Patients with coronary microvascular dysfunction (CMD) have significantly higher rates of cardiovascular events, including hospitalization for heart failure, sudden cardiac death, and myocardial infarction (MI). In CMD, several pathophysiological changes lead to functional and structural abnormalities in the coronary microvasculature, which disrupt the ability of the vessels to vasodilate and augment myocardial blood flow in response to increased myocardial oxygen demand, causing ischemia and angina. With the advent of more advanced non-invasive cardiac imaging techniques, the coronary microvasculature has been subjected to more intense study in the past two decades—this has led to further insights into the diagnosis, pathophysiology, treatment, prognosis and follow-up of CMD. This review will highlight and compare the salient features of the currently available non-invasive imaging modalities used in these patients, and discuss the clinical utility of these techniques in the workup and management of these patients. In the past 10 to 15 years, coronary microvascular dysfunction (CMD) has gained more recognition and is being increasingly diagnosed as a cause of angina and morbidity in patients who have objective evidence of myocardial ischemia but do not have obstructive coronary artery disease (CAD) on angiography. These patients often experience “microvascular angina” , which iThe coronary microvasculature represents the distal-most compartment of the coronary arterial system and comprises intramural arterioles with diameters of less than 100 μm  6]. The. The6]. Coronary microvascular function is a crucial determinant of perfusion. Coronary autoregulatory mechanisms maintain a relatively constant coronary perfusion despite wide range of variations in perfusion pressures ,10. ThisCMD results from heightened sensitivity of the coronary microcirculation to vasoconstrictor stimuli associated with a limited microvascular vasodilator capacity. This manifests as suboptimal coronary vasodilator response to exercise or pharmacological stress, which can be measured by various invasive and noninvasive techniques ,7,11,12.Many patients with CMD also have macrovascular atherosclerosis, albeit usually nonobstructive disease . CMD plaPatients with CMD do not have a benign prognosis as was traditionally believed. They have a higher incidence of cardiovascular events, including hospitalization for heart failure, sudden cardiac death, and MI as compared to age-matched controls, irrespective of gender ,20,21,22A.Primary CMD:CMD can be differentiated into three major categories: ,12A.PriB.Secondary CMD:(i)CMD in the presence of obstructive CAD. Microvascular dysfunction can concomitantly exist with stable and unstable CAD.(ii)CMD in the presence of myocardial disease. Microvascular dysfunction can occur secondary to arterial remodeling, intimal hypertrophy along with interstitial and perivascular fibrosis resulting from various cardiomyopathies.This is further classified in to two categories.C.Iatrogenic CMD:Microvascular dysfunction in the absence of imaging and clinical evidence of obstructive CAD or myocardial disease constitutes this category. It can be a precursor of CAD and/or can result from vasomotor instability secondary to genetic or acquired cardiovascular risk factors. This condition has also been variably termed microvascular angina or syndrome X .B.SeconCoronary microcirculation can become dysfunctional subsequent to a percutaneous coronary intervention that can lead to vasoconstrictor response and/or distal embolization caused at the time of revascularization.Direct assessment of microvascular flow is complex as no technique allows direct visualization of the coronary microcirculation. Microvascular perfusion cannot be directly assessed through coronary blood flow . MyocardIn clinical practice, non-invasive measurement of CMD relies on the principle of the coronary flow reserve (CFR). CFR represents the increase in coronary blood flow (CBF) that is achieved in going from basal coronary perfusion to maximal coronary vasodilation in response to a vasodilatory stimulus . In patiCFR is determined by taking measurements of coronary blood flow both at rest  and with maximal hyperemia achieved by pharmacological/vasodilator stress. CFR is then expressed as the ratio of blood flow during hyperemia to the blood flow at rest ,12,27,28CT, relies on myocardial segmentation and simulated flow using Navier-Stokes equations and correlates well with invasively measured values.The reference standard for measurement of CFR and hence diagnosis of CMD used to be invasive coronary reactivity testing (CRT). This involves the use of vasoactive substances to test endothelial and nonendothelial-dependent coronary function. CMD measured by CRT predicts adverse events in both men and women with and without obstructive CAD ,22. StanExercise stress or dobutamine contrast echocardiography can detect ischemia in the presence of a hemodynamically significant epicardial stenosis; however, it has limited utility in the diagnosis of CMD if an ultrasound contrast agent is not employed. The reason for this is that CMD usually produces subendocardial ischemia, whereas gross hypokinesis by qualitative visual examination, as is done frequently for large vessel stenosis, requires a greater amount of transmural ischemic burden in the myocardial segments subtended by the stenotic artery. Similarly, patchy CMD would not be detected. In addition, there can be significant inter-observer variability in the interpretation of mild localized hypokinesia and hence results are not very reproducible ,32. The CT) is a sensitive tool for hemodynamic evaluation of lesion specific ischemia. It involves quantification of MBF and FFRCT at a specified point in the coronary vasculature through computational fluid dynamics and uses a 3-D derived coronary model that simulates maximal hyperemia. The relationship between FFRCT and CMD is not fully defined yet [3/g vs. 30.0 ± 6.5 mm3/g; p = 0.007) [The advent of multi-detector dynamic CT imaging has improved the capability of CT to go beyond anatomic assessment of coronary luminal stenosis alone. Newer technological advances such as 256 and 320 row detectors allow for single heartbeat acquisition, which permits serial myocardial and left ventricular cavity sampling for quantifying the MBF . Iodinatined yet ,43,45, bined yet . Grover = 0.007) . The maj= 0.007) ,49.99mTc-sestamibi, 99mTc-tetrofosmin and 99m Tc-teboroxime) have relatively low first-pass extraction, show significant roll-off of radiotracer uptake at higher flow rates, and have significant liver or intestinal uptake. This, along with poor camera sensitivity and temporal resolution (with the common sodium-iodide cameras), accounts for the suboptimal quantification of MBF [SPECT imaging has had limited diagnostic utility in the past for assessment of CMD, largely because of pharmacokinetics of the radiotracers used for SPECT myocardial imaging. The most commonly used technetium-based SPECT perfusion radiotracers  and solid-state high sensitivity cadmium-zinc-telluride detectors (CZT), dynamic SPECT can be used for quantification of MBF and hence for the assessment of CMD [15O–water PET) as having a high diagnostic value for detecting impaired MFR in patients with stable CAD [However, with the recent advent of high-sensitivity cardiac cameras, iodinated rotenone compounds  and minimal roll-off. However, the latter 2 are not as readily available for day-to-day clinical use.The commonly used PET radiotracers are yclotron . It has PET has been validated against invasive modalities of flow estimation in numerous studies. Absolute quantification of MBF and CFR is highly reproducible over a wide range of MBF (0.5–6 mL/g per minute) .82Rb PET predicted hard cardiac events independent of the summed stress score and other parameters. They also suggested that routine assessment of 82Rb PET–quantified MBF and MPR could improve risk stratification for patients being investigated for ischemia. PET has also been used to validate CMD seen in metabolic syndrome patients [CMD detected by PET as abnormal myocardial perfusion reserve (MPR) has also been correlated with adverse outcomes . Ziadi epatients . These fpatients ,15,19,22patients .Cardiac magnetic resonance (CMR) is an ideal noninvasive modality for assessing patients with microvascular angina/CMD. Two types of stress CMR modalities have been tested—stress perfusion and stress T1 mapping.Stress CMR perfusion can detect myocardial perfusion abnormalities with high spatial resolution without exposure to ionizing radiation. The qualitative evaluation is done by the visual analysis of first-pass gadolinium images ,59. ThisQuantitative and semi-quantitative evaluation of the first-pass perfusion images can be used to calculate objective parameters of perfusion, such as the global stress myocardial flow reserve (SMFR) and the myocardial perfusion reserve index (MPRI), which is an indexed ratio of perfusion-time intensity curve upslopes in response to vasodilator stress . Other, Kotecha et al. showed that an automated pixel-wise quantitative myocardial perfusion mapping technique can be used to detect and differentiate CMD from three-vessel disease with good accuracy. They suggested an algorithm for the detection of obstructive coronary artery disease and CMD based on regional and global stress MBF . PatientAnother novel CMR technique, known as T1 mapping, represents a breakthrough in the non-invasive assessment of microvascular ischemia when performed during vasodilatory stress ,63. It hAssessment of the coronary vasculature using T1 mapping relies on the principle of coronary vasodilatory reserve and myocardial blood volume (MBV). In healthy myocardium and coronary vasculature, MBV may increase two-fold during coronary vasodilatory stress, representing significant coronary reserve. This corresponds to a 6% increase in myocardial T1 during adenosine vasodilatory stress . In patiThe difference in diagnostic performances of perfusion CMR and stress T1 mapping is due to different mechanisms for ischemia detection as described above. Hence, although MBF, as assessed quantitatively by perfusion CMR, is similar downstream of obstructive and nonobstructive coronary arteries, there is a significant observed difference in resting myocardial T1.Arterial spin labeling (ASL) is an emerging technique that has been used successfully in non-cardiac MR modalities in the past to measure regional cerebral, renal and skeletal muscle blood flow ,70,71. IMore recently, arterial blood deoxygenation techniques with hyperventilation have been used to detect CMD in heart transplant recipients using oxygen sensitive CMR sequences. CMD can occur even in the absence of overt allograft vasculopathy and increases the risk of adverse cardiac outcomes .Non-contrast-based CMR techniques are the future of CMR-derived CMD assessment. Besides higher diagnostic performance, they have the potential to address the limitations of gadolinium-based MBF assessments including imaging artifacts, long scan time, interobserver variability, problems with the absolute quantitation of MBF, restricted use in chronic kidney disease patients and a lack of widespread availability of quantitative first-pass sequences .The multifactorial pathophysiology and varied phenotypes of CMD makes it a challenging clinical entity to manage. Treatment thus far has been empirical and involves cardiovascular disease (CVD) risk factor modification and conventional pharmacological options for obstructive atherosclerotic CAD. Lifestyle modification with smoking cessation, weight loss, regular exercise and improved nutrition along with the optimization of underlying hypertension, diabetes mellitus and dyslipidemia has been shown to improve overall ischemic burden by improving microvascular circulation .Pharmacological therapies to target microvascular angina can be chosen based on specific CMD phenotype. Antiplatelets and lipid lowering drugs are the standard of care because of the strong association of atherosclerosis and CMD. Statins with evident mortality benefit in obstructive CAD have been shown to improve microvascular perfusion by increasing CFR . SymptomA number of validated, noninvasive cardiovascular imaging modalities are presently available to measure MBF and CFR in the setting of CMD (PET is currently the most studied and validated modality, but CMR-derived MBF and T1-mapping measures are being increasingly used to diagnose patients and assess their response to treatment. In clinical practice, the type of imaging modality used is dependent on individual risk–benefit ratio and cost, in addition to local expertise and availability of the technology. Additional studies are currently examining integrative imaging approaches and regional versus global MPR assessments. The ultimate goal of using these modalities will be to define prognostic differences, therapeutic interventions, and treatment approaches, such that we can make an impact on the profound morbidity and non-negligible mortality associated with this condition.


