsw.gov.au Keywords: basal ganglia; striatum; striatal necrosis; pattern recognition; MRI Abbreviations: ADEM ¼ acute-disseminated encephalomyelitis; ANE ¼ acute necrotizing encephalopathy; BG ¼ Basal ganglia; BGE ¼ autoimmune basal ganglia encephalitis; BPAN ¼ beta-propeller protein-associated neurodegeneration; CP ¼ cerebral palsy; GA1 ¼ glutaric aciduria type 1; GP ¼ globus pallidus; HIE ¼ hypoxic ischaemic encephalopathy; MEGDEL ¼ 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome; MPAN ¼ mitochondrial membrane protein-associated neurode- generation; NBIA ¼ Neurodegeneration with brain iron accumulation; PDHC ¼ pyruvate dehydrogenase complex deficiency; PKAN ¼ pantothenate kinase-associated neurodegeneration; PLAN ¼ PLA2G6-associated degeneration; SN ¼ substantia nigra; STN ¼ subthalamic nucleus; T1W ¼ T1-weighted; T2W ¼ T2-weighted MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 3 of 23 | 3 Graphical Abstract Introduction radiological evidence is often required to reach a definite diagnosis. In presumed genetic causes, such composite The basal ganglia are paired deep grey matter nuclei in evidence can help define pathogenicity of identified gene the brain comprised of the caudate and putamen (referred variants and assist ‘reverse phenotyping’ when new genet- to as the ‘striatum’), globus pallidus (GP), substantia ic associations are proposed. MRI, which is available nigra (SN), subthalamic nuclei (STN) and nucleus accum- worldwide, is central to this approach for disorders of bens. These high energy-dependent regions of the brain the nervous system. In clinical practice, the presence of are susceptible to toxic, hypoxic or ischaemic injury bilateral basal ganglia abnormalities has a large differen- (Fahn, 1976; Beltz and Mullins, 2010) and have a predi- tial, which may prompt the use of extensive and some- lection for involvement in some genetic and degenerative times, invasive investigations. MRI pattern recognition disorders. Progressive basal ganglia cavitation and atro- has been highly influential in white matter disorders, phy with pathological evidence of necrosis, when involv- including new gene discovery (van der Knaap et al., ing the striatum, is termed ‘striatal necrosis’. Sometimes 1991; van der Knaap et al., 1999; Steenweg et al., 2010). ‘striatal necrosis’ is loosely and incorrectly used to lump Such a radiological approach for bilateral basal ganglia together various basal ganglia MRI patterns (Tonduti lesions has not been undertaken before in a cross-aetio- et al., 2016). A combination of clinical, biomarker and logical cohort, although narrative reviews have proposed 4 | BRAIN COMMUNICATIONS 2020: Page 4 of 23 S. S. Mohammad et al. decision-making approaches (Ho et al., 1993; Krageloh- changes on MRI. Ethics approval was attained at both Mann et al., 2002; Finelli and DiMario, 2003; Anderson sites (Sydney—QIE-2014-11-10, London—CA-1618/ et al., 2004; Lim, 2009; Hegde et al., 2011; Bekiesi nska- 2014). The database search was undertaken using the Figatowska et al., 2013; Quattrocchi et al., 2013; Zuccoli same keywords as in the literature review as well as et al., 2015; Tonduti et al., 2016). In this multicentre using individual diagnostic categories found on literature study using a large cohort of children with MRI bilateral review. The database search included clinic letters, dis- basal ganglia disease of broad aetiologies, we used a charge summaries and MRI reports. No patients from standard radiological scoring proforma and cluster ana- any disease categories were excluded if they fulfilled in- lysis to define MRI features that group different disorders clusion criteria. Other experts in Barcelona, Spain, Leeds in common clusters. We further incorporated findings and Birmingham, UK and Portland, USA were contacted from literature review to develop a diagnostic algorithm after appropriate amendment to the ethics approval and and a prototypic electronic decision-making tool. additional data transfer agreement at GOSH to contrib- ute anonymized scans for some rare disorders identified during the literature review. All eligible scans were ano- Materials and methods nymized at export from the respective hospitals and com- piled in coded DICOM folders using HorosTM—a free, Inclusion and exclusion criteria open source, 64-bit medical image viewer for OS X avail- able at the time of the study under the GNU Lesser The inclusion criteria for the study were children (0– General Public License, Version 3 (LGPL-3.0) (https:// 18 years) with bilateral basal ganglia signal abnormalities www.horosproject.org) (June 2020, accessed). Definitions reported on available MRI. We excluded cases with basal for 34 diagnostic categories for which scans were identi- ganglia atrophy without signal abnormalities on any MRI fied for this study are outlined in Supplementary Table 2. dataset, basal ganglia hypoplasia and malformations. Disorders of neuronal migration, neoplastic disorders like neurofibromatosis, cerebrovascular insult-related basal MRI rating and proforma ganglia injury and unilateral basal ganglia abnormalities The DICOM folders exported from HorosTM were were excluded as they have typical MRI appearances and reviewed and rated using SYNGO PLAZA and SYNGO do not provide the same diagnostic challenges. The first FASTVIEW (V C Siemens Healthcare GmbH, 2016). A available MRI scan showing bilateral basal ganglia ab- scoring proforma for rating the MRI scans adapted from normality was included for analysis in all patients. All Pillai et al. (2015) was used (Supplementary Table 3). available subsequent scans till the age of 18 years were Various brain regions including each of the basal ganglia also evaluated. The scans were done as part of standard nuclei and ‘non-basal ganglia’ structures were scored for clinical service, hence the first included scan for some presence or absence of abnormalities on different MRI patients was not necessarily an acute scan in relation to datasets. WKC, paediatric neuroradiologist at GOSH, disease onset, and timing of subsequent scans was not undertook the primary rating with S.S.M., who verified standardized. the ratings before entry into the study spreadsheet. The primary raters were not blinded to the diagnosis. A ran- Review of literature dom sample of 30 scans was independently rated by two A literature review was undertaken in Medline and paediatric neuro-radiologists R.G. and K.P. in Sydney, EMBASE to identify conditions reported with bilateral Australia to examine usability of the proforma. Cohen’s basal ganglia MRI abnormalities. The search results in- and Fleiss’ Kappa (for two raters) and Fleiss’ Kappa (for clude conditions described in peer-reviewed publications three raters) (Fleiss, 1971) were calculated using the on- available in full-text format till 31 December 2019. A line calculator available at https://www.statstodo.com/ keyword search was done using the terms—‘MRI’ AND CohenKappa_Pgm.php, last accessed in June 2016. Inter- ‘basal ganglia, putamen, caudate, SN, subthalamic nu- rater comparisons between K.P. and R.G. showed a cleus, GP, pallidum, accumbens, striatum, lentiform’, mean Kappa of 0.84 (95% CI 0.67–1.00) and Inter-rater using truncation where needed. A list of possible causes comparisons between three sets of raters (R.G., K.P., of MRI basal ganglia lesions in children was drawn up W.K.C./S.S.M.) showed a mean Kappa of 0.87 (95% CI to enable patient search (Supplementary Table 1). 