Thousands of people are affected by central nervous system (CNS) dysfunctions each year, with stroke and spinal cord injury (SCI) being the most frequent causes. Although there is some evidence of partial CNS self-repair , due to restricted regeneration capacity in mammals, acute or chronic spinal cord injuries cannot be repaired completely. Therefore, to expand the availability of treatment options for SCI, research on highly regenerative animals has become essential. Among vertebrates, axolotl, a salamander species, has been emerging as a powerful model to explore the molecular mechanisms of regeneration due to its exceptional regenerative capacity. In this study, gene expression modulation for regenerative-capable neotenic axolotl during spinal cord regeneration has been investigated. Next-generation sequencing was applied for the collected regeneration samples at zero and seven days post-amputation (dpa). The data obtained from the analyzed samples revealed 363 genes differentially expressed, mostly downregulated, between zero dpa and seven dpa. The extracellular matrix, cell-cell adhesion, and immune system-related processes and pathways were enriched by gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Based on these data, we conclude that the downregulation of immune system-related biological processes is crucial for spinal cord regeneration. Spinal cord injury (SCI) is one of the more common acute central nervous system (CNS) injuries seen throughout the world. Currently, limited treatment options are available for spinal cord repair and regeneration . Lack ofAmbystoma mexicanum), also known as Mexican salamander, possesses an exceptional regeneration capacity compared to other species at the adult stage [Among vertebrates, the amphibian axolotl  and seven days post-amputation (dpa), the blastema/regeneration time point. Gene expression analysis of these samples pinpointed the biological processes that have a suppressive or stimulating effect on spinal cord regeneration. This work constitutes one of the very first efforts to chart the axolotl gene expression profile during spinal cord regeneration.Axolotls  used in the experiments were bred in the Istanbul Medipol University Animal Care Facility. The followed procedures were approved by the Istanbul Medipol University Animal Experiments Local Ethical Committee (authorization number 38828770-E.2499). Animals were maintained at 18°C in 20% Holtfreter’s solution, kept in chambers as one animal per aquarium, and fed once a day using staple food  throughout the experimental period as described elsewhere . AxolotlRNAs were extracted from the collected samples using Trizol reagent  according to the manufacturer’s protocol. The RNA quantities were determined by Qubit assay according to the manufacturer’s protocol . For each replicate, the RNA concentration was measured at a concentration greater than 200 ng/µl. The quality of isolated RNAs was checked on 1% agarose gel. After quantity and quality controls, a TrueSeq Stranded messenger RNA (mRNA) kit  was used for mRNA library preparation by following the manufacturer’s protocol. The Illumina NextSeq 500 platform was employed for RNA sequencing by using a NextSeq 500/550 High Output Kit v2.5 150 cycles .Demultiplexing and barcode removal for the paired-end sequencing dataset obtained from samples was performed using the Illumina BaseSpace platform. The resulting barcode-free raw sequencing data were retrieved and preprocessed using Illumina FASTQC software, followed by Cutadapt software -15. WhilGene ontologies and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the list of differentially expressed (DE) genes between seven dpa and zero dpa neotenic samples were queried using the clusterProfiler R/Bioconductor package ,19. VisuA total of 363 genes were found to be differentially expressed after running DESeq2 analyses. To inspect those genes with the most significant fold change (FC), genes having an FC ranging between 2 and -2 were selected, leaving a total of six upregulated and 346 downregulated genes remaining after filtering. Afterward, genes that had no matching mouse orthologue were filtered out, yielding a total of 148 genes. Genes were then queried to get their corresponding EntrezID that was then used in the downstream enrichment analysis, yielding a total of 140 matched genes. Some of the accession numbers redundantly corresponded to the same gene ID, and so they were accounted for by taking the mean of the corresponding FC, resulting in a total of 129 genes. The final list of genes used for enrichment consisted of two upregulated and 127 downregulated genes (Table Many of the DE genes in neotenic seven dpa vs. zero dpa samples were enriched in several biological processes; the top 10 of these are visualized in Figure Enrichment of the DE genes in neotenic seven dpa versus zero dpa samples was evident in several pathways, such as fluid shear stress and atherosclerosis, transcriptional misregulation in cancer, amoebiasis, proteoglycans in cancer, as well as 16 other pathways Figure . InteresSCI is still a devastating neurological disorder, and exploring the regulatory factors of spinal cord regeneration is an important scientific question to address. Despite the growing body of regeneration-related research on mammalian model organisms, due to limited regenerative capacity in mammals, the comprehensive profiling and elucidation of key players in this process have remained largely elusive. However, highly regenerative animal models such as axolotl offer an excellent system to study spinal cord regeneration. In this respect, the presented work is a step towards filling this research gap.Most of the DE genes were found as downregulated at seven dpa as compared to zero dpa. Interestingly these genes were enriched mainly in cell-cell or cell-ECM interaction related biological processes such as positive regulation of cell adhesion, regulation of cell−cell adhesion, leukocyte cell−cell adhesion, and extracellular matrix organization. As shown in previous studies, for successful regeneration, the dedifferentiation of specialized cells, cell division, and cell migration processes provided by the reorganization of cell-cell and cell-ECM adhesion capacity are required to facilitate the formation of blastema tissue ,20. ThusAnother intriguing observation of the analyzed data was the enrichment of immune system-related KEGG pathways such as the IL-17 signaling pathway, TNF signaling pathway, NF-kappa B signaling pathway, and cytokine-cytokine receptor interactions by the downregulated genes at seven dpa, which is underlying the decreased activity of immune system at blastema stage during spinal cord regeneration. In previous studies, it has been postulated that the enhanced activity of the immune system may interfere with a regenerative capacity . TherefoThe limitations of this study included an analysis based on a single time point of regeneration. Multiple time points in the course of regeneration would have provided more insights into the molecular regulation of spinal cord regeneration. The current study is further limited by a lack of functional studies that are required to arrive at mechanistic explanations for spinal cord regeneration.This is a pioneering study on axolotl spinal cord regeneration that aims to explore the molecular and cellular mechanisms of spinal cord regeneration. In this study, we observed that regulation of cell-cell adhesion, ECM organization, and immune activity might be important for successful regeneration. Further follow-up validation and characterization research, particularly on the impact of the immune system during regeneration, could provide new insights into understanding spinal cord regeneration and possibly advance the development of regenerative therapies for injuries and disabilities related to SCI in mammals.