0.71–1.00) indicating ‘almost perfect’ agreement (Supplementary Figs 1a and b) and the rating proforma was therefore used unchanged. Where available, T2 fluid- Study cohort compilation attenuated inversion recovery sequences were also used in Patient databases—PowerchartTM at the Children’s scoring, but the score was coded together with the T2 Hospital at Westmead in Sydney, Australia and weighted (T2W) category. Susceptibility weighted sequen- Electronic document management systemTM at Great ces such as SWI/SWAN/T2* were scored as ‘increased Ormond Street Hospital (GOSH) in London, UK were susceptibility’ based on age and conventional departmen- searched for retrospective patients with basal ganglia tal reporting practice. The term ‘increased susceptibility’ MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 5 of 23 | 5 in the context of MRI reporting and the remainder of not noted in this study cohort but described in literature this paper implies hypointense signal on susceptibility- (if required). The final categorization was used to build a weighted sequences. standalone electronic application (available for download from http://www.kidsneuroscience.org.au/resources-epi lepsy) using FileMaker Pro 16 AdvancedTM (FileMaker, Statistical analysis Inc.). Example images were incorporated in the applica- Statistical analysis was performed using SPSS v20.0.0. tion for diagnostic categories included in the study and Proportions between the groups were compared using selected references for other diagnostic categories from lit- Chi-square test. Medians were compared using non-para- erature review are provided in Supplementary Table 6 to metric tests—Mann-Whitney U test or Kruskal–Wallis. direct readers to typical imaging examples. This pilot ap- plication is based on results from this study and literature Cluster analysis review, requires validation and should not be used for clinical decision-making. Agglomerative hierarchical clustering analysis was per- formed using ‘R’ software for statistical computing (R Core Team, 2019). Twenty-three MRI features on the first Data availability included MRI scan were used for the cluster analysis. The data that support the findings of this study are avail- These MRI features were based on the location of MRI able from the corresponding author, upon reasonable re- abnormality and type of MRI abnormality (e.g. increased quest. The electronic tool described is downloadable from susceptibility/T1W hyperintensity, etc.), derived from the http://www.kidsneuroscience.org.au/resources-epilepsy main study data (Supplementary Section 1) and were scaled (October 2020, accessed). before entering into the clustering algorithm. Various dis- similarity measures (Euclidean, Manhattan and Minkowski) were used with different agglomeration methods (Ward, Results single, complete, average, weighted and gaverage). Incremental cluster plots from 2 to 8 were generated using Three hundred and five MRI brain scans from 201 multiple clustering methods and analysed using NbClust, patients were reviewed and rated. Two or more sequen- an ‘R’ Package (Charrad et al., 2014) which helped deter- tial scans were available for 84/201 patients. The distri- mine the optimal number of clusters. Each patient was rep- bution of patients across various diagnostic categories is resented by a unique number in the cluster plots. Cluster detailed in Table 1. Forty per cent of the scans were validation statistics showed Euclidean dissimilarity measure done on a 1.5 Tesla (T) MRI machine (GE, Siemens) and with average agglomeration method as the ‘best-fit’ algo- the remaining on 3.0 T Machines (GE, Siemens). Clinical rithm for cluster generation (Fig. 1 and Supplementary Fig. syndromes are used to describe most categories, but gene 2). Patients in each cluster were compared using propor- notations are used for recent disorders where syndromic tions and chi-square test (for presence of distinguishing descriptions are still expanding. MRI abnormalities that separated them into different clus- The ‘best-fit’ Euclidean-average algorithm resulted in ters or similar MRI abnormalities that clustered them to- most diagnostic categories segregating into one of four gether). Discriminatory MRI features were used to generate discrete clusters (Figs 1 and 2, third column) based on a proportion-based heatmap (Fig. 2). Representative images ratings from their first included MRI scans. Only a were selected to highlight MRI patterns in the four clusters smaller fraction of patients (7/201) in some diagnostic (Figs 3–5). MRI features differentiating the study cohort categories [ADAR-1/7, mitochondrial complex 1 defi- into four Euclidean-average clusters were integrated with ciency-2/5, Kearns Sayre syndrome-1/5, propionic acidae- findings from the literature review to develop a branching mia-1/11, pyruvate dehydrogenase complex deficiency algorithm (Fig. 6 and Supplementary Section 2). (PDHC)-1/6 and hypermanganesemia associated with SLC39A14-1/6] were represented in a second cluster, while still showing dominant clustering in one cluster. Development of a decision-making MRI abnormalities noted to contribute to clustering are application represented as proportion of patients within each diag- nostic category in Fig. 2. The presence or absence of 30 discrete MRI abnormal- ities was categorized for each of the 34 diagnostic catego- ries from this study. MRI data from a further 59 Bilateral basal ganglia abnormalities diagnostic categories from literature review, correspond- can be segregated into four ing to the same 30 MRI abnormalities were incorporated into the categorization along with clinical summaries different clusters (Supplementary Table 5). As described in Supplementary MRI scans grouped together in one of four clusters Section 3, categorization for the study cohort was modi- (Fig. 1) based on the following findings from their first fied after literature review to account for MRI changes included scans: 6 | BRAIN COMMUNICATIONS 2020: Page 6 of 23 S. S. Mohammad et al. Figure 1 ‘Best fit’ Euclidean-average four cluster plot. Cluster plot derived using Euclidean distance and average agglomeration algorithm divides the cohort of 201 first MRI scans into four clusters. Each individual number within the clusters represents one patient. The major MRI features that determined cluster distribution are: Cluster 1: T2W hyperintensities in the putamen, Cluster 2: T2W hyperintensities or increased susceptibility in the GP/SN/STN, Cluster 3: T2W hyperintensities in the GP, brainstem and cerebellum with diffusion restriction and Cluster 4: T1W hyperintensities in the basal ganglia without T2W hyperintensities or diffusion restriction. Dim, dimension; GP, globus pallidus; SN, substantia nigra; STN, subthalamic nucleus. a. Cluster 1: T2W hyperintensities in the putamen ADAR, mitochondrial complex 1 deficiency and b. Cluster 2: T2W hyperintensities or increased susceptibil- SLC19A3. A rim-like distribution of more prominent ity in the GP T2W hyperintensity around the putaminal edge and c. Cluster 3: T2W hyperintensities in the GP, brainstem sometimes including surrounding structures was noted in and cerebellum with diffusion restriction acute-disseminated encephalomyelitis (ADEM)(1/11), acute d. Cluster 4: T1-weighted (T1W) hyperintensities in the necrotizing encephalopathy (ANE)(3/5) (Fig. 3C), auto- basal ganglia. immune basal ganglia encephalitis (BGE)(1/10), myelinol- ysis (2/3) (Fig. 3D) and SLC19A3 (1/6). All patients with Cluster 1: Bilateral putaminal T2W cerebral palsy due to hypoxic ischaemic encephalopathy (HIE) at term (referred hereafter as CP) had a typical hyperintensities pattern of T2W hyperintensities in bilateral motor strips, The presence of bilateral putaminal T2W hyperintensities corticospinal tracts in the internal capsules, posterior was the major determinant for 91/201 patients from 15 putamina and ventrolateral thalami (Fig. 3E and F). different diagnostic categories to group together in Thalamic T2W hyperintensities with diffusion restriction Cluster 1 (Fig. 2). In addition, Cluster 1 had a higher were seen with swelling of the thalami in all cases of number of patients as a proportion of the whole cohort ANE (Fig. 3C), while distinct linear T2W hyperintensities with T2W hyperintensities in the caudate, thalamus, were noted in the internal medullary lamina of the tha- white matter and cortical grey