Relapsing demyelinating syndromes (RDS) in children encompass a diverse spectrum of entities including multiple sclerosis (MS) acute disseminated encephalomyelitis (ADEM), aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to these, there are “antibody-negative” demyelinating syndromes which are yet to be fully characterized and defined. The paucity of specific biomarkers and overlap in clinical presentations makes the distinction between these disease entities difficult at initial presentation and, as such, there is a heavy reliance on magnetic resonance imaging (MRI) findings to satisfy the criteria for treatment initiation and optimization. Misdiagnosis is not uncommon and is usually related to the inaccurate application of criteria or failure to identify potential clinical and radiological mimics. It is also notable that there are instances where AQP4 and MOG antibody testing may be falsely negative during initial clinical episodes, further complicating the issue. This article illustrates the typical clinico-radiological phenotypes associated with the known pediatric RDS at presentation and describes the neuroimaging mimics of these using a pattern-based approach in the brain, optic nerves, and spinal cord. Practical guidance on key distinguishing features in the form of clinical and radiological red flags are incorporated. A subsection on clinical mimics with characteristic imaging patterns that assist in establishing alternative diagnoses is also included. MS is the most common RDS in children. The diagnosis of MS is based on the revised 2017 McDonald criteria which integrates clinical, radiological, and laboratory findings , peripheral (or eccentric) on axial imaging, and cover less than half the cord circumference. A predilection for the cervical and thoracic cord has been noted .Unlike in adults, optic nerve involvement in children, especially in those under 10 years of age tends to be more commonly bilateral with severe loss of visual acuity . HoweverAquaporin-4 (AQP4) is a membrane protein that assists with the transfer of water molecules across cell membranes. NMO-IgG targets the water channel AQP4 and is positive by serology in up to 70% of NMOSD patients. The diagnosis of AQP4-NMOSD is based on the 2015 international consensus criteria which comprises of core clinical characteristics, AQP4 antibody status, and MRI features . These cSpecific to neuroimaging, the absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson's fingers, presence of longitudinally extensive transverse myelitis and presence of periependymal lesions along lateral ventricles supports the diagnosis of AQP4-NMOSD .Other regions typically involved in the disease process, and on imaging are regions of high AQP4 expressivity and are located in the periependymal region surrounding the 3rd ventricle and cerebral aqueduct, dorsal brainstem adjacent to the 4th ventricle including the area postrema and nucleus tractus solitaries , 16.The classically described findings are present in ~50% of cases. Other brain imaging patterns in AQP4-NMOSD include large hemispheric lesions, longitudinally extensive lesions along white matter tracts specifically corticospinal tracts, and, at times, even normal appearances.Spinal cord involvement is usually in the form of longitudinally extensive transverse myelitis (LETM) involving more than three vertebral segments. The lesions often span >50% of the cross-section of the cord and demonstrate a central-predominant cord distribution. Short segment involvement has, however, also been described in a third of cases .Optic nerve involvement is most commonly longitudinally extensive and bilateral, with a propensity for intracranial segments including the optic chiasm .MOG-AD represents a group of inflammatory demyelinating disorders united by the presence of IgG antibodies to myelin oligodendrocyte glycoprotein. MOG tends to affect younger children who presenting clinically with an ADEM-like picture. Older patients (>9 years) are more likely to present with optic neuritis or an AQP4-NMOSD-like picture .The clinical presentations in MOG-AD are heterogeneous. Seizures have been described as a presenting clinical feature in MOG-AD with a higher frequency when compared to other RDS, namely AQP4-NMOSD and MS. Hypothesized theories for seizures associated with MOG-AD are cortical involvement by an encephalitic process, and also the co-existence of anti N-Methyl D-Aspartate antibodies .The brain lesions on imaging are often large, ill-defined, and involve the white matter. There is variable deep gray matter involvement, with a predilection for the thalamus . CorticaSpinal cord lesions are typically longitudinally extensive. Unlike other RDS, there is a predilection for the conus medullaris .Optic neuritis with MOG-AD has distinct features, such as bilateral optic nerve involvement, anterior optic pathway predilection with optic disc swelling, and rapid visual impairment . RelapseThe key radiological patterns that emerge in the spectrum of pediatric relapsing demyelinating syndromes are listed below. An understanding of these patterns will help one approach the imaging mimics in a structured fashion.The specific imaging patterns of ON in MS, AQP4-NMOSD, and MOG-AD have been described in the relevant sections. ON may be the first presentation of a systemic RDS in up to 23% of children  and may In addition to the previously described RDS, there is a wide differential diagnoses for ON in the pediatric age group. Systemic inflammatory and rheumatological disorders, vasculitis and other granulomatous disorders including sarcoidosis also need consideration and exclusion. Whilst MRI is not strictly necessary for confirmation of the diagnosis of ON, it can be helpful for assessing the pattern of optic nerve involvement and in cases where there are atypical clinical features such as insidious symptom onset, severe optic nerve pallor or acute visual loss .In addition to conventional MRI, there are clinical and further imaging modalities such as spectral domain optical coherence tomography (S-OCT) that can help differentiate between the possible underlying etiology of ON with a high degree of specificity. In a recent Italian cohort study of 22 pediatric patients with ON, MOG antibody positivity was strongly associated with optic disc swelling, increased retinal nerve fiber layer (RNFL) thickness on S-OCT and better recovery .Prior to a more detailed discussion on disorders that may mimic pediatric demyelinating disease, it is important to note that there are several important clinical red flags that should raise concern for a mimic prior to performing any imaging . SpecifiDiscrete white matter lesions of the brain can be seen as incidental or “non-specific” findings in many conditions and are, at times, erroneously reported as “possible inflammatory demyelinating” lesions . IncreasOn closer inspection, however, the morphology and location of these lesions most often do not satisfy the McDonald criteria of being “periventricular” or “juxtacortical,” and such lesions are typically deep and subcortical in location. Often, a rim of normal-appearing white matter separates these lesions from the ventricular margin and cortex, respectively.PRRT-2) gene mutation. PRRT-2 gene mutations result in a truncated defective proline-rich transmembrane protein-2 in presynaptic terminals leading to an impaired neurotransmitter release. Presentation is in the form of distinct clinical syndromes which can vary with age, can overlap, and even evolve into other defined syndromes. These include benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD/BFIE overlap syndromes, namely infantile convulsions with choreoathetosis (ICCA) and hemiplegic migraine (HM). Scattered white matter hyperintensities may be present in imaging and can be mistaken for demyelinating lesions  and T2 axial (B) images show hyperintense lesions in deep and subcortical whitematter (white arrows in B). Note the presence of normal white matter between the lesions and ventricular surface and cortex (white arrows in A).T2 coronal Intracranial lesions can also be confluent in a variety of disease states, mimicking primary or secondary progressive MS when in the posterior periventricular regions, or MOG-AD when more cortical-subcortical in location . These iWhen these lesions occur infratentorially, such as in the case of rhombencephalitis or Alexander disease, they may be confused for AQP4-NMOSD, particularly if there is involvement of the area postrema, as shown in A teenager presented with severe vomiting. His premorbid health was normal except for mild intellectual disability.His MRI imaging showed focal hyperintensity and swelling of the area postrema with intense enhancement. CSF studies showed no oligoclonal bands. Both AQP4 and MOG antibodies were negative in serum and CSF. He was subsequently diagnosed with juvenile Alexander disease.Homogenous intense enhancement and absence of AQP4 antibodies were the features that led to further investigation and alternate diagnosis.This case illustrates that many diseases can have common areas of selective vulnerability. (A) and T1 post contrast axial (B) images show hyperintensity and swelling of area postrema with intense nearly homogenous enhancement (white arrows).T2 sagittal Alexander disease (AD) is a glial fibrillary acidic protein (GFAP) related astrocytopathy characterized by an abundance of Rosenthal fibers in astrocytes, particularly in subpial and subependymal locations. The distribution of lesion in AD is reminiscent of AQP-4 NMOSD . JuvenilInfections account for a large group of potential MS mimics. Isolated, multifocal, or confluent lesions of the white and gray matter are often seen in infections, presenting in a rather non-specific manner . ClinicaImaging red flags concerning for infectious mimics of RDS include meningeal enhancement (meningitis), complete ring enhancement with restricted diffusion (abscess), venous sinus thrombosis, calcification as in neurocysticercosis and toxoplasmosis, and bilateral striatal and thalamic involvement as commonly in viral encephalitis. Acute haemorrhagic leukoencephalitis (AHLE) is thought to be another post-infectious phenomenon presenting with white matter demyelination. It can occur after viral or bacterial infections.Borrelia burgdorferi causing Lyme disease deserves special mention as the CNS imaging demonstrates “MS-like” subcortical and periventricular white matter lesions, including the callososeptal interface . The preEpstein Barr virus (EBV) encephalitis also presents with multiple lesions in the cerebral cortex/subcortical white matter, thalami, basal ganglia, and, sometimes, brainstem or cerebellum. Rarely, it can cause optic neuritis, further confounding the diagnosis .Cytomegalovirus (CMV) has a predilection for the ependymal, germinal matrix, and capillary endothelial cells. The pattern of involvement may mimic MS with a periventricular distribution of lesions .Multifocal lesions, usually related to a microvascular etiology can also be observed in viral diseases such as HTLV-1 and HIV . The lacProgressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC polyomavirus (JCV). Supratentorial white matter lesions are typically multifocal, asymmetric, bilateral, and at times with confluent lobar involvement. PML can affect the deep gray nuclei also involve the brainstem and cerebellum. Generally, there is no enhancement or mass effect .Acute disseminated encephalomyelitis (ADEM), an autoimmune-mediated white matter disorder that often follows a viral upper respiratory tract infection , can appear very similar to MS. It is characterized by multifocal lesions of the deep and juxtacortical white matter, sometimes involving the cortex, as well as thalami, basal ganglia and also the brainstem and cerebellum. A history of recent upper respiratory infection or vaccination is often present and should be actively sought.“Open ring” or incomplete peripheral enhancement deemed specific for demyelinating lesions, particularly MS, is useful for differentiating between demyelination and other space-occupying lesions like neoplasm or an abscess. However, CNS infections such as neurocysticercosis and occasionally tuberculosis, as well as ADEM can also be associated with MS-like “open ring” enhancement .SSPE is a progressive measles virus mediated encephalitis that may present with brain MRI findings similar to a demyelinating disease. It is believed to be associated with an immature immune system and is seen in children with the onset of the primary infection in the first two years of life . On imagWhile there may be some overlap on imaging between SSPE and demyelination, the clinical examination is very specific, characterized by insidious onset of behavioral changes followed by mental deterioration. Seizures, myoclonus, dementia, and inexorable progression to death occur.Pathological findings include predominant involvement of the gray matter with white matter demyelination, perivascular lymphocytic cuffing, intracellular viral inclusions, neuronophagia, and gliosis .PRES may rarely be confused as demyelination mimic on imaging, especially when the lesions are discretely distributed in the white matter, or when there is considerable cortical-subcortical involvement. With PRES however the clinical context is extremely relevant. Usually, there is an apparent predisposing factor such as chemotherapy, hypertension or an underlying systemic condition. The clinical presentation may however partly overlap with RDS, particularly MOG-AD with features such as encephalopathy and seizures .The exact pathophysiology of PRES remains unclear however it is hypothesized to relate to cerebral vascular auto-regulatory and endothelial dysfunction. PRES itself may be considered a misnomer as the lesions are not always located posteriorly, nor are they always reversible . The topLeukodystrophies can share similarities with demyelinating disorders on imaging. In addition, demyelinating disorders have been shown to co-exist in patients with mitochondriopathies. It remains unclear whether the mutations underpin an autoimmune trigger for demyelination or if these cases are indeed unusual presentations of mitochondrial disorders . ClinicaLeber's hereditary optic neuropathy (LHON), a mtDNA mutation disorder with specific point mutations in complex 1, occurs in patients with MS at a frequency ~50 times greater than in the general population . AnotherPOLG includes a set of nuclear genes with the function of maintaining the mtDNA pool through mtDNA duplication. POLG related disorders have vastly overlapping clinical phenotypes of varying severity. Unusually, a relapsing-remitting illness with MS-like lesions and ADEM like white matter lesions has been described , CARASIL (HTRA1), 6p25 deletion syndrome, cerebral small-vessel diseases (FOXC1 and PITX2) are the typical entities within this group. Whilst most of these disorders have an onset after the 3rd decade, pediatric-onset disease has been rarely described.NOTCH3 encodes a transmembrane protein expressed in vascular smooth muscles and heterozygous mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The clinical features include recurrent subcortical ischaemic strokes with cognitive decline. Patchy multifocal white matter abnormalities involving the deep and periventricular white matter are common in the described pediatric cases  is inflammation limited to the arteries of the CNS . SecondaImaging, although variable and sometimes transient, shows multiple small/punctate lesions or even tumefactive enhancing lesions in the subcortical white matter and gray matter, more often affecting the anterior than posterior circulation. Basal ganglia involvement is frequently noted. Diffuse leptomeningeal enhancement may also be seen .Additional findings include microhemorrhages and multifocal infarction . SystemiHLH is severe systemic hyperinflammatory syndrome of a dysfunctional immune response characterized by unchecked proliferation of natural killer cells and T-lymphocytes . While aCNS involvement is common in both inherited and acquired forms of HLH. The most common imaging pattern is asymmetric confluent white matter lesions with subcortical and deep white matter distribution . CerebelA nodular perivascular pattern of enhancement, which is often seen, may help in differentiation. Very occasionally more focal well-circumscribed lesions may be present mimicking MS lesions. Some of these cases were previously incorrectly labeled as CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids).RAB27A mutations (utations .Case Vignette 3—Griscelli type 2 syndrome (HLH) An adolescent presented to the neurology services with a long history of recurrent episodes of blurred vision and ataxia. Clinically the patient was diagnosed as demyelination.CSF analysis showed normal protein with no cells or organisms. Genetic testing subsequently confirmed Griscelli type 2 syndrome. The suspicion was also raised on the grounds of the clinical picture which included abnormal hair pigmentation.Although MOG-AD can also present with large fluffy ill-defined white matter lesions and show a predilection to cerebellar peduncles, the pattern of enhancement seen here is quite atypical. Nodular intense enhancement in a perivascular distribution is more characteristic of the inflammatory and vasculitis spectrum of disorders. HLH also demonstrates a pontine and cerebellar peduncle predominant distribution.(A–C): Initial imaging at age 12. (A) Sagittal T2 FLAIR-weighted imaging through the brain demonstrates evidence of signal hyperintensity within the calloso-septal interface, callosal splenium (white arrow), dorsal brainstem, and cervical spine.  Axial T2-weighted sequences of the brain show a juxtacortical lesion in the left perirolandic region (arrow) and ill-defined areas of abnormal signal in the pons and cerebellar hemispheres bilaterally (R>L).Top row (D–F)—Initial imaging at age 12.  Sagittal T2 and post-contrast T1-weighted sequences show the extent of signal abnormality within the brainstem and spinal cord. All the T2 hyperintense parenchymal lesions show enhancement. F-Axial post-contrast T1 Weighted sequence through the posterior fossa shows enhancement corresponding to the T2 hyperintense areas of abnormal signal in the pons and cerebellar hemispheres bilaterally (R>L). In addition, there is folial enhancement suggesting pial involvement.Bottom row Anti-NMDARE presents with a characteristic clinical spectrum of abnormal behavior, speech dysfunction, memory/cognitive disturbance, seizures, movement disorder, and even decreased level of consciousness and autonomic dysfunction . CSF mayKnowing that there is an overlap between anti-NMDARE and demyelinating disease (AQP4-NMOSD and MOG-AD) is important as patients may present clinically with concurrent or separate episodes of demyelination and/or atypical psychomotor features. The presence of different antibodies has implications for treatment and prognosis. Testing for anti-NMDA, AQP4 and MOG antibodies may therefore be warranted in such cases .There is a higher prevalence of anti-NMDARE in children with herpes simplex virus (HSV) 1 IgG antibodies, including those without clinically evident encephalitis . AlthougMR imaging is often normal at initial presentation, but when abnormal shows non-specific cortical and subcortical lesions with no clear localization. Optic neuritis can also be a feature . StriataNeurosarcoidosis is a disorder of unknown etiology, characterized by non-caseating granulomas histologically. It is rare in the pediatric population. NS can affect any part of the nervous system. Uveitis, optic neuropathy, hypothalamic dysfunction, mass-like brain lesions, and encephalopathy are features seen in pediatric NS . The mosImaging in children with neurosarcoidosis more commonly shows enhancing parenchymal lesions than its adult counterpart. Discrete to confluent white matter and cerebellar hyperintensities with punctate or discrete enhancing lesions are noted. Leptomeningeal, pituitary stalk or cranial nerve enhancement are additional features , 71.Neurocutaneous and microangiopathic disorders with asymmetrical CNS white matter involvement can also mimic pediatric demyelinating disorders on imaging and should be borne in mind.k-B essential modulator (NEMO) gene -MO) gene . ClinicaMO) gene . ImagingMO) gene , 74.Hypomelanosis of Ito, a disorder of chromosomal mosaicism, with several underlying genetic defects has typical hypopigmented skin lesions along the lines of Blaschko. White matter involvement in the form of asymmetrical deep and periventricular white matter hyperintensities can be present, often with dilated cystic or perivascular spaces .Whilst periventricular hyperintensities may be present on imaging in HSP, the clinical phenotype of progressive spastic paraparesis with a relevant family history serve as useful differentiators . AdditioSS is another rare condition in the pediatric age group. It is an autoimmune microangiopathic disorder resulting in occlusion of the branch retinal arteries and microinfarction of the central nervous system and cochlea. The onset of all three characteristic features at presentation is seen in only a minority of patients, reported as low as 13% , 77. AltOptic nerve involvement with swelling, T2- hyperintensity and enhancement is not specific for demyelinating disorders and can be seen in other inflammatory, infective, ischemic, toxic, and neoplastic conditions . That saExtra-neural