matter as well as with cor- lami in cases with propionic acidaemia (Fig. 3G). tical grey matter atrophy (Fig. 3A). Conversely, very few Prominent swelling of the putamina was noted in 38/91 patients in Cluster 1 demonstrated any MRI abnormal- patients across Cluster 1, sometimes appearing very strik- ities in the GP or cerebellum. Within Cluster 1 some typ- ing, as in cases with SLC19A3 (Fig. 3H). Cortical grey ical patterns of abnormalities were observed in different matter T2W hyperintensities were noted in a patchy dis- diagnostic categories. A distinct pattern was noted in the tribution in ADEM, infectious encephalitis and mitochon- striatum in all patients with 3-methylglutaconic aciduria drial complex 1 deficiency and were diffuse and with deafness, encephalopathy and Leigh-like syndrome homogenous in BGE, while changes with distinct patterns (MEGDEL) with spared sections in the putamen sand- were noted in other diagnostic categories—external cap- wiched between anterior and posterior sections of T2W sule (ANE), motor cortex (CP) (Fig. 3F) and a unique hyperintensities (Fig. 3B). Partial sparing of regions with- multifocal pattern with diffusion restriction (SLC19A3) in the putamen was also noted in single cases with (Fig. 3I). T2W hyperintensities in the white matter in MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 7 of 23 | 7 Figure 2 Proportion-based heatmap of selected MRI features on first included scan. The figure describes the presence and absence of specific MRI features on the first included MRI from 201 patients. Diagnostic categories are shown in the second column and are organized according to grouping in one of four clusters depicted in the first column. The third column shows the number of cases for each diagnostic category that grouped in the respective cluster depicted by the heat map shading as per the included scale. Increasingly darker shades depict higher proportions of patients. The fourth column shows the total number of cases for each diagnostic category included in the study. The remaining cells provide a heat map of the proportion of patients in each diagnostic category demonstrating the specific MRI features. An overall picture of the percentage of patients demonstrating specific MRI features can be gained by the heat map colour scheme with the included scale providing a guide to increasing proportion of patients with increasing depth of the blue shading. ADEM, acute-disseminated encephalomyelitis; ANE, acute necrotizing encephalopathy; BGE, autoimmune basal ganglia encephalitis; BPAN, beta-propeller protein-associated degeneration; CP, cerebral palsy; GA1, glutaric aciduria type 1; GM, grey matter; GP, globus pallidus; MEGDEL, 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome; MMA, methyl malonic acidaemia; MPAN, mitochondrial membrane protein-associated neurodegeneration; PDHC, pyruvate dehydrogenase complex deficiency; PKAN, panthothenate kinase-associated degeneration; PLAN, PLA2G6- associated neurodegeneration; SSADH, succinic semialdehyde dehydrogenase deficiency. patients in Cluster 1 were typically multifocal in the sub- showing MRI abnormalities in other brain regions in their cortical white matter in ADEM, while these were domin- final sequential scan. Striatal atrophy was noted in 27/50 antly seen in the parasagittal white matter and patients from Cluster 1 on follow-up scans with both cystic corticospinal tracts in CP and non-specific in other diag- change and atrophy in the striatum noted in 7/50 patients. nostic categories. In Cluster 1, 50/91 patients had one or more sequential MRI scans that were rated as a part of this study. Only 4/ Cluster 2: T2W hyperintensities or 50 of these patients (3/11 with ADEM, 1/6 with increased susceptibility in bilateral SLC19A3) showed complete resolution of all MRI abnor- malities in their final sequential scan. One additional pa- GP tient with ADEM and 2/4 with infectious encephalitis The first MRI scan of 85 patients from 18 diagnostic cat- showed resolution of basal ganglia abnormalities while still egories who grouped together in Cluster 2 showed either 8 | BRAIN COMMUNICATIONS 2020: Page 8 of 23 S. S. Mohammad et al. Figure 3 Cluster 1. T2W (A–H) and diffusion (I) axial MRI images from patients in Cluster 1, all of whom had putaminal T2W hyperintensities. (A) MRI of a 9-month-old boy with bi-allelic ADAR mutations showing bilateral T2W hyperintensities in the putamina along with bilateral fronto-temporal atrophy; (B) MRI of an 18-month-old girl with MEGDEL associated with bi-allelic SERAC1 mutations showing bilateral T2W hyperintensities with regions of sparing in the posterior third of both putamina; (C) MRI of a 3-year-old boy with sporadic ANE showing patchy T2W hyperintensities in bilateral putamina and thalami, thalamic swelling and a rim of T2W hyperintensity in the external capsule and claustrum around both putamina; (D) MRI of a 16-year-old girl with myelinolysis showing T2W hyperintensities in bilateral posterior putamina along with a rim of brighter T2W hyperintensities along the internal and external capsules around the putamina; (E) MRI of a 6-year-old boy with dystonic CP after HIE at birth (40 weeks of gestation) showing T2W hyperintensities in posterior putamina and ventrolateral thalami; (F) MRI of the same 6-year-old boy as in ‘E’ with dystonic CP showing T2W hyperintensities in the cortical grey matter in bilateral rolandic regions and parasagittal regions as well as surrounding white matter; (G) MRI of a 4-year-old girl with propionic acidaemia showing T2W hyperintensities in bilateral caudate nuclei and anterior putamina along with linear T2W hyperintensities in the internal medullary lamina of bilateral thalami; (H) MRI of a 3-year-old boy with thiamine responsive basal ganglia disease associated with bi-allelic SLC19A3 mutations at presentation showing bilateral putaminal swelling and T2W hyperintensity; (I) MRI of a 2-year-old girl with thiamine responsive basal ganglia disease associated with bi- allelic SLC19A3 mutations at presentation showing bilateral, extensive multifocal regions of cortical grey matter diffusion restriction. T2W hyperintensities or increased susceptibility in bilat- surrounding hypomyelinated white matter (Fig. 4A). Very eral GP (Fig. 2). In addition, most patients with imma- few patients with striatal T2W hyperintensities and none ture myelination and cerebellar atrophy grouped together with increased striatal susceptibility were part of Cluster in Cluster 2. Bilateral T2W hypointensities of the ventro- 2. The T2W hyperintensities in the GP were either lateral thalami were noted in 7/85 patients in Cluster 2. restricted to the anterior GP (Fig. 4B) or involved the en- The thalami appeared relatively darker compared to the tire GP (Fig. 4C–E), rarely with adjacent striatal MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 9 of 23 | 9 Figure 4 Cluster 2. Patterns of MRI changes seen with T2W hyperintensities or increased susceptibility in the GP in patients in Cluster 2. (A) MRI of a 6-year-old boy with a TUBB4A mutation showing hypomyelination of the white matter along with T2W hypointensities in bilateral globi pallidi and relatively hypointense appearing thalami due to surrounding hypomyelinated white matter; (B) MRI of a 3-year-old girl with succinic semialdehyde dehydrogenase deficiency (SSADH) showing T2W hyperintensities in bilateral anterior globus pallidi; (C) MRI of a 5-year-old boy with methylmalonic acidaemia (MMA) showing T2W hyperintensities in bilateral globus pallidi; (D) MRI of a 4-year- old girl with PDHC showing T2W hyperintensities in bilateral globus pallidi, adjacent posterior tips of both putamina and dorsomedial nuclei of the thalamus; (E) MRI of a 1.5-year-old boy with kernicterus showing T2W hyperintensities in bilateral globi pallidi; (F) MRI of a 7-year-old boy with PKAN showing T2W hypointensities in bilateral globus pallidi, with persisting anterior