involvement of other orbital structures is also a good indicator that one is not dealing with a primary demyelinating disorder, but rather a granulomatous, infectious or neoplastic cause. In addition, abnormal dural and leptomeningeal enhancement should also raise the suspicion of granulomatous disease, particularly sarcoidosis , 80.Viral infections can present with optic neuritis. Specifically, EBV and Lyme disease should be considered. In such cases, there may be additional intracranial imaging findings which should be carefully sought , 82.Tumors are typically less challenging to differentiate. Optic nerve glioma can be distinguished by expansion, relatively lessT2 hyperintensity and paucity of enhancement of the nerve, whereas optic nerve sheath meningiomas are characterized by enhancing expansion of the optic nerve sheath complex along with tram-track calcification, usually better shown on CT .For practical purposes, the spinal mimics of relapsing demyelinating disorders can be subdivided into diseases with short segment cord involvement , and thoFASI's have been described within the spinal cord of children with NF1. Short segment, non-enhancing intramedullary lesions demonstrating stability or regression on follow-up have been described . These aCNS vasculitis with spinal involvement may occur as a part of a systemic vasculitic process such as Bechet disease, systemic lupus erythematosus or granulomatosis with polyangiitis. Primacy CNS vasculitis involving the spinal cord only is a rare entity . The imaIntramedullary spinal tumors represent 4–10% of all central nervous system tumors. They are predominantly of glial origin and account for up to 35% of all intradural tumors in children . The imaLongitudinally extensive transverse myelitis (LETM) presents clinically with a bilateral, symmetric or asymmetric sensorimotor and autonomic spinal cord dysfunction. Typically, there is a clearly defined sensory level and a progression to the nadir of clinical deficits between 4 h and 21 days after symptom onset. The primary mimics of spinal demyelination with a longitudinally extensive pattern include tumors (covered above), sarcoidosis, infections, vascular abnormalities, nutritional deficiencies such as vitamin B12 or copper deficiency, and rarely, certain metabolic entities such as biotinidase deficiency, and mitochondriopathies.Spinal disease may occur in the absence of intracranial disease. Myelopathy associated with sarcoidosis is typically in the form of longitudinally extensive spinal cord lesions affecting the dorsal part of the cord, extending laterally at times as a crescent, but also less commonly the anterior aspect of the cord . OccasioClinically, infective myelitis can present in a similar fashion to idiopathic myelitis with constitutional symptoms and fever. The pathogenic cause may be viral, bacterial, fungal or parasitic. Certain findings on MRI may help point toward a particular infectious pathogen.In Lyme disease, MRI shows early enhancement of the pial region followed by non-specific T2 hyperintensities and enhancement of the cord parenchyma , 90.CMV is associated with thickening, clumping, and enhancement of nerve roots and leptomeninges along the conus medullaris, often with associated long-segment T2 high signal of the cord .Herpesviruses, including types 1, 2, 6, and 7 are most frequently associated with myelitis and share an overlapping imaging presentation, characterized by long-segment T2 high signal with variable enhancement .In varicella-zoster myelitis, when a concomitant skin lesion is present (in 33% of patients), the dorsal root and posterior horns of the spinal cord are affected and usually correspond to the affected dermatome . AdditioAnother presentation of viral diseases, characterized by a poliomyelitis-like syndrome is seen in the picornavirus family  and in some flaviviruses, including Dengue and West Nile viruses. Imaging demonstrates unilateral or bilateral high signal on T2 sequences in the anterior horns of the spinal cord across multiple segments with variable enhancement .Spinal cord presentation in HTLV-1 usually reflects involvement of the dorsolateral columns, with T2 high signal long-segment involvement of the lateral columns, less commonly extending to the dorsal columns, occasionally with enhancement , 91. HIVMycoplasma is one of the most common bacterial infections resulting in post-infectious transverse myelitis. The imaging findings are not specific and a high index of suspicion is needed to exclude it as best as possible .Neurocysticercosis and occasionally tuberculosis, in some stages, are associated with MS-like “open ring” enhancing lesions as mentioned previously .Acute spinal cord infarction results in a sudden onset anterior spinal artery syndrome, with loss of function of the ventral two-thirds of the spinal cord, pain, and characteristic dissociative sensory disturbance. There is usually a cardiovascular risk factor for the development of cord infarction . On MRI,Fibrocartilage embolism should be considered when there is an additional finding of altered signal in the disc or in the posterior aspect of the vertebral body .Spinal vascular malformations is an umbrella term encompassing a number of entities which include arterio-venous malformations (AVM), dural arterio-venous fistula (dAVF), cavernous malformations, and capillary telangiectasias. A spinal vascular malformation should be included in the differential diagnosis for any child who presents with slowly progressive or acute symptoms of radiculopathy or myelopathy.Nutritional deficiencies can cause appearances in the spinal cord that can mimic findings similar to those of transverse myelitis.The characteristic clinical triad of subacute combined degeneration caused by vitamin B12 deficiency includes symmetric diminished vibration sense, pyramidal signs, and peripheral neuropathy , 97.Symmetric T2 signal hyperintensity with a general lack of enhancement in the lateral and dorsal columns has been reported to be the characteristic neuroimaging finding . In suchA myelopathy similar to that seen in vitamin B12 deficiency with the involvement of the dorsal column and corticospinal tracts also may be seen in copper deficiency myelopathy , 98.RDS in children encompass a diverse spectrum of entities. There are a multitude of acquired and genetic disorders that can mimic RDS in children both clinically and radiologically. Furthermore, false negative test results for antibodies associated with RDS, as well as overlap with other syndromes such as anti-NMDARE can make the process of reaching an accurate diagnosis challenging.A knowledge of the specific and distinct MRI patterns and clinical red-flags can help differentiate between the relapsing demyelinating syndrome subtypes and their clinical and radiological mimics.PM and NR: compilation of manuscript. SC: contribution to manuscript, final manuscript review, and compilation of images. KMa: project oversee, final manuscript reviews, and corrections. SS: manuscript outlay and proof reads. KMu: neurology input and tables. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy.Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/mBetween July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane.2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin , and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure.Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/mThe concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines. In the 2 . Similar40 mg/m2 –9.We sought to determine whether dexrazoxane would be cardioprotective in patients without the current indications for its use. Here, we present a consecutive series of patients from a single institution with preexisting cardiomyopathy, who were treated with anthracyclines, and compare their cardiovascular and cancer-related outcomes to those of similar patients who subsequently received concomitant off-label dexrazoxane with anthracycline-based chemotherapy.In the two years preceding the initiation of the Lahey cardio-oncology program (July 2013 to June 2015), we noted that several patients with either preexisting cardiomyopathy, or those who experienced anthracycline-induced cardiomyopathy, developed worsening LV systolic function and major adverse cardiovascular events including heart failure, cardiogenic shock, arrhythmias, and cardiovascular death, despite the use of maximally tolerated, guideline-directed heart failure therapy.After evaluating the evidence on the use of dexrazoxane for cardioprotection against anthracycline-induced cardiotoxicity, we developed a clinical practice algorithm Fig.  based onBeginning in July 2015, five consecutive patients with preexisting asymptomatic LV systolic dysfunction, who required anthracycline-based chemotherapy, were treated with dexrazoxane as a cardioprotectant as per our consensus protocol. Three consecutive patients with preexisting asymptomatic LV systolic dysfunction who received anthracycline based chemotherapy between July 2013 and June 2015 were identified for comparison.All five patients received off-label dexrazoxane in a 10:1 ratio of dexrazoxane to doxorubicin, or at a reduced dose based on their creatinine clearance, 30 min before each anthracycline dose  throughoAll patients receiving dexrazoxane were followed in our cardio-oncology clinic, either before each subsequent or alternate cycle of anthracycline chemotherapy, as deemed appropriate by their providers. All patients were thoroughly examined for signs or symptoms of heart failure. We also collected data on cardiovascular and cancer-related outcomes  during follow-up. Patients were followed until death or loss to follow-up.2 for acute myeloid leukemia (LVEF 45%) , and patient #3 received daunorubicin (cumulative dose 540 mg/m2).Between July 2013 and June 2015, we had treated three consecutive male patients treated with anthracycline but without dexrazoxane  at the Lahey Hospital and Medical Center. Patient #1 had preexisting asymptomatic non-ischemic cardiomyopathy (LVEF 40%), patient #2 had preexisting asymptomatic ischemic cardiomyopathy (LVEF 45%), and patient #3 had anthracycline-induced cardiomyopathy that developed after receiving a cumulative daunorubicin dose of 270 mg/m2 of daunorubicin with further worsening of his cardiomyopathy (LVEF 30%) that persisted, despite treatment with neurohormonal antagonists.All three patients in this group experienced marked reductions in LV systolic function (the mean LVEF decreased from 42.5% at baseline to 18% after chemotherapy), and developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy, either during or within the first six months after completion of chemotherapy (Table 2).The dexrazoxane protocol was implemented in the next five