T2W hyperintensities (‘eye of the tiger’); (G) MRI image of a 6-year-old girl with MPAN showing T2W hypointensities in bilateral globus pallidi and sparing of bilateral internal medullary lamina; (H) Susceptibility-weighted MRI image of a 2-year-old girl with fucosidosis showing increased susceptibility in bilateral globi pallidi with sparing of the internal medullary and accessory lamina with the pallidi; (I) Earlier MRI of the same patient with PKAN as in ‘F’ at the age of 3 years showing T2W hyperintensities in bilateral anterior globus pallidi. involvement in patients with PDHC (Fig. 4D). in the thalami in 2/3 patients with fucosidosis, and in the Homogenous T2W hyperintensities in the GP were noted red nucleus in 2/3 patients with juvenile Huntington’s dis- in all 17 patients with kernicterus (Fig. 4E). Out of 39 ease). Most patients in Cluster 2 demonstrated either patients with increased basal ganglia susceptibility in T2W hyperintensities or increased susceptibility in the Cluster 2, this was noted in the GP in 37/39 patients and GP. Three patients with pantothenate kinase-associated in the GP, SN and STN in 16/39 patients. Outside the neurodegeneration (PKAN) had coexisting areas of T2W basal ganglia nuclei, increased susceptibility was noted hyperintensity and increased susceptibility in the anterior only in 4/85 patients in Cluster 2 (increased susceptibility portion of the medial medullary lamina of the GP 10 | BRAIN COMMUNICATIONS 2020: Page 10 of 23 S. S. Mohammad et al. Figure 5 Clusters 3 and 4. Patterns of MRI changes in patients in Clusters 3 and 4 (A) Diffusion-weighted MRI of a 9-month-old boy with vigabatrin toxicity areas that were diffusion restricted—bilateral globus pallidi and ventral diencephalic regions including the hypothalamus; (B) Diffusion-weighted MRI of a the same patient as in ‘A’ with vigabatrin toxicity showing hyperintensity of the central tegmental tracts in the dorsal pons and in the dentate nuclei; (C) MRI of the same patient as in ‘A’ with vigabatrin toxicity showing T2 hyperintensities in the midbrain; (D) MRI of a 8-month-old girl with Krabbe disease showing expansion of the optic tract; (E) MRI of a 4-year-old boy with hypermanganesemia associated with SLC30A10 showing T1W hyperintensity in a linear pattern from the GP, STN, pons to the cerebellar white matter as well as T1W hyperintensity in the anterior pituitary (F) MRI of the same patient as in ‘E’ showing diffuse T1W hyperintensities in bilateral putamen and GP as well as diffuse but less intense T1W signal change diffusely in the white matter; (G) MRI of the same patient as in ‘E’ showing T1W hyperintensity in the dentate nuclei and deep cerebellar grey matter; (H) MRI of an 11-year-old girl with hypermanganesemia associated with SLC39A14 showing T1W hyperintensities in bilateral globi pallidi as well as diffuse but less intense T1W signal change diffusely in the white matter; (I) MRI of the same patient as in ‘H’ at 18 years of age showing diffuse T1W hyperintensities in bilateral caudate, putamen and GP and a rim of hyperintensity around the STN as well as diffuse T1W hyperintensity diffusely in the white matter. resembling the ‘eye of the tiger’ (Fig. 4F). An identical disorders PKAN, PLA2G6-associated degeneration pattern was not noted in any other diagnostic category in (PLAN) and BPAN only demonstrated GP T2W hyperin- this cohort but some other patients demonstrated con- tensities in their first scan. The medial medullary lamina comitant T2W hyperintensity and increased susceptibility in the GP was noted to be spared on T2W and suscepti- in the GP—beta-propeller protein-associated neurodegen- bility sensitive data sets in all 7/7 patients with mitochon- eration (BPAN) (1/6), gangliosidosis (1/3) and SLC39A14 drial membrane protein-associated neurodegeneration (1/6). Some patients with typical brain iron accumulation (MPAN) (Fig. 4G) and 1/7 patients with PLAN. MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 11 of 23 | 11 Figure 6 Branching algorithm to approach bilateral basal ganglia abnormalities on MRI. The algorithm is based on cluster analysis of MRI features from 34 diagnostic categories included in this study and review of literature of a further 59 diagnostic categories. End-points of the algorithm denoted by alphabets correspond to rows in Table 2 and to sections in discussion as noted. SN, substantia nigra. *Either striatal or GP abnormalities only amongst the basal ganglia nuclei. Other brain regions could be abnormal. Accessory lamina in the GP appeared prominent due to patients with sequential scans where this had been initially sparing on T2W and susceptibility sensitive data sets in noted and was noted as a new finding in one patient with all 3/3 patients with fucosidosis (Fig. 4H). Kearns Sayre syndrome on their sequential scan. Thirty out of 85 patients in Cluster 2 had one or more Significant caudate atrophy was noted in 1/3 patients with sequential MRI scans that were rated as a part of this juvenile Huntington’s disease where it had been scored as study. There were no new MRI changes noted in patients normal on the first scan. Cystic changes encompassing a with kernicterus. Increased susceptibility in the GP was large part or the whole GP were noted in 3/5 patients noted on sequential scans in all those patients with PKAN with Kearns Sayre syndrome on sequential scans. (Fig. 4I), PLAN and BPAN who had demonstrated only T2W hyperintensities in the GP on their first rated MRI. All patients with MPAN (5/5) who had sequential scans Cluster 3: T2W hyperintensities in demonstrated increased susceptibility in the GP, SN and the GP, brainstem and cerebellum STN, though the hypointensity in the GP was noted to be more prominent than the SN/STN on visual comparison. with diffusion restriction None of the sequential scans from Cluster 2 showed reso- Eleven patients grouped together in Cluster 3 with their lution of MRI abnormalities. Myelination was noted to be first MRI scans showing a combination of T2W hyperin- persistently immature suggesting a hypomyelinating pattern tensity in the GP and at all levels of the brainstem in 2/8 patients with BPAN and 5/5 patients with TUBB4A (Fig. 5A–C). This included all patients with vigabatrin tox- on their final scored sequential scans. Sequential scans icity and Krabbe disease and isolated patients with PDHC, were scored for all patients with TUBB4A noting progres- mitochondrial translation disorder and Kearns Sayre syn- sion of cerebellar atrophy while striatal atrophy was noted drome. In addition, most MRI scans in Cluster 3 also in only 2/5 patients in their final scored scans, thus not showed T2W hyperintensities in the cerebellum and thal- fulfilling the full radiological appearance of hypomyelina- amus as well as accompanying diffusion restriction in the tion with atrophy of the basal ganglia and cerebellum. GP (Figs 2 and 5A). Prominent T2W hyperintensity and Cerebellar atrophy was noted to have progressed in all diffusion restriction was noted in the hypothalamus, 12 | BRAIN COMMUNICATIONS 2020: Page 12 of 23 S. S. Mohammad et al. Table 1 Distribution of 201 patients across 34 included diagnostic groups fulfilling inclusion criteria Diagnosis (arranged in alphabetical N Sex Mean age at first Patients with follow-up Follow-up MRI scans order with gene names in brackets) (female/ MRI scan (range) in MRI scans Median duration of last male) years scored scan from first scana (range in years) ADEM 11 3/8 4.7 (0.4–12.1) 6/11 0.34 (0.1–1.0) ANE 5 3/2 4.0 (1.6–7.5) 3/5 0.9 (0.1–7.5) ADAR-related bilateral striatal necrosis 7 3/4 2.2 (0.8–6.1) 4/7 1.4 (0.8–4.3) BGE 10 1/9 6.3 (3.0–12.7) 7/10 0.5 (0.1–5.4) BPAN (WDR45) 8 7/1 11.6 (1.3–17.0) 3/8 4 (3.9–10.6) Cockayne syndrome (ERCC8) 1 0/1 7.5 (a) 0/1 – Fucosidosis (FUCA1) 3 1/2 4.6 (2.5–7.0) 1/3 11.6 (–) Gangliosidoses GM1 and GM2 (GLB1, 3 3/0 4.0 (1.0–10.0) 0/3 – HEXA, GM2A) Glutaric aciduria type 1 (GCDH) 9 6/3 5.1 (5.0–11.6) 0/9 – Hypermanganesemia with dystonia 1 9 4/5 6.9 (0.1–12.0) 3/9 2.6 (0.3–4.9) (SLC30A10) Hypermanganesemia with dystonia 2 6 5/1 2.8 (1.4–5.1) 1/6 14.2 (–) (SLC39A14) HIE (term neonates) 6 1/5 2.6 (0.8–5.5) 0/6 – Infectious encephalitis 4 3/1 5.1 (2.2–8.7) 3/4 0.1–0.2 (0.1) Juvenile Huntington’s disease 3 2/1 10.6 (6.9–16.3) 1/3 4.5 (–) Kearns Sayre syndrome 5 1/4 6.9 (3.2–10.5) 4/5 4.2 (2.3–6.4) Kernicterus 17 5/12 2.6 (0.1–9.0) 5/17 1.7 (0.3–3.2) Krabbe disease (GALC) 2 0/2 0.8 (0.7–0.8) 0/2 – MEGDEL (SERAC1) 4 2/2 3.1 (1.2–6.9) 3/4 0.8 (0.7–4.3) Methylmalonic acidaemia (multiple genesb) 6 3/3 3.0 (0.5–7.6) 1/6 (-) Mitochondrial membrane protein-associ- 8 4/4 14.1 (10.0–18.0) 5/8 1.5 (1.0–7.0) ated neurodegeneration (C19orf12) Myelinolysis 3 1/2 8.9 (2.7–16.6) 1/3 0.5 (–) Other mitochondrial disordersb 18 3.4 (0.3–11.7) Complex 1 deficiency 5 4/1 Complex 1 deficiency 3/5 1.7 (0.1–9.9) Complex IV deficiency 4 2/2 Complex IV deficiency 1/4 Complex V deficiency 8 3/5 Complex V deficiency 6/8 Mitochondrial translation 1 1/0 Mitochondrial translation 0/1 Pantothenate kinase-associated 7 4/3 7.6 (3.0–16.0) 0/7 – neurodegeneration (PANK2) PLA2G6-associated neurodegeneration 8 5/3 7.2 (1.7–14.9) 2/8 2.5 (0.2–4.7) (PLA2G6) Propionic acidaemia (PCCA, PCCB) 11 6/5 3.4 (0.1–16.0) 4/11 2.9 (2.0–13) PDHC (multiple genesb) 6 2/4 6.8 (0.9–11.9) 3/6 2.2 (0.5–3.8) Succinic semialdehyde dehydrogenase 2 2/0 5.8 (1.1–10.5) 0/2 – deficiency (ALDH5A1) Thiamine responsive basal ganglia disease 6 3/3 5.2 (0.1–15.6) 3/6 1.7 (0.7–3.0) (SLC19A3) TUBB4A 5 1/4 5.1 (1.6–10.1) 5/5 3.2 (1.0–7.9) Vigabatrin toxicity 6 1/5 1.4 (0.7–2.8) 6/6 1.5 (0.6–1.8) Wilson’s disease (ATP7B) 2 0/2 15.5 (15.0–15.9) 0/2 – TOTAL 201 92/109 5.4 (0.1–18.0) 84/201 – MEGDEL, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome. a Single cases—the number denotes the duration of longest follow-up for that case in years rather than the median. b Genotype associations in Supplementary Table 2.1. central tegmental tracts and dentate nuclei in all patients Cluster 4: Prominent T1W with vigabatrin toxicity (Fig. 5B). Thickening of the optic hyperintensity without tracts was detected in both patients with Krabbe disease (Fig. 5D) who also had white matter signal changes track- accompanying T2W or DWI ing along bilateral corticospinal tracts. One or more se- hyperintensity quential MRI scans of 8/11 patients from Cluster 3 were available for rating. On follow-up, all MRI abnormalities Almost all patients with hypermanganesemia—SLC39A14 had completely reverted to normal in all six patients with (5/6) and SLC30A10 (9/9) grouped together in Cluster 4 vigabatrin toxicity while there was persistence of abnor- (Fig. 5–I). Patients with hypermanganesemia were distin- malities in other patients. guishable from others with T1W hyperintensity because MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 13 of 23 | 13 of diffuse, homogeneous and prominent appearance of http://www.kidsneuroscience.org.au/resources-epilepsy) T1W hyperintensity without accompanying T2W hyperin- (October 2020, accessed). tensity or diffusion restriction on either first or sequential scans. In this study, diffuse T1W hyperintensity in both the striatum and GP was noted in all nine patients with SLC30A10 and 1/6 patients with SLC39A14. T1W Discussion hyperintensities in the GP without striatal involvement In this study, we rated 305 different MRI scans with bi- was noted in other patients with SLC39A14. In patients lateral basal ganglia lesions of children (n ¼ 201) with with SLC30A10, this was so prominent that it was not varied medical disorders (n ¼ 34). Four different clusters possible to discern anatomical boundaries between the emerged based on the first MRI findings from this study caudate, putamen and GP on T1W datasets (Fig. 5F). cohort and all disorders segregated mainly within one of These patients also had a typical pattern of T1W hyper- these four clusters. Moreover, in this study we use the intensity seen in the SN and other brain regions stretch- imaging results of our cohort and those reported in lit- ing from the basal ganglia to the cerebellum (Fig. 5E and erature with bilateral basal ganglia abnormalities, to de- G). Very few patients in Cluster 4 had increased suscepti- rive a diagnostic algorithm and a decision-making tool. bility in regions that were hyperintense on T1W imaging The decision-making tool incorporates a short summary (Fig. 2). This was in contrast to more prominent suscepti- of key clinical features of 91 different disorders that will bility and less prominent, patchy or partial T1W hyperin- further guide diagnostic evaluations in the clinical setting tensity seen in disorders classically associated with brain (also available via Supplementary Table 5). iron deposition which grouped together in Cluster 2 (Fig. 4F–H) (Supplementary Fig. 3). Sequential MRI scans were available for one patient with SLC39A14 which showed spread of T1W hyperintensity to the putamen Cluster 1 and associated conditions adjoining the GP with blurring of the anatomical bound- The disorders that grouped together in Cluster 1 in this ary between these nuclei (Fig. 5I). study had predominant striatal T2W hyperintensities with very infrequent GP abnormalities. This pattern was seen Diagnostic algorithm and decision- in all patients with inflammatory disorders included in this study which aligns with cases reported in the litera- making tool ture—both direct infectious and immune-mediated as well On the basis of the MRI features that led to grouping of as auto-inflammatory syndromes. Furthermore, according diagnostic categories in four clusters a diagnostic algo- to the literature, some metabolic disorders—organic acid- rithm was designed to guide stepwise review of MRI aemias and thiamine responsive basal ganglia disease scans with bilateral basal ganglia abnormalities. On lit- associated with SLC19A3 tend to predominantly have a erature review, 59 additional disease categories matching striatal—Cluster 1 pattern. Likewise, this pattern has the inclusion criteria for this study were identified with been reported in the following monogenic and neurome- reported bilateral basal ganglia MRI abnormalities. A few tabolic disorders—2-Methyl-3-Hydroxybutyryl-CoA disorders with reported onset in adulthood such as aceru- Dehydrogenase Deficiency (Cazorla et al., 2007; Su et al., loplasminaemia and neuroferritinopathy were included as 2017), AFG3L2 (Eskandrani et al., 2017; Tunc et al., they are often considered in continuation with other gen- 2019), DNAJC19 (Ucar et al., 2017), giant axonal neur- etically determined neurodegenerative disorders. In the lit- opathy (Hentati et al., 2013), L-2-OH-glutaric aciduria erature review, mitochondrial disorders have been (Cachia and Stine, 2013), Leber hereditary optic neur- retained as in this study, categorized either based on dis- opathy (Mercuri et al., 2017; Miyaue et al., 2019), tinct syndromes such as Kearns Sayre syndrome or NUP62 (Basel-Vanagaite et al., 2006), PDE8B MEGDEL and alternatively categorized based on bio- (Appenzeller et al., 2010; Ni et al., 2019), PDE10A chemical findings—e.g. mitochondrial complex 1 defi- (Diggle et al., 2016; Mencacci et al., 2016; Esposito ciency, etc. as MRI pattern correlations in genotyped et al., 2017; Knopp et al., 2019) and VPS13A (Nicholl patients with mitochondrial disorders are still being et al., 2004; Lee et al., 2011). While many disorders can described. Moreover, there is often phenotypic pleiotropy cause homogenous T2W hyperintensity in the striatum, in the same genetic subgroups of mitochondrial disorders partial sparing of the mid-portion of the putamen, is even though some genotypes can be linked to particular highly suggestive of MEGDEL which has been reported biochemical subgroups (Supplementary Table 2.2) (Lake in nearly all confirmed cases in one large series et al., 2016; Rahman et al., 2017). Likewise, disorders (Wortmann et al., 2015) (Fig. 3B). In this study, partial with primary familial brain calcification remain grouped sparing of parts of the putamen, though not as symmetric together. Further findings from the literature review looking as seen in MEGDEL, was also noted in other which expand the consideration of differential diagnoses mitochondrial disorders, ADAR and thiamine responsive were incorporated to finalize the algorithm (Fig. 6) and basal ganglia disease (SLC19A3). This has been reported the decision-making application (downloadable from in literature in other mitochondrial disorders including 14 | BRAIN COMMUNICATIONS 2020: Page 14 of 23 S. S. Mohammad et al. DNAJC19 (Ucar et al., 2017) as well as in PDE8B (Ni period, similar to reported with bilirubin toxicity, can be et al., 2019) and Wilson’s disease. transiently seen in normal babies in the first 3–4 weeks of In children with injury related to HIE at term the quite life (Barkovich, 1998; Newman et al., 2002). The GP distinctive pattern of T2W hyperintensities in the motor normally transitions from appearing hyperintense com- cortex, along the corticospinal tract, including the poster- pared to the striatum on T2W datasets to become in- ior putamen and ventrolateral thalami has a high diag- creasingly hypointense. T2W hyperintensities in the GP nostic value. Corticospinal tract abnormalities may also due to kernicterus may be missed as the appearance of accompany basal ganglia MRI changes in other disorders the GP appears isointense or ‘pseudonormal’ compared to (Table 2, category ‘D’). The pattern in CP (Fig. 3E and F the neighbouring striatum during the transition phase and Supplementary Fig. 4) which has been termed (Shapiro, 2010; van Toorn et al., 2016) (Supplementary ‘Rolandic type cerebral palsy’ (Maller et al., 1998) may Fig. 5). On 1.5 T MRI, this phase is typically in the se- be less well recognized as it often does not show a dom- cond year of life but may be evident later into early inant pattern of leukomalacia or cystic encephalomalacia childhood if the patient is clinically delayed. Amongst as would be noted in antenatal HIE or HIE in preterm genetic disorders, dominant pallidal T2W hyperintensities neonates (Rademakers et al., 1995; Huang and Castillo, indicate a higher likelihood of some metabolic and mito- 2008; Griffiths et al., 2010). Recognition of this pattern chondrial disorders (Table 2, category ‘I’). allows counselling of likely perinatal injury as the cause In spite of many disorders clustering to a dominant of CP and helps avoid further diagnostic testing. Apart pallidal or striatal pattern of T2W hyperintensities in this from HIE, other disorders that can cause brain injury study, it is evident from literature that several disorders through various mechanisms can also demonstrate a stri- can have MRI changes that overlap within the same or atal dominant pattern. These comprise extrapontine mye- different patients namely striatal, pallidal or both pairs of linolysis (Gocht and Colmant, 1987; Miller et al., 1988; nuclei showing T2W hyperintensities. In this study, con- Brown and Caruso, 1999; Bekiesinska-Figatowska et al., comitant pallidal and striatal T2W hyperintensities were 2001; Ranger et al., 2012), haemolytic uraemic syndrome seen in some patients with mitochondrial complex I de- (Sherwood and Wagle, 1991; Jeong et al., 1994), ethylene ficiency, propionic acidaemia and PDHC (Fig. 2). In the glycol (Moore et al., 2008; Malhotra et al., 2017) and literature, this is reported in some cases with Alexander methanol poisoning (Anderson et al., 2004). disease (van der Knaap et al., 2001; Graff-Radford Striatal necrosis, which is a pathological diagnosis, was et al., 2014), beta ketothiolase deficiency (Buhaş et al., not scored in this study as a distinct radiological feature. 2013; O’Neill et al., 2014; Wojcik et al., 2018), Striatal atrophy, however, was observed in patients with Cathepsin A-related arteriopathy with strokes and leu- ADAR, ADEM, ANE, glutaric aciduria type 1 (GA1), koencephalopathy (Bugiani et al., 2016), cyanide poi- BGE, juvenile Huntington’s disease, various mitochondrial soning (Rachinger et al., 2002; Beltz and Mullins, disorders, MEGDEL, PDHC, SLC19A3 and TUBB4A. 2010), maple syrup urine disease (Gropman, 2012), From literature review, other disorders in which striatal metachromatic leukodystrophy (Eichler et al., 2009), atrophy on MRI has been reported include—Alexander sulphite oxidase and molybdenum cofactor deficiency disease, isovaleric acidaemia, MECR, Neuroferritinopathy, (Tonduti et al., 2016). A similar overlap can be seen in NUP62, PDE8B, PDE10A, PRKRA, UFM1, VAC14, other mitochondrial disorders, apart from those VPS13A, VPS13D, Wilson’s disease, other mitochondrial described with a dominant striatal or pallidal pattern disorders and as sequelae to inflammatory disorders and (disorders mentioned here map to the end-point of com- toxin exposure. bined striatal and pallidal T2W hyperintensities in Fig. 6). Increased susceptibility in the pallidum and other basal Cluster 2 and associated conditions ganglia nuclei may be noted in various disorders that in- The disorders that grouped together in Cluster 2 in this clude the deposition of paramagnetic materials such as study included conditions with either predominant pal- iron deposition in the disorders of neurodegeneration lidal T2W hyperintensities or those with predominant with brain iron accumulation (NBIA), disorders with ac- increased susceptibility in the GP. The largest diagnostic cumulation of copper or manganese and disorders with category in Cluster 2 in this study was that of patients primary or secondary basal ganglia calcification. In add- with kernicterus. In all patients with kernicterus, there ition, there are several other disorders that are designated was a very consistent pattern with appearance of bilateral as ‘NBIA mimics’ such as alpha mannosidosis, fucosido- GP T2W hyperintensities sometimes associated with T2W sis, gangliosidoses and mucolipidosis type IV. In our hyperintensities in the SN/STN or the dentate nuclei. In study, when the MRIs of patients with these disorders some cases, the GP was atrophic, nevertheless, the pattern were analysed, they all grouped together in Cluster 2. remained stable over time. A note of caution should be TUBB4A and KMT2B should also considered in the dif- made when interpreting signal changes in the pallidum, ferential diagnosis of increased basal ganglia susceptibility particularly with the question of bilirubin-related neuro- (Meyer et al., 2017) in addition to several other disorders logical injury. T1W hyperintensities in the neonatal including some recent monogenic associations (Table 2)— MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 15 of 23 | 15 Table 2 Selected MRI changes and clinical features that aid narrowing down diagnostic differentials for disorders with MRI basal ganglia changes MRI/clinical feature Diagnostic differential A Calcification accompanying BPAN brain iron deposition CoPAN PKAN SQSTM1 B Cerebellar atrophy witd increased Aceruloplasminemia basal ganglia susceptibility AFG3L2 Alpha mannosidosis Aspartylglucosaminuria BPAN Choline transporter-like 1 deficiency (SLC44A1) Congenital disorder of glycosylation, type IIn (SLC39A8) Cockayne syndrome FAHN Fucosidosis GM1 and GM2 Gangliosidoses GTPBP2 Kufor Rakeb syndrome Langerhans cell histiocytosis C Cerebellar atrophy with MPAN basal ganglia T2W hyperintensity Mucolipidosis type IV Neuroferritinopathy PKAN PLAN REPS1 SQSTM1 TUBB4A AFG3L2 Aspartylglucosaminuria DNAJC19 GM1 and GM2 Gangliosidoses L-2-OH-glutaric aciduria MEGDEL Mitochondrial disorders (various) PDHC Sequelae of infectious encephalitis SSADH UFM1 VPS13D Wilson’s disease D Corticospinal tract T2W hyperintensity 3-HMG-CoA lyase deficiency CP Cerebrotendinous xanthomatosis Krabbe disease SLC19A3 VPS13D E Dentate T2W hyperintensities 3-HMG-COA Lyase deficiency