consecutive eligible patients , one man and four women, four with non-ischemic cardiomyopathy and one with ischemic cardiomyopathy. The mean pre-chemotherapy LVEF for these five dexrazoxane-treated patients was 39%  Table . PatientThe median follow-up period was 13.5 months . Two patients treated without dexrazoxane died and none were lost to follow-up.The mean post-chemotherapy LVEF in this group was 34% and all five completed planned chemotherapy without any major adverse cardiovascular events Table . PatientSerum concentrations of cTnI and BNP were not elevated in any of the five patients. Patients #4 and #8 had sporadic episodes of non-sustained ventricular tachycardia, but no sustained arrhythmias were noted Table .Three of the five patients in this group experienced significant neutropenia (absolute neutrophil count < 500/μL), and two patients experienced neutropenic fever requiring treatment with antibiotics. None of the patients developed any detectable end-organ damage as a result. No clinically important abnormalities were noted in any other laboratory parameters including serum liver function, kidney function, and zinc, iron, and magnesium concentrations.The patients in our case series had preexisting cardiomyopathy that placed them at increased risk for cardiotoxicity from anthracycline-based chemotherapy. Off-label use of concomitant dexrazoxane as a cardioprotectant allowed successful administration of planned anthracycline-based chemotherapy, without symptomatic cardiac decompensation. In contrast, similar patients who received anthracyclines without cardioprotection, experienced a significant decline in their LVEF, coupled with adverse cardiovascular outcomes including death. It is also important to note that in our case series, dexrazoxane was not associated with either a reduced anti-tumor response or the development of secondary malignancies during the median follow-up period of 13.5 months. Our data, although limited, support the use of concomitant dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracycline therapy.With an aging population, and with an increase in the number of patients with cardiovascular disease (CVD) and cancer survivors, greater overlap between CVD and cancer is expected –17. The Anthracyclines have been widely used to treat a variety of solid and hematological cancers in children and adults since the 1950s [Anthracycline-related cardiotoxicity ranges from subclinical cardiomyopathy to florid heart failure. Cardiotoxicity may occur within the first week of anthracycline treatment or even decades later ; howeverDoxorubicin is not the only anthracycline associated with cardiotoxicity; epirubicin and daunorubicin, other commonly used anthracyclines to treat several cancers, have also caused similar cardiotoxicity, especially at high doses –26. In tAnthracyclines are believed to cause cardiotoxicity by multiple mechanisms; including both the generation of oxygen free radicals and by inhibition of topoisomerase 2B. Substantial experimental data support the involvement of iron in anthracycline-induced cardiotoxicity, including evidence suggesting the importance of the HFE gene in regulating cardiac iron accumulation after exposure to anthracyclines, irrespective of a patient’s systemic iron load .Dexrazoxane is an iron chelator that binds free iron or removes iron from the doxorubicin-iron complex, thereby preventing oxygen free radical formation. This property may explain how dexrazoxane reduces some of the cardiotoxic effects of anthracyclines . However2. These patients experienced a marked reduction in cardiovascular events, despite the late introduction of dexrazoxane  [The current approved use of dexrazoxane in adults is based on two multicenter, randomized controlled trials (088001 and 088006) involving more than 500 women with advanced breast cancer [P = 0.007), although the overall time-to-progression and overall survival were not affected. Response rates were not significantly different in trial 088006. However, despite these disparate results, this led to a concern that dexrazoxane may reduce the anti-tumor efficacy of anthracyclines. Furthermore, in studies of children receiving dexrazoxane, there was an initial concern of an increased incidence of secondary malignancies, such as acute myeloid leukemia and myelodysplastic syndrome. Further follow-up of those same study patients has subsequently found that the concern for reduced oncologic efficacy was not correct [2, and out of concern for reduced anti-tumor efficacy as well as increased risk of secondary malignancy, the FDA and EMA restricted its use to adults with advanced breast cancer receiving higher cumulative doses of doxorubicin [2 [In trial 088001, the dexrazoxane group had a lower antitumor response rate  when compared to the placebo group  of anthracyclines [Based on the efficacy of dexrazoxane as a cardioprotective agent in patients with a wide variety of cancers and with evolving safety data demonstrating that it does not impair chemotherapeutic efficacy and is not associated with an increased risk of secondary malignancies, in 2015 the European marketing authorization holder for Cardioxane  submitted an application to all relevant national regulatory authorities to widen the indication from “advanced and/or metastatic adult breast cancer patients” to “cancer patients” and remove the contraindication in children and adolescents. The proposal to widen the indication was declined. However, after a careful review of dexrazoxane’s risk-benefit profile, the contraindication was lifted for children and adolescents requiring high doses  will lead to a higher quality of life for these patients.This is a pragmatic study under real-world conditions. Although bias is possible in any case series, by including consecutive patients who met inclusion and exclusion criteria and comparing the outcomes with a historical group of anthracycline-treated patients who did not receive dexrazoxane, we attempted to minimize bias. Our objectives were clear, the outcomes were clinically relevant, and the data were prospectively collected. Finally, there was no loss to follow-up in either group. However, we recognize the limitations of findings based on only a few patients from a single center. Data collection in the patients treated earlier without dexrazoxane was limited by its retrospective nature.Our results, albeit limited, support the use of concomitant dexrazoxane for cardioprotection in patients with preexisting cardiomyopathy from the beginning of anthracycline therapy, regardless of cancer type or stage. Larger prospective trials are warranted to examine the expanded use of dexrazoxane in high-risk patients, including those with preexisting cardiomyopathy; cancers other than those affecting the breast; and without a minimum cumulative anthracycline dose.


We report a rare case of an 18-year-old male with unilateral hand tremor who was finally diagnosed with Hirayama disease (HD).An 18-year-old male presented with unilateral polymyoclonus that aggravated with neck flexion. The patient did not complain of muscle weakness or muscle atrophy. The needle electromyography showed giant motor unit potentials in right cervical 7 and 8 innervated muscles. The cervical magnetic resonance imaging on supine and flexion state showed prominent forward effacement of posterior dural sac that was compatible with HD.HD usually presents with unilateral distal hand weakness, muscle atrophy and tremor. Although it is a benign and self-limiting disease, early diagnosis may lead to less clinical deterioration. Moreover, electromyography should be completed in the differentiation of young male patients who present with polymyoclonus without hand weakness or atrophy. Benign focal amyotrophy, or Hirayama disease (HD), is a rare self-limiting cervical myelopathy that predominantly affects adolescent males. It is clinically characterized by asymmetric weakness of the upper extremity muscles that are innervated by C7-T1 roots. Recent literature describes the high prevalence of cold paresis, fasciculation, paresthesia, numbness, and tremor in association with the disease . Only reAn 18-year-old boy presented with a 1-year history of hand tremor of the right hand, which worsened with neck flexion. He had no previous history of autoimmune diseases, including thyroid disease or family history of genetic disease. The initial neurological examination revealed no significant muscle weakness or atrophy, and except for a mildly decreased right triceps tendon reflex, deep tendon reflexes were normal. He complained of hand tremor of the right hand that worsened during neck flexion (Video The pathogenic mechanism of HD is yet to be elucidated, but recent imaging studies have strongly suggested microcirculatory ischemia in the anterior horn cells caused by direct cord compression resulting from forward effacement of the posterior dural sac . This caThe underlying mechanism of hand tremor has not yet been elucidated, but a recent report of multiparametric brain MRI on an HD patient revealed brain hyperactivation that may explain the hand tremor associated with HD. A case report described coexisting juvenile myoclonic epilepsy in a young male HD patient . AnotherAlthough HD is a self-limiting disease, it is important to recognize the disease that should lead to the avoidance of neck flexion because it usually aggravates the symptoms. Few reports have described positive results after cervical surgery or cervical collar therapy that reduced functional disability among HD patients , 9.Only recent publications have begun to illustrate and emphasize polymyoclonus as a clinical feature of HD. A recent case report described a 17-year-old boy who presented with polymyoclonus along with decreased muscle bulk associated with weakness. Of note, the myoclonus was aggravated by outstretching the arms . AnotherOur report is of clinical significance as it describes the first reported patient who presented with isolated polymyoclonus without muscle weakness or muscle atrophy. The patient also had no complaints related to muscle weakness or muscle atrophy. Furthermore, the myoclonus was aggravated by neck flexion, corresponding well with the hypothesis of direct cord compression, which is generally accepted as the main pathophysiologic mechanism of HD. Clinicians should be aware of a self-limiting disease, such as HD, when evaluating young,most frequently male patients who present with predominant functional polymyoclonus that is worse with neck flexion and perform an electromyography study for the earlier diagnosis that may prevent further clinical deterioration.Additional file 1: Video 1. The video shows polymyoclonus of the right hand which is aggravated by neck flexion.


This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults  from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli . For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and increases in neural response to emotional faces and shapes in men (multivariate  Studies on the biological basis of depression using in vivo neuroimaging or postmortem gene expression often focus on the same neural circuits, but have largely run in parallel, precluding an integrative understanding of this complex and heterogeneous disease. In vivo neuroimaging10 and postmortem transcriptome studies11 have nonetheless independently converged to associate depression with dysregulation in a distributed corticolimbic circuit (CLC), which lies at the intersection of affective, cognitive, and perceptual processing.Major depressive disorder (MDD or depression) is the leading cause of disability worldwide6. These studies associate depression with increased amygdala reactivity to threat3, which may predate the development of depressive symptoms4 and persist after remission6. Consistent with the heterogeneity of the disease, however, other studies have reported blunted amygdala reactivity in individuals with, or at risk for, depression12. Although the behavioral implications of these divergent neural phenotypes are incompletely understood, amygdala hyper-reactivity has generally been interpreted as reflecting a depression risk pathway associated with high anxiety and stress sensitivity4, while hypoactivity may reflect reduced behavioral engagement, consistent with co-occurring trait-like psychomotor slowing12 and motivational deficits10. Functional connectivity studies using both hypothesis- and data-driven approaches have additionally reported reduced coupling between amygdala and prefrontal regulatory regions14, as well as broader dysconnectivity within and beyond the CLC20.Functional neuroimaging studies of the CLC in depression have typically focused on the amygdala as a primary region of interest, because this structure serves as a processing hub through which associative learning of threat and related physiological and behavioral responses are coordinated11 identified 566 genes consistently up- or downregulated in individuals with depression across the amygdala, subgenual anterior cingulate, and dorsolateral prefrontal cortex11. The altered molecular pathways suggested by these transcriptomic findings include reduced neurotrophic support, neuronal signaling, and GABA function. These pathways have also been implicated in normal lifelong aging of the brain22, lending support to the notion that depression may be associated with accelerated, or anticipated, molecular brain aging23. Finally, functional neuroimaging studies suggest that normal aging is associated with blunted CLC processing of emotional faces24, mirroring neural activity patterns observed in specific depression subtypes12.In parallel to this functional neuroimaging work, postmortem studies in depression have demonstrated changes in gene expression patterns in key CLC nodes, which may partially explain the observed macroscale CLC dysregulation noted above. A recent meta-analysis of eight transcriptome datasetsDespite this promising convergence, postmortem findings have limited clinical utility, as they provide little insight into the link between gene expression changes in the CLC and in vivo CLC reactivity or any clinically relevant premortem symptoms. To address this important translational gap, we developed a novel transcriptome-based polygenic risk score (T-PRS) comprised of common gene expression-altering variants, partially mimicking the postmortem depression CLC transcritpome. Using a data-driven multivariate approach  regression), we then mapped this score onto fMRI-assessed neural processing of social stimuli in a large sample of young adults participating in the Duke Neurogenetics Study (DNS).25). Given well-documented sex differences in depression risk30, and CLC function34, sex was included as a moderating factor in all analyses. We hypothesized that both PRS will be associated with heightened neural responses to threatening faces and increased depressive symptoms.In a subsequent validation analysis, we compared the effects of this novel T-PRS to those of a nonoverlapping PRS based on variants identified using more established polygenic risk scoring techniques derived from case-control genome-wide association studies by the Psychiatric Genomics Consortium MDD working group (PGC-PRS35 for full exclusionary criteria). Participants were screened for DSM-IV Axis I and select Axis II disorders  using the eMINI36, but a current or lifetime diagnosis of a disorder was not exclusionary  who successfully completed the DNS. All participants provided informed consent in accordance with Duke University guidelines prior to participation and were in good general health  were assessed and used as reference panel for ethnicity. Two individuals from current sample that did not cluster with the 1000 genomes, Europeans were excluded from analysis , used also for all further analyses, to generate ten principal components. The first component (C1) alone was able to explain more than 40% of the variance, therefore it was included in all analyses as a covariate correcting for residual population substructure38 . In pairs of individuals showing a PIHAT higher than 0.2, the individual showing higher genotype missingness (lower CR) was excluded from analysis. In order to avoid spurious associations due to population stratification, after filtering by self-reported ethnicity we further assessed any residual stratification using a multidimensional scaling (MDS) and clustering method implemented in PLINK v1.910. A T-PRS characterizing depression-related gene expression changes in the CLC were developed based on a list of 566 genes generated by a prior meta-analysis of case-control postmortem brain transcriptome datasets . Relying on the GTEx “cortex” tissue as a reference transcriptome, the PrediXcan tool40 successfully “imputed” relative cortical expression levels on the individual participant level for 76 out of these 566 genes based on peripheral SNPs assessed in the DNS  with higher T-PRS reflecting a more depression-like CLC transcriptome. To allow easy computation of our novel T-PRS scores in other studies, we provide a list of the 76 genes in Supplementary Table DNA extraction and genotyping was performed as previously described in Nikolova et al.25. including genome-wide SNPs from the meta-analysis excluding 23andMe was downloaded from the PGC website and QC cleaned. Cleaning included checking the effect allele, confirming the genome build ; filtering effect variants by minimum allelic frequency (MAF > 0.01) and quality of imputation (INFO > 0.80). No ambiguous SNPs were identified in the current sample . There were no duplicated SNPs in this dataset and no sex-chromosome variants reported. There is also no sample overlap or related individuals between PGC and DNS sample. PGC-PRS was calculated using the PLINK v1.938—score function and multiple p value thresholds . DNS data were clumped according to the p values in the Summary statistics following the parameters of significance threshold for index SNPs of 1, an LD threshold of 0.1, and a physical distance of 250 kb between the index and the SNPs to be clumped. Using this strategy, 3979,908 variants out of 6372,415 variants were missing in the main dataset (13 loci from the 44 significant in Wray 2018 paper), and 166,296 clumps were formed and used to calculate the PRS. Total number of variants included in each score is indicated in Supplementary Table Summary statistics from Wray et al.41 was used to provide information on general distress symptoms shared between depression and anxiety  or symptoms unique to anxiety  subscale) or depression 41. Early and recent life stress were assessed using the Childhood Trauma Questionnaire (CTQ42) and the Life Events Scale for Students43, respectively.The short form of the Mood and Anxiety Symptom Questionnaire (MASQ)44 at the Duke-UNC Brain Imaging and Analysis Center using one of two identical research-dedicated General Electric MR750 3T scanners. Briefly, participants were presented with blocks of neutral and emotional faces, interleaved with blocks of simple geometric shapes as a control condition, and were asked to indicate which one of two faces/shapes shown at the bottom of the screen was identical with a target face/shape shown at the top. Detailed information regarding the face-matching task as well as the acquisition protocol are provided in the BOLD fMRI data were acquired during a face-matching task46 was used to identify the functional impact of the T-PRS at the whole-brain level. PLS regression combines features of principal component analysis and multiple regression and is a multivariate approach that allows the simultaneous mapping of a multidimensional set of independent predictors  onto a multidimensional set of intercorrelated outcome variables . This is achieved through the identification of a smaller set of latent variables (LVs), which best capture covariance between the independent variables and distributed spatial patterns of neural activity, without the need for a priori selected contrasts across experimental conditions or regions of interest45. The PLS thus identified LVs representing a spatial pattern of brain regions which share a common relationship between polygenic risk and brain activity in each condition , separately by group . The LVs are similar to the components derived via principal component analysis (though optimized to detect relationships across a set of predictor variables); the number of LVs is determined by the input data and LVs explain progressively less covariance between the predictors.PLS regressionIn order to assess the statistical relevance of the LVs, a permutation approach was employed, rerunning the PLS while randomly resampling the order of conditions across 500 permutations to create a null distributions of saliences across LVs. This approach can be used to assess significance. As the permutation test works on the whole PLS model, it is not then necessary to correct for multiple comparisons for individual LVs.47. A parallel analysis using the same parameters was conducted for all PGC-PRS to examine convergence between our novel T-PRS and a depression PRS generated based on more conventional polygenic risk modeling methods. PLS analyses involving the nine distinct PGC-PRS were corrected for multiple comparisons using a Bonferroni correction, wherein the significance threshold for an LV identified in each individual PGC-PRS analysis was set to pcorr. = 0.05/9 = 0.005.Following LV identification, a bootstrapping procedure with 1000 iterations was used to test which specific voxels are reliably related to each significant LV. A bootstrap ratio for each voxel was calculated as the voxel salience divided by its bootstrap standard error. A bootstrap ratio of 2.5 (corresponding to >95% reliability) was used to threshold for all voxel pattern maps in PLS, as previously describedFinally, we conducted additional exploratory analyses linking PRS, multivariate brain activity patterns and symptoms. To this end, we extracted individual-level “brainscores” for the significant conditions, reflecting subject-specific fit to multivariate brain activation patterns, and correlated them with each of the MASQ scales. This analysis was undertaken to examine whether the degree to which an individual participant fit the PRS-associated brain activity pattern was associated with symptoms measured independently . We opted for this approach, rather than including PRS and symptoms in the same multivariate model, as we were primarily interested in validating the potential behavioral and clinical relevance of pre-identified genetically driven alterations in brain response, rather than identifying novel brain patterns where genetic and symptom effects converge. Further details regarding the PLS regression analysis are provided in the p < 0.01), which accounted for 39.27% of crossblock covariance . The spatial pattern of brain activity in this LV mapped onto 29 clusters >20 voxels, spanning a distributed network including the mid-frontal and frontal superior regions, supplementary motor area, hippocampus, caudate, thalamus, and cerebellum . Across thresholds, PLS analyses involving PGC-PRS identified a single significant LV , which accounted for 37.92% of crossblock covariance and mapped onto 94 clusters >20 voxels spanning anterior cingulum, amygdala, insula, postcentral, temporal, occipital regions, and cerebellum . Similar negative relationship was also observed in females between the PGC-PRS-associated blunting of neural response to neutral faces and anhedonia . No additional associations with self-report symptoms emerged for the emotional faces or the shapes condition in men .Additional exploratory analyses correlated PLS-derived “brainscores” for the significant conditions  is associated with female-specific widespread reductions in activity across cortex, subcortex, and cerebellum to neutral faces, and indirectly, with increased anhedonia, in a nonclinical sample of young adults. To validate these results, we demonstrated that similar female-specific blunting of neural reactivity to neutral faces was associated with an independent polygenic score derived using more traditional polygenic risk modeling approaches .This proof-of-principle study demonstrates that T-PRSs may serve as a translational bridge between postmortem molecular data and in vivo neuroimaging, and offers important preliminary support for this novel polygenic risk scoring approach. Collectively, these results additionally suggest the possibility that some of the postmortem gene expression changes observed in individuals with MDD may be genetically driven and therefore possibly predate disorder development. Further, these genetically driven changes may bias neural circuit function and associated anhedonia symptoms in similar ways as variants associated with MDD diagnosis in vivo. The fact that T-PRS and PGC-PRS showed both common and distinct patterns of association with brain activity further suggests the two polygenic risk scoring approaches may be complementary and could provide synergistic insight into disorder mechanisms.Our multivariate PLS analyses associated both T-PRS and the best-fit PGC-PRS with reduced activity to neutral faces across an extensive network of regions, including, but not limited to the CLC. Specifically, T-PRS was associated with female-specific reduction in activity to neutral faces and male-specific increases in activity to emotional faces and shapes in the mid-frontal and frontal superior regions, supplementary motor area, hippocampus, thalamus, caudate, and cerebellum. The PGC-PRS was similarly associated with lower activity to neutral faces in females. While the networks associated with each of the PRS partially overlapped, the PGC-PRS-associated network did not include such a strong response in the frontal and reward regions present in the T-PRS-associated network but instead included the insula, postcentral and occipital regions.Intriguingly, in males with higher T-PRS activity in these same clusters was also blunted in the neutral face condition, although this effect did not reach significance. In contrast, higher T-PRS in males was associated with relatively elevated activity in the shapes and emotional faces conditions. These findings suggest sex-specifictiy of the T-PRS effects, which merits further investigation in future work. Of note, however, only the brain scores associated with the neutral condition were found to be potentially clinically relevant via their association with self-reported anhedonia in women.48, as well as trait-like reductions in amygdala reactivity to both negative and neutral faces, relative to non-face stimuli, in young adults with seasonal depression7. Similarly, reduced CLC reactivity to faces, often accompanied by slower psychomotor speed24, is also commonly observed in healthy older adults41 or young adults at genetic risk for accelerated brain aging49. This phenotypic convergence is consistent with the overlap in molecular pathways implicated in depression and age-related processes, which is well-documented in postmortem gene expression studies21 and captured by our T-PRS11. Our T-PRS neural reactivity results may thus reflect a genetically driven risk pathway shared between specific depression subtypes, including but not limited to seasonal depression, and both pathological and accelerated aging. No similar relationship was found by the univariate analyses between the PGC-PRS score and amygdala reactivity. However, these univariate ROI-based findings should be interpreted with caution since the T-PRS-based PLS results did not identify the amygdala as a key region and Elliott et al.50 showed that task-fMRI measures of regional activation have poor reliability in general and that ROIs targeted by the task paradigm are rarely more reliable than nontarget ROIs.For continuity with prior work, we supplemented our multivariate analyses with traditional contrast-based measures focused on the amygdala. Consistent with our multivariate analyses, we found that T-PRS was associated with reduced amygdala reactivity specifically to neutral faces independent of participant sex. Moreover, we demonstrated that the reduced amygdala reactivity to neutral faces mediated the relationship between T-PRS and anhedonia. While the majority of prior work on CLC function in depression has focused on threat-related amygdala reactivity, our results are broadly consistent with recent studies, which have found hypoactivity to neutral, but not emotional faces, in youth with severe mood impairment11, while the independently derived and uncorrelated PGC-PRS is comprised of variants near genes associated with largely nonoverlapping biological pathways pertaining to HPA axis hyperactivation, neuroinflammation, and obesity25. Collectively, these results suggest that in women, multiple distinct pathways of genetic risk may converge onto a common neural phenotype characterized by blunted neural response to neutral faces. The results are also consistent with the possibility that this neural phenotype may be sensitive to overall genetic risk for depression, independently of any specific underlying molecular mechanism.Despite the markedly distinct provenance of the PGC-PRS and T-PRS, we found that the two had convergent effects in our multivariate analyses. Both scores were associated with reduced neural reactivity to neutral faces in women across a broader network of regions. This convergence is especially intriguing in light of the fact that the two scores likely reflect distinct biological processes. Specifically, the T-PRS is mainly defined by genes associated with cell signaling and age-related processes such as trophic factor function and cell death6, which may partially reflect enhanced neural sensitivity to environmental stress4 and may be part of a pathophysiological mechanism shared with comorbid anxiety disorders51, the putative novel risk pathway we identify here likely reflects reduced behavioral engagement, which may be depression-specific and relatively independent of experiential factors. These results should be interpreted with caution as the analyses linking brain patterns to mood symptoms were exploratory and therefore uncorrected for multiple comparisons. Nonetheless, the specific link between T-PRS, blunted reactivity to neutral faces and elevated anhedonia emerged in both the univariate and multivariate analyses, giving additional confidence in the potential involvement of T-PRS in an anhedonic pathway of depression risk. Additional caution is warranted in light of the fact that our sample consisted of relatively healthy and highly functioning young adults who likely did not represent the full range of symptom severity. Future studies should aim to test the effects of T-PRS and similar transcriptome-based scores on brain activity in larger clinical populations.Both univariate and multivariate analyses further linked this T-PRS-associated blunting of reactivity to neutral faces with anhedonia, the only depression-specific facet of the MASQ. Furthermore, this association was independent of the remaining three MASQ domains, which capture symptoms unique to anxiety (AA) or shared between depression and anxiety , and all of these results were independent of early or recent life stress. While prior studies have associated depression with elevated threat-related amygdala reactivity53, our results suggest that multivariate methods leveraging whole-brain voxel-wise co-activation patterns may be better powered to capture complex polygenic effects than analyses focusing on a single region or contrast of interest. Relatedly, task-elicited functional activity in a priori regions of interest, including the amygdala, have generally poor reliability50 thereby limiting the utility of such measures in individual differences research such as that reported herein57. Our multivariate analysis may further mitigate this limitation, especially since it models responses to faces and shapes independently of each other, and these independently assessed activity patterns  have been shown to have higher reliability than difference scores directly contrasting the faces and shapes conditions58. Another limitation of this work is that our results are restricted to non-Hispanic Caucasians. We focused our analysis on this group in order to match the demographic characteristics of the GTEx reference dataset as well as the Ding et al. postmortem dataset, both of which included primarily individuals of European ancestry . While this decision likely increased our power to detect significant effects, it limits the generalizability of our results to other ethnic groups. Future research using larger multiethnic samples for both postmortem and neuroimaging analyses is required to elucidate the functional impact of depression-related transcriptomic changes on brain function across ethnicities.Our results should be interpreted in the context of several limitations. First and foremost, while our PLS analyses accounted for 38–39% of variance shared between PRS and brain activity, effect sizes in our amygdala-focused univariate analyses were relatively small, on the order of 1–2% variance explained. Although these effect sizes are consistent with those seen in other PRS studies using similar or smaller sample sizesThese limitations notwithstanding, our results introduce a novel tool for bridging depression-associated postmortem molecular gene expression patterns with in vivo brain function and identify a pathway of depression risk associated with reduced neural activity to social stimuli, which may be partially shared with age-related processes. Pending further refinement, this analytic framework bridging postmortem gene expression work with neuroimaging data may offer novel insight into molecular mechanisms underlying MDD or risk thereof and serve to inform future individualized treatment or prevention efforts.Supplementary MaterialSupplementary Figure 1Supplementary Figure 2Supplementary Figure 3Supplementary Figure 4Supplementary Figure 5Supplementary Figure 6