ADEM Alexander disease Arboviral encephalitis Beta ketothiolase deficiency Canavan disease Cerebrotendinous xanthomatosis Giant axonal neuropathy Glutaric aciduria type 1 Kearns Sayre syndrome Kernicterus Krabbe disease L-2-OH-glutaric aciduria Langerhans cell histiocytosis Maple syrup urine disease MEGDEL (continued) 16 | BRAIN COMMUNICATIONS 2020: Page 16 of 23 S. S. Mohammad et al. Table 2 Continued MRI/clinical feature Diagnostic differential MMA Mitochondrial disorders (various) Neuroferritinopathy PDHC Propionic acidaemia SLC19A3 SSADH Sulphite oxidase and molybdenum cofactor deficiency Vigabatrin toxicity Wilson’s disease F Hypomyelination with increased BPAN basal ganglia susceptibility ADAR Alpha mannosidosis Aspartylglucosaminuria Cockayne syndrome Fucosidosis GM1 and GM2 Gangliosidoses Idiopathic basal ganglia calcification Mucolipidosis type IV TUBB4A G Hypomyelination with 3-HMG-COA Lyase deficiency basal ganglia T2W hyperintensity Alexander disease Canavan disease Cerebral creatine deficiency syndromes GM1 and GM2 Gangliosidoses Glutaric aciduria type 1 Methylmalonic acidaemia Mitochondrial disorders (various—particularly Complex 1 deficiency) POLR3A Propionic acidaemia SSADH UFM1 H Hypothalamus T2W hyperintensity ADEM ANE Kearns Sayre syndrome Langerhans cell histiocytosis LHON ADEM (NMO spectrum disorder) PDHC Vigabatrin toxicity Fucosidosis Hypothalamus T1W hyperintensity Manganese toxicity Liver failure (likely due to secondary manganese accumulation) I Mainly pallidal T2W hyperintensity 3-HMG-COA Lyase deficiency without striatal abnormalities Canavan disease Cerebrotendinous xanthomatosis Carbon monoxide poisoning Creatine deficiency syndromes—monogenic and secondary Isovaleric acidaemia Kearns Sayre syndrome Kernicterus Krabbe disease MMA PDHC SSADH Vigabatrin toxicity J Optic atrophy with increased AP4 deficiency basal ganglia susceptibility FAHN Kufor Rakeb syndrome (continued) MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 17 of 23 | 17 Table 2 Continued MRI/clinical feature Diagnostic differential MPAN PLAN K Optic atrophy with Giant axonal neuropathy basal ganglia T2W hyperintensity Mitochondrial disorders—LHON and others MECR Methanol toxicity NUP62 L Optic tract/chiasm thickening ADEM (NMO spectrum disorder) Alexander disease Krabbe disease LHON M Pituitary signal change/atrophy Langerhans cell histiocytosis SLC30A10 SLC39A14 Woodhouse Sakati syndrome N Short stature/poor growth 3-HMG-COA Lyase deficiency AP4 deficiency Choline transporter-like 1 deficiency (SLC44A1) Cockayne syndrome KMT2B Mitochondrial disorders O Retinopathy 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency Aceruloplasminemia BPAN Kearns Sayre syndrome Methanol toxicity Mitochondrial disorders (various) Mucolipidosis type IV PKAN VAC14 P Rim of T2W hyperintensity ADEM around the putamen ANE BGE Encephalitis—Arboviruses Gangliosidoses Metabolic acidosis Myelinolysis Propionic acidaemia SLC19A3 Uraemia Wilson’s disease Q Sensorineural hearing loss 3-HMG-COA lyase deficiency Alpha mannosidosis Cockayne syndrome Kernicterus MEGDEL Metachromatic leukodystrophy SCP2 Mitochondrial disorders (various) Woodhouse Sakati syndrome R Increased striatal susceptibility Aceruloplasminemia Alpha mannosidosis Aspartylglucosaminuria Basal ganglia calcification Kufor Rakeb syndrome Multiple system atrophy Mucolipidosis type IV Neuroferritinopathy SLC30A10 SQSTM1 Wilson’s disease (continued) 18 | BRAIN COMMUNICATIONS 2020: Page 18 of 23 S. S. Mohammad et al. Table 2 Continued MRI/clinical feature Diagnostic differential S T1W hyperintensities Ephedrine toxicity in the basal ganglia—Diffuse Hypermanganesemia—TPN, environmental SLC30A10 SLC39A14 Wilson’s disease (particularly with porto-sys- temic shunt) In association with increased basal ganglia sus- ceptibility (less hyperintense than disorders with manganese accumulation) T T1W hyperintensities Basal ganglia calcification in the basal ganglia—Patchy Carbon monoxide poisoning Cyanide poisoning PDE8B Sequelae of inflammatory disorders U T2W hypointensities in the thalamus Alpha mannosidosis Aspartylglucosaminuria Fucosidosis Gangliosidoses Metachromatic leukodystrophy ADEM, acute-disseminated encephalomyelitis; ANE, acute necrotizing encephalopathy; BGE, autoimmune basal ganglia encephalitis; BPAN, beta-propeller protein-associated degen- eration; CoPAN, COASY protein-associated neurodegeneration; CP, cerebral palsy (due to HIE in term babies); FAHN, FA2H-associated neurodegeneration; LHON, Leber’s heredi- tary optic neuropathy; MEGDEL, 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome; MMA, methyl malonic acidaemia; MPAN, mitochondrial membrane protein-associated neurodegeneration; NMO, neuromyelitis optica spectrum disorder; PDHC, pyruvate dehydrogenase complex deficiency; PKAN, Panthothenate kinase-associated degeneration; PLAN, PLA2G6-associated neurodegeneration; SSADH, succinic semialdehyde dehydrogenase deficiency. AP4 deficiency (Moreno-De-Luca et al., 2011; Vill et al., neurological Wilson’s disease, rather striatal T2W 2017; Roubertie et al., 2018), CRAT (Drecourt et al., hyperintensities may be more obvious in childhood, as 2018), GTPBP2 (Jaberi et al., 2016), RAB39B noted in this study and discussed in literature (Gupta (Giannandrea et al., 2010; Wilson et al., 2014; Shi et al., et al., 2014). In addition to clinical features, neuroimag- 2016), REPS1 (Drecourt et al., 2018; Levi and Tiranti, ing features that can assist in navigating differential 2019), SCP2 (Horvath et al., 2015; Morarji et al., 2017), diagnoses in the presence of increased basal ganglia sus- SQSTM1 (Muto et al., 2018), VPS13D (Gauthier et al., ceptibility include calcification on CT scan, cerebellar 2018; Seong et al., 2018), VAC14 (Lenk et al., 2016; de atrophy, increased striatal susceptibility or atrophy, Gusmao et al., 2019; Lyon et al., 2019), VPS13A optic atrophy, hypomyelination and thalamic hypointen- (Nicholl et al., 2004; Lee et al., 2011), Choline transport- sities (Autti et al., 2007) (Table 2). er-like 1 deficiency (SLC44A1) (Fagerberg et al., 2020) Besides primary familial brain calcification (mainly and Langerhans cell histiocytosis (Ertan and Huisman, caused by SLC20A2, and PDGFRB mutations), many 2010; Grois et al., 2010; Jezierska et al., 2018; de Haan other disorders can lead to basal ganglia calcification et al., 2019). (Table 2 and Supplementary Table 7). MRI patterns in As noted in sequential MRI scans in our study, in some of these disorders have been previously described patients with suspected NBIA disorders, the stage of (Livingston et al., 2013, 2014). Some patients with disease progression is important in correlating MRI ADAR in particular may have pure pallidal susceptibility findings. To begin with, increased striatal susceptibility due to calcification on MRI rather than a Cluster 1 stri- is uncommon in childhood (Table 2, category ‘R’). atal pattern as seen in this study. Also, early stages of disease may not show increased susceptibility in basal ganglia nuclei in common NBIA disorders such as PLAN and PKAN (see Fig. 4F and I); Cluster 3 and associated conditions furthermore, in surviving individuals, increased striatal In this study, a distinct pattern was noted in patients susceptibility may develop in several classic NBIA disor- with toxicity due to vigabatrin, which is a GABA trans- ders like MPAN. In a child with increased, homogenous aminase inhibitor. These patients grouped together in striatal susceptibility Wilson’s disease should be ruled Cluster 3 demonstrating T2W hyperintensities and diffu- out, and if increased striatal susceptibility is patchy or sion restriction in the pallidum as well as the brainstem asymmetric, disorders with basal ganglia calcification and cerebellum. Hypothalamic changes in particular were should also be considered. Furthermore, iron deposition noted in all patients with vigabatrin toxicity. Only few can also accompany deposition of other metals as in other disorders are reported to show hypothalamic signal Wilson’s disease (Dusek et al., 2017, 2018). Increased abnormalities accompanying basal ganglia MRI changes susceptibility may not be seen in all patients with (Table 2, category ‘H’). MRI changes are estimated to MRI patterns in basal ganglia disorders BRAIN COMMUNICATIONS 2020: Page 19 of 23 | 19 occur in 22–32% of patients on vigabatrin (Pearl et al., single entity or a short list of differentials with the aim 2009; Wheless et al., 2009), more likely to be seen in of rationalizing clinical testing. A pattern that may be children with cryptogenic infantile spasms (Dracopoulos typical of monophasic ADEM, BGE, CP or kernicterus et al., 2010). Young age and higher doses of vigabatrin for example, should subsequently obviate the need to have been proposed to be risk factors (Pearl et al., 2009; keep repeating MRI scans or pursue other unnecessary Dracopoulos et al., 2010). Other disorders in Cluster 3 investigations. In the correct clinical context, if the imag- included Krabbe disease and Kearns Sayre syndrome ing pattern fits a treatable disorder such as BGE, ADEM where the presence of optic tract thickening, or retinop- or, SLC19A3 empiric treatment may be instituted while athy, respectively, aid differential diagnosis. MRI changes awaiting other results. In the same vein, some patterns, in different parts of the visual pathway with basal gan- such as the ‘eye of the tiger’ or the ‘face of the giant glia MRI changes can help indicate some other disorders panda’ tend to become associated with certain diseases as (Table 2). pathognomonic associations. However, the absence of such patterns may indicate an early stage of the disease Cluster 4 and associated conditions and should not lead to exclusion of these differentials. Our retrospective study design did enable cross-sectional Exceptionally prominent bilateral basal ganglia T1W comparisons between diseases but did not permit accurate hyperintensity in Cluster 4 was helpful in discerning longitudinal assessment of resolution or progression of hypermanganesemia associated with SLC39A14 and imaging features. SLC30A10. Even though manganese is a metal, increased Sometimes, the finding of changes in parts of the brain susceptibility is noted in very few patients with manga- that are not classically involved in a particular disease, nese deposition. Other differentials for diffuse T1W may be described as an ‘expansion of the phenotype’. hyperintensity in the basal ganglia include calcification, These may at times, be due to comorbid conditions or iron deposition, Wilson’s disease and secondary hyper- complications, for example, immature myelination in one manganesemia due to occupational exposure, liver failure patient with kernicterus in this study was likely due to and ephedrone toxicity (Varlibas et al., 2009) all of extreme prematurity. Likewise, metabolic disturbances which have characteristic diagnostic features of their like hypoglycaemia in disorders like 3-HMG-CoA lyase own. Toxic exposure to manganese can appear radio- deficiency, 2-Methyl-3-Hydroxybutyryl-CoA dehydrogen- logically identical to the changes noted in genetically ase deficiency may lead to occipital changes typical of determined hypermanganesemia. In most children with low glucose levels. SLC39A14, the T1W hyperintense signal seemed to re- Our study was performed using a retrospective cohort main dominantly in the GP until an older age (Fig. 5I) where MRI scans were done as part of the standard clin- compared to SLC30A10 where this diffusely involved all ical evaluation in children with different neurological dis- basal ganglia nuclei even at an early age, always includ- orders; therefore, there was an inherent variability in the ing the GP. In contrast, disorders with basal ganglia cal- MRI protocols, having used different machines and image cification may sometimes show striatal T1W acquisition timing. The major inclusion criteria in this hyperintensities without involving the GP and vice versa. study and for the cases selected from the literature was Patchy T1W hyperintensities may often be noted with the obligatory presence of bilateral basal ganglia MRI resolving haemorrhagic change or dystrophic calcification abnormalities. The differentials and approach discussed after the acute phase of several disorders including in- here only become relevant in patients with those disor- flammatory disorders, episodes of decompensation in ders when there is bilateral basal ganglia abnormality to metabolic, including mitochondrial disorders or toxin ex- start with. Some disorders included in this study may ac- posure as well as in cases of bilateral basal ganglia neo- tually have a more typical and common MRI appearance plasia which we have not reviewed here. Although that may not involve the basal ganglia. This study cohort quantification of signal change is not routinely possible was heterogenous with different patient numbers for in clinical practice, the T1W hyperintensity noted with included diagnostic categories, and some of the groups manganese deposition is much brighter and diffuse than had very small numbers of patients. Therefore, MRI fea- seen in other disorders. tures that are not always seen in a diagnostic category may have been missed. Also, MRI changes seen transient- Importance of basal ganglia MRI ly may not have been obvious in scans in this study that pattern recognition and study were done later in the disease course, for example diffu- sion restriction is only present in the newborn period for limitations babies with HIE. The ascertainment of paediatric neurological conditions The primary raters were not blinded to the diagnostic with basal ganglia involvement is best accomplished first categories leaving a major potential for bias to over with defining the clinical phenotype in detail. reporting well-known imaging features while underreport- Subsequently, the recognition of characteristic MRI pat- ing unusual, unrecognized or novel MRI features. In terns in the basal ganglia can help to consider either a order to balance against these caveats, a subset of 20 | BRAIN COMMUNICATIONS 2020: Page 20 of 23 S. S. Mohammad et al. patients was rated by three independent radiologists who travel for this study and held postgraduate research scholar- were blinded to each other’s ratings and we leveraged by ships from the National Health and Medical Research performing a literature review and incorporating other Council, Australia and the Petre foundation at the time of findings into Table 2 and the subsequent decision-making this study. tool. Lastly, this cohort and study were restricted to childhood-onset disorders. Although there may be similar- ities and overlap with adult-onset disorders, it is likely there would be disease-related and radiological phenotyp- Competing interests ic differences in adult-onset disorders—future studies could develop an adult-onset cohort for study. None of the authors have any competing interests to declare. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the National institute for Conclusion health research, (NIHR) Great Ormond Street Hospital In children with neurological symptoms and MRI abnor- Biomedical Research Centre. The views expressed are those malities affecting the basal ganglia, clustering of neuroi- of the author(s) and not necessarily those of the NHS, the maging patterns as described in this study can NIHR or the Department of Health. complement clinical information to aid differential diag- nosis and guide diagnostic testing. This pattern recogni- tion approach to basal ganglia disorders may help References identify currently unrecognized patient subgroups that Anderson JC, Costantino MM, Stratford T. Basal ganglia: anatomy, could increase the yield of genetic testing. We propose pathology, and imaging